Bradley and Daroff's Neurology in Clinical Practice [8 ed.]

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PART I

Common Neurological Problems

1 Diagnosis of Neurological Disease Joseph Jankovic, John C. Mazziotta, Nancy J. Newman, Scott L. Pomeroy

OUTLINE Neurological Interview, 2 Chief Complaint, 2 History of the Present Illness, 2 Review of Patient-Specific Information, 3 Review of Systems, 3 History of Previous Illnesses, 3 Family History, 4 Social History, 4 Examination, 4 Neurological Examination, 4

General Physical Examination, 5 Assessment of the Cause of the Patient’s Symptoms, 5 Anatomical Localization, 5 Pathophysiological Mechanisms and Generating a Differential Diagnosis, 6 Investigations, 7 Management of Neurological Disorders, 7 The Experienced Neurologist’s Approach to the Diagnosis of Common Neurological Problems, 7

Neurological diagnosis is sometimes easy, sometimes quite challenging, and specialized skills are required. If a patient shuffles into the physician’s office, demonstrating a pill-rolling tremor of the hands and loss of facial expression, Parkinson disease comes readily to mind. Although making such a “spot diagnosis” can be very satisfying, it is important to consider that this clinical presentation may have another cause entirely—such as neuroleptic-induced parkinsonism—or that the patient may be seeking help for a totally different neurological problem. Therefore an evaluation of the whole problem is always necessary. In all disciplines of medicine, the history of symptoms and clinical examination of the patient are key to achieving an accurate diagnosis. This is particularly true in neurology. Standard practice in neurology is to record the patient’s chief complaint and the history of symptom development, followed by the history of illnesses and previous surgical procedures, the family history, personal and social history, and a review of any clinical features involving the main body systems. From these data, one formulates a hypothesis to explain the patient’s illness. The neurologist then performs a neurological examination, which should support the hypothesis generated from the patient’s history. Based on a combination of the history and physical findings, one proceeds with the differential diagnosis to generate a list of possible causes of the patient’s clinical features. What is unique to neurology is the emphasis on localization and phenomenology. When a patient presents to an internist or surgeon with abdominal or chest symptoms, the localization is practically established by the symptoms, and the etiology then becomes the

primary concern. However, in clinical neurological practice, a patient with a weak hand may have a lesion localized to muscles, neuromuscular junctions, nerves in the upper limb, brachial plexus, spinal cord, or brain. The formal neurological examination allows localization of the offending lesion and then a focused list of potential causes of problems in that specific location can be generated. Similarly, a neurologist skilled in recognizing phenomenology should be able to differentiate between tremor and stereotypy, both rhythmical movements; among tics, myoclonus, and chorea, all jerklike movements; and among other rhythmical and jerklike movement disorders, such as seen in dystonia. In general, the history provides the best clues to localization, disease mechanisms and etiology, and the examination is essential for localization confirmation and appropriate disease categorization—all critical for proper diagnosis and treatment. This diagnostic process consists of a series of steps, as depicted in Fig. 1.1. Although standard teaching is that the patient should be allowed to provide the history in his or her own words, the process also involves active questioning of the patient to elicit pertinent information and systematic review of previous pertinent medical records. At each step, the neurologist should consider the possible anatomical localizations, the potential pathophysiological mechanisms of disease, and the possible etiologies of the symptoms, especially for the most likely localizations (see Fig. 1.1). From the patient’s chief complaint and a detailed history, an astute neurologist can derive clues that lead first to a hypothesis about the location and then to a hypothesis about the etiology of the neurological lesion. From these hypotheses, the experienced neurologist can predict what neurological abnormalities

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PART I

Common Neurological Problems

Task

Goal

Chief complaint

Possible anatomical localization

right or left handed?” For children, questions like “Where do you go to school?” or “What sports or other activities do you like?” After this, it is easier to ask, “How can I be of service?” “What brings you to see me?” or “What is bothering you the most?” Such questions establish the physician’s role in the relationship and encourage the patient to volunteer an initial history. At a follow-up visit, it often is helpful to start with more personalized questions: “How have you been?” “Have there been any changes in your condition since your last visit?” Another technique is to begin by asking, “How can I help you?” This establishes that the doctor is there to provide a service and allows patients to express their expectations for the consultation. It is important for the physician to get a sense of the patient’s expectations from the visit. Usually the patient wants the doctor to find or confirm the diagnosis and cure the disease. Sometimes the patient comes hoping that something is not present (“Please tell me my headaches are not caused by a brain tumor!”). Sometimes the patient claims that other doctors “never told me anything” (which may sometimes be true, although in some cases the patient did not hear, did not understand, or did not like what was said).

Possible pathophysiologies

History

Possible anatomical localization

Possible pathophysiologies

Neurological examination

List of possible pathophysiologies

Confirmation of anatomical localization

CHIEF COMPLAINT

List of possible diseases

Review of patient-specific features

Rank order of likelihood of possible diseases

Differential diagnosis

Fig. 1.1 The diagnostic path is illustrated as a series of steps in which the neurologist collects data (Task) with the objective of providing information on the anatomical localization and nature of the disease process (Goal).

should be present and what should be absent, thereby allowing confirmation of the site of the dysfunction during the neurological examination. Alternatively, analysis of the history may suggest two or more possible anatomical locations and disease mechanisms and etiologies, each with a different predicted constellation of neurological signs. The findings on neurological examination can be used to determine which of these various possibilities is the most likely. To achieve a diagnosis, the neurologist needs to have a good knowledge not only of the anatomy and physiology of the nervous system but also of the clinical features and pathology of neurological diseases.

NEUROLOGICAL INTERVIEW The neurologist may be an intimidating figure for some patients. To add to the stress of the neurological interview and examination, the patient may already have a preconceived notion that the disease causing the symptoms may be progressively disabling and possibly life threatening. Because of this background, the neurologist should present an empathetic demeanor and do everything possible to put the patient at ease. It is important for the physician to introduce himself or herself to the patient and exchange social pleasantries before leaping into the interview. A few opening questions can break the ice: “Who is your doctor, and who would you like me to write to?” “What type of work have you done most of your life?” “How old are you?” “Are you

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The chief complaint (or the several main complaints) is the usual starting point of the diagnostic process. The complaints serve to focus attention on the questions to be addressed in taking the history and provide the first clue to the anatomy and etiology of the underlying disease. The chief complaint also provides insight into the patient’s level of understanding of his or her symptoms. For example, the patient may present with the triad of complaints of headache, clumsiness, and double vision. In this case, the neurologist would be concerned that the patient may have a tumor in the posterior fossa affecting the cerebellum and brainstem. The mode of onset is critically important in investigating the etiology. For example, in this case, a sudden onset usually would indicate a stroke in the vertebrobasilar arterial system. A course characterized by exacerbations and remissions may suggest multiple sclerosis, whereas a slowly progressive course points to a neoplasm. Paroxysmal episodes suggest the possibility of seizures, migraines, or some form of paroxysmal dyskinesia, ataxia, or periodic paralysis.

HISTORY OF THE PRESENT ILLNESS As one continues interviewing the patient, localization, figuring out from where the problem originates, remains paramount. In addition, a critical aspect of the information obtained from this portion of the interview has to do with establishing the temporal-severity profile of each symptom reported by the patient. Such information allows the neurologist to categorize the patient’s problems based on the profile. For example, a patient who reports the gradual onset of headache and slowly progressive weakness of one side of the body over weeks to months could be describing the growth of a space-occupying lesion in a cerebral hemisphere. The same symptoms occurring rapidly, in minutes or seconds, with maximal severity from the onset, might be the result of a hemorrhage in a cerebral hemisphere. The symptoms and their severity may be equal at the time of the interview, but the temporal-severity profile leads to totally different hypotheses about the mechanism and etiology. Often the patient will give a very clear history of the temporal development of the complaints and will specify the location and severity of the symptoms and the current level of disability. However, in other instances, the patient, particularly if elderly, will provide a tangential account and insist on telling what other doctors did or said, rather

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CHAPTER 1 Diagnosis of Neurological Disease than relating specific signs and symptoms. Direct questioning often is needed to clarify the symptoms, but it is important not to “lead” the patient. Patients frequently are all too ready to give a positive response to an authority figure, even if it is incorrect. It is important to consider whether the patient is reliable. Reliability depends on the patient’s intelligence, memory, language function, and educational and social status and on the presence of secondary gain issues, such as a disability claim or pending lawsuit. The clinician should suspect a somatoform or psychogenic disorder in any patient who claims to have symptoms that started suddenly, particularly after a traumatic event, manifested by clinical features that are incongruous with an organic disorder, or with involvement of multiple organ systems. The diagnosis of a psychogenic disorder is based not only on the exclusion of organic causes but also on positive criteria. Getting information from an observer other than the patient is important for characterizing many neurological conditions such as seizures and dementia. Taking a history from a child is complicated by shyness with strangers, a different sense of time, and a limited vocabulary. In children, the history is always the composite perceptions of the child and the parent. Patients and physicians may use the same word to mean very different things. If the physician accepts a given word at face value without ensuring that the patient’s use of the word matches the physician’s, misinterpretation may lead to misdiagnosis. For instance, patients often describe a limb as being “numb” when it is actually paralyzed. Patients often use the term “dizziness” to refer to lightheadedness, confusion, or weakness, rather than vertigo as the physician would expect. Although a patient may describe vision as being “blurred,” further questioning may reveal diplopia. “Blackouts” may indicate loss of consciousness, loss of vision, or simply confusion. “Pounding” or “throbbing” headaches are not necessarily pulsating. The neurologist must understand fully the nature, onset, duration, and progression of each sign or symptom and the temporal relationship of one finding to another. Are the symptoms getting better, staying the same, or getting worse? What relieves them, what has no effect, and what makes them worse? In infants and young children, the temporal sequence also includes the timing of developmental milestones. An example may clarify how the history leads to diagnosis: A 28-year-old woman presents with a 10-year history of recurrent headaches associated with her menses. The unilateral quality of pain in some attacks and the association of flashing lights, nausea, and vomiting together point to a diagnosis of migraine. On the other hand, in the same patient, a progressively worsening headache on wakening, new-onset seizures, and a developing hemiparesis suggest an intracranial space-occupying lesion. Both the absence of expected features and the presence of unexpected features may assist in the diagnosis. A patient with numbness of the feet may have a peripheral neuropathy, but the presence of backache combined with loss of sphincter control suggests that a spinal cord or cauda equina lesion is more likely. Patients may arrive for a neurological consultation with a folder of results of previous laboratory tests and neuroimaging studies. They often dwell on these test results and their interpretation by other physicians. However, the opinions of other doctors should never be accepted without question, because they may have been wrong! The careful neurologist takes a new history and makes a new assessment of the problem. However, integration of objective data such as dates and test results into the patient’s subjective narrative is essential. The history of how the patient or caregiver responded to the signs and symptoms may be important. A pattern of overreaction may be of help in evaluating the significance of the complaints. Nevertheless,

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a night visit to the emergency department for a new-onset headache should not be dismissed without investigation. Conversely, the child who was not brought to the hospital despite hours of seizures may be the victim of child abuse or at least of neglect.

REVIEW OF PATIENT-SPECIFIC INFORMATION Information about the patient’s background often greatly helps the neurologist to make a diagnosis of the cause of the signs and symptoms. This information includes the history of medical and surgical illnesses; current medications and allergies; a review of symptoms in non-neurological systems of the body; the personal history in terms of occupation, social situation, and alcohol, tobacco, and illicit drug use; and the medical history of the parents, grandparents, siblings, and children, looking for evidence of familial diseases. The order in which these items are considered is not important, but consistency avoids the possibility that something will be forgotten. In the outpatient office, the patient can be asked to complete a form with a series of questions on all these matters before starting the consultation with the physician. This expedites the interview, although more details often are needed. What chemicals is the patient exposed to at home and at work? Did the patient ever use alcohol, tobacco, or prescription or illegal drugs? Is there excessive stress at home, in school, or in the workplace, such as divorce, death of a loved one, or loss of employment? Are there hints of abuse or neglect of children or spouse? A careful sexual history is also important information. The doctor should question children and adolescents away from their parents if obtaining more accurate information about sexual activity and substance abuse seems indicated.

Review of Systems The review of systems should include the elements of nervous system function that did not surface in taking the history, as well as at least, a general review of all systemic organ systems. Regarding the former, the neurologist should query the following: cognition, personality, and mood change; hallucinations; seizures and other impairments of consciousness; orthostatic faintness; headaches; special senses, including vision and hearing; speech and language function; swallowing; limb coordination; slowness of movement; involuntary movements or vocalizations; strength and sensation; pain; gait and balance; and sphincter, bowel, and sexual function. A positive response may help to clarify a diagnosis. For instance, if a patient complaining of ataxia and hemiparesis admits to unilateral deafness, an acoustic neuroma should be considered. Headaches in a patient with paraparesis suggest a parasagittal meningioma rather than a spinal cord lesion. The developmental history must be assessed in children and also may be of value in adults whose illness started during childhood. The review of systems must also include all organ systems. Neurological function is adversely affected by dysfunction of many systems, including the liver, kidney, gastrointestinal tract, heart, and blood vessels. Multiorgan involvement characterizes several neurological disorders such as vasculitis, sarcoidosis, mitochondrial disorders, and storage diseases.

History of Previous Illnesses Specific findings in the patient’s medical and surgical history may help to explain the present complaint. For instance, seizures and worsening headaches in a patient who previously had surgery for lung cancer suggest a brain metastasis. Chronic low back pain in a patient complaining of numbness and weakness in the legs on walking half a mile suggests neurogenic claudication from lumbar canal stenosis. The record of the

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PART I

Common Neurological Problems

history should include dates and details of all surgical procedures, significant injuries including head trauma and fractures, hospitalizations, and conditions requiring medical consultation and medications. For pediatric patients, obtain information on the pregnancy and state of the infant at birth. Certain features in the patient’s history should always alert the physician to the possibility that they may be responsible for the neurological complaints. Gastric surgery may lead to vitamin B12 deficiency. Sarcoidosis may cause Bell palsy, diabetes insipidus, vision loss, and peripheral neuropathy. Disorders of the liver, kidney, and small bowel can be associated with a wide variety of neurological disorders. Systemic malignancy can cause direct and indirect (paraneoplastic) neurological problems. The physician should not be surprised if the patient fails to remember previous medical or surgical problems. It is common to observe abdominal scars in a patient who described no surgical procedures until questioned about the scars. Medications often are the cause of neurological disturbances, particularly chemotherapy drugs. In addition, isoniazid may cause peripheral neuropathy and ethambutol a bilateral optic neuropathy. Lithium carbonate may produce tremor, ataxia, and nystagmus. Neuroleptic agents can produce a Parkinson-like syndrome or dyskinesias. Most patients do not think of vitamins, oral contraceptives, nonprescription analgesics, and herbal compounds as “medications,” and specific questions about these agents are necessary.

Family History Some neurological disorders are hereditary. Accordingly, a history of similar disease in family members or of consanguinity may be of diagnostic importance. However, the expression of a gene mutation may be quite different from one family member to another with respect not only to the severity of neurological dysfunction but also to the organ systems involved. For instance, the mutations of the gene for Machado-Joseph disease (SCA3) can cause several phenotypes. A patient with Charcot-Marie-Tooth disease (hereditary motor-sensory neuropathy) may have a severe peripheral neuropathy, whereas relatives may demonstrate only pes cavus. Reported diagnoses may be inaccurate. In families with dominant muscular dystrophy, affected individuals in earlier generations are often said to have had “arthritis” that put them into a wheelchair. Some conditions, such as epilepsy or Huntington disease, may be “family secrets.” Therefore the physician should be cautious in accepting a patient’s assertion that a family history of a similar disorder is lacking. If the possibility exists that the disease is inherited, it is helpful to obtain information from parents and grandparents and to examine relatives at risk. Some patients wrongly attribute symptoms in family members to a normal consequence of aging or to other conditions such as alcoholism. This is particularly true in patients with essential tremor. At a minimum, historical data for all first- and second-degree relatives should include age (current or at death), cause of death, and any significant neurological or systemic diseases.

Social History It is important to discuss the social setting in which neurological disease is manifest. Family status and changes in such can provide important information about interpersonal relationships and emotional stability. Employment history is often quite important. Has an elderly patient lost his or her job because of cognitive dysfunction? Do patients’ daily activities put them or others at risk if their vision, balance, or coordination is impaired or if they have alterations in consciousness? Does the patient’s job expose him or her to potential injury or toxin exposure? Are they in professions where the diagnosis of a neurological disorder would require reporting them to a regulatory agency (e.g., airline pilot,

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professional driver)? For children, asking whether they have successfully established friendships or other meaningful social connections, or whether they might be the victim of bullying is very important. A travel history is important, particularly if infectious diseases are a consideration. Hobbies can be a source of toxin exposure (e.g., welding sculpture). Level and type of exercise provide useful clues to overall fitness and can also suggest potential exposures to toxins and infectious agents (e.g., hiking and Lyme disease).

EXAMINATION Neurological Examination Neurological examination starts during the interview. A patient’s lack of facial expression (hypomimia) may suggest parkinsonism or depression, whereas a worried or astonished expression may suggest progressive supranuclear palsy. Ptosis may suggest myasthenia gravis or a brainstem lesion. The pattern of speech may suggest dysarthria, aphasia, or spasmodic dysphonia. The presence of abnormal involuntary movements may indicate an underlying movement disorder. Neurologist trainees must be able to perform and understand the complete neurological examination, in which every central nervous system region, peripheral nerve, muscle, sensory modality, and reflex are tested. However, the full neurological examination is too lengthy to perform in practice. Instead, the experienced neurologist uses a focused neurological examination to examine in detail the neurological functions relevant to the history in addition to performing a screening neurological examination to check the remaining parts of the nervous system. This approach should confirm, refute, or modify the initial hypotheses of disease location and causation derived from the history (see Fig. 1.1). Both the presence and absence of abnormalities may be of diagnostic importance. If a patient’s symptoms suggest a left hemiparesis, the neurologist should search carefully for a left homonymous hemianopia and for evidence that the blink or smile is slowed on the left side of the face. Relevant additional findings would be that rapid, repetitive movements are impaired in the left limbs, that the tendon reflexes are more brisk on the left than the right, that the left abdominal reflexes are absent, and that the left plantar response is extensor. Along with testing the primary modalities of sensation on the left side, the neurologist may examine the higher integrative aspects of sensation, including graphesthesia, stereognosis, and sensory extinction with double simultaneous stimuli. The presence or absence of some of these features can separate a left hemiparesis arising from a lesion in the right cerebral cortex or from one in the left cervical spinal cord. The screening neurological examination (Table 1.1) is designed for quick evaluation of the mental status, cranial nerves, motor system (strength, muscle tone, presence of involuntary movements, and postures), coordination, gait and balance, tendon reflexes, and sensation. More complex functions are tested first; if these are performed well, then it may not be necessary to test the component functions. For example, the patient who can walk heel to toe (tandem gait) does not have a significant disturbance of the cerebellum or of joint position sensation. Similarly, the patient who can do a pushup, rise from the floor without using the hands, and walk on toes and heels will have normal limb strength when each muscle group is individually tested. Asking the patient to hold the arms extended in supination in front of the body with the eyes open allows evaluation of strength and posture. It also may reveal involuntary movements such as tremor, dystonia, myoclonus, or chorea. A weak arm is expected to show a downward or pronator drift. Repeating the maneuver with the eyes closed allows assessment of joint position sensation.

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CHAPTER 1 Diagnosis of Neurological Disease

Outline of the Screening Neurological Examination

TABLE 1.1

Description/Observation/ Examination Component Maneuver Mental Status

Assessed while recording the history

Cranial Nerves (CNs): CN I

Should be tested in all persons who experience spontaneous loss of smell, in patients suspected to have Parkinson disease, and in patients who have suffered head injury Each eye: Visual acuity with glasses/contacts Visual fields by confrontation Swinging flashlight to detect relative afferent pupillary defect Fundoscopy Horizontal and vertical eye movements (saccades, pursuit, vestibulo-ocular reflex) Pupillary symmetry and reactivity Presence of nystagmus or other ocular oscillations Pinprick and touch sensation on face, corneal reflex Jaw strength Close eyes, show teeth Perception of whispered voice in each ear or rubbing of fingers; if hearing is impaired, look in external auditory canals, and use tuning fork for lateralization and bone-versus-air sound conduction Palate lifts in midline, gag reflex present Shrug shoulders Protrude tongue Separate testing of each limb: Presence of involuntary movements Muscle mass (atrophy, hypertrophy) and look for fasciculations Muscle tone in response to passive flexion and extension Power of main muscle groups Coordination Finger-to-nose and heel-to-shin testing Performance of rapid alternating movements Tendon reflexes Plantar responses Pinprick and light touch on hands and feet Double simultaneous stimuli on hands and feet Joint position sense in hallux and index finger Vibration sense at ankle and index finger Spontaneous gait should be observed; stance, base, cadence, arm swing, tandem gait should be noted Postural stability should be assessed by the pull test Stand with eyes open and then closed

CN II

CN III, IV, VI

CN V

CN VII CN VIII

CN IX, X CN XI CN XII Limbs

Gait and Balance

Romberg Test

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Of importance, the screening neurological examination may miss important neurological abnormalities. For instance, a bitemporal visual field defect may not be detected when the fields of both eyes are tested simultaneously; it will be found only when each eye is tested separately. Similarly, a parietal lobe syndrome may go undiscovered unless visuospatial function is specifically assessed. It is sometimes difficult to decide whether something observed in the neurological examination is normal or abnormal, and only experience prevents the neurologist from misinterpreting as a sign of disease something that is a normal variation. Every person has some degree of asymmetry. Moreover, what is abnormal in young adults may be normal in the elderly. Loss of the ankle reflex and loss of vibration sense at the big toe are common findings in patients older than 70 years. The experienced neurologist appreciates the normal range of neurological variation, whereas the beginner frequently records mild impairment of a number of different functions. Such impairments include isolated deviation of the tongue or uvula to one side and minor asymmetries of reflexes or sensation. Such soft signs may be incorporated into the overall synthesis of the disorder if they are consistent with other parts of the history and examination; otherwise, they should be disregarded. If an abnormality is identified, seek other features that usually are associated. For instance, ataxia of a limb may result from a corticospinal tract lesion, sensory defect, or cerebellar lesion. If the limb incoordination is due to a cerebellar lesion, other findings will include ataxia on finger-to-nose and heel-to-shin testing, abnormal rapid alternating movements of the hands (dysdiadochokinesia), and often nystagmus and ocular dysmetria. If some of these signs of cerebellar dysfunction are missing, examination of joint position sense, limb strength, and reflexes may demonstrate that this incoordination is due to something other than a cerebellar lesion. At the end of the neurological examination, the abnormal physical signs should be classified as definitely abnormal (hard signs) or equivocally abnormal (soft signs). The hard signs, when combined with symptoms from the history, allow the neurologist to develop a hypothesis about the anatomical site of the lesion or at least about the neurological pathways involved. The soft signs can then be reviewed to determine whether they conflict with or support the initial conclusion. An important point is that the primary purpose of the neurological examination is to reveal functional disturbances that localize abnormalities. The standard neurological examination is less effective when used to monitor the course of a disease or its temporal response to treatment. Measuring changes in neurological function over time requires special quantitative functional tests and rating scales.

General Physical Examination The nervous system is damaged in so many general medical diseases that a general physical examination is an integral part of the examination of patients with neurological disorders. Atrial fibrillation, valvular heart disease, or an atrial septal defect may cause embolic strokes in the central nervous system. Hypertension increases the risk for all types of stroke. Signs of malignancy raise the possibility of metastatic lesions of the nervous system or paraneoplastic neurological syndromes such as a subacute cerebellar degeneration or sensory peripheral neuropathy. In addition, some diseases such as vasculitis and sarcoidosis affect both the brain and other organs.

ASSESSMENT OF THE CAUSE OF THE PATIENT’S SYMPTOMS Anatomical Localization Hypotheses about lesion localization, neurological systems involved, and pathology of the disorder can be formed once the history is

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PART I

Common Neurological Problems

complete (see Fig. 1.1). The neurologist then uses the examination findings to confirm the localization of the lesion before trying to determine its cause. The initial question is whether the disease is in the brain, spinal cord, peripheral nerves, neuromuscular junctions, or muscles. Then it must be established whether the disorder is focal, multifocal, or systemic. A system disorder is a disease that causes degeneration of one part of the nervous system while sparing other parts of the nervous system. For instance, degeneration of the corticospinal tracts and spinal motor neurons with sparing of the sensory pathways of the central and peripheral nervous systems is the hallmark of the system degeneration termed motor neuron disease, or amyotrophic lateral sclerosis. Multiple system atrophy is another example of a system degeneration characterized by slowness of movement (parkinsonism), ataxia, and dysautonomia. The first step in localization is to translate the patient’s symptoms and signs into abnormalities of a nucleus, tract, or part of the nervous system. Loss of pain and temperature sensation on one half of the body, excluding the face, indicates a lesion of the contralateral spinothalamic tract in the high cervical spinal cord. A left sixth nerve palsy, with weakness of left face and right limbs, points to a left pontine lesion. A left homonymous hemianopia indicates a lesion in the right optic tract, optic radiations, or occipital cortex. The neurological examination plays a crucial role in localizing the lesion. A patient complaining of tingling and numbness in the feet initially may be thought to have a peripheral neuropathy. If examination shows hyperreflexia in the arms and legs and no vibration sensation below the clavicles, the lesion is likely to be in the spinal cord, and the many causes of peripheral neuropathy can be dropped from consideration. A patient with a history of weakness of the left arm and leg who is found on examination to have a left homonymous hemianopia has a right cerebral lesion, not a cervical cord problem. The neurologist must decide whether the symptoms and signs could all arise from one focal lesion or whether several anatomical sites must be involved. The principle of parsimony, or Occam’s razor, requires that the clinician strive to hypothesize only one lesion. The differential diagnosis for a single focal lesion is significantly different from that for multiple lesions. Thus a patient complaining of left-sided vision loss in both eyes and left-sided weakness is likely to have a lesion in the right cerebral hemisphere, possibly caused by stroke or tumor. On the other hand, if the visual difficulty is due to a central scotoma in the left eye only, and if the upper motor neuron weakness affects the left limbs but spares the lower cranial nerves, two lesions must be present: one in the left optic nerve and one in the left corticospinal tract below the medulla—as seen, for example, in multiple sclerosis. If a patient with slowly progressive slurring of speech and difficulty walking is found to have ataxia of the arms and legs, bilateral extensor plantar responses, and optic atrophy, the lesion must be either multifocal (affecting brainstem and optic nerves, and therefore probably multiple sclerosis) or a system disorder, such as a spinocerebellar degeneration. The complex vascular anatomy of the brain can sometimes cause multifocal neurological deficits to result from one vascular abnormality. For instance, a patient with occlusion of one vertebral artery may suffer coincident strokes from artery to artery emboli that result in a midbrain syndrome, a hemianopia, and an amnestic syndrome. Synthesis of symptoms and signs for anatomical localization of a lesion requires a good knowledge of neuroanatomy, including the location of all major pathways in the nervous system and their interrelationships at different levels. In making this synthesis, the neurologist trainee will find it helpful to refer to diagrams that show transverse sections of the spinal cord, medulla, pons, and midbrain; the brachial and lumbosacral plexuses; and the dermatomes and myotomes. Knowledge of the functional anatomy of the cerebral cortex and the blood supply of the brain and spinal cord also is essential.

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TABLE 1.2 Pathophysiological Mechanisms of Neurological Disease Inflammatory Infectious Noninfectious (autoimmune) Vascular Arterial Venous Compressive/infiltrative Neoplastic Non-neoplastic Degenerative/hereditary Toxic/metabolic/nutritional Mechanical Trauma Disorders of intracranial pressure

Symptoms and signs may arise not only from disturbances caused at the focus of an abnormality—focal localizing signs—but also at a distance. One example is the damage that results from the shift of intracranial contents and alterations in intracranial pressure produced by an expansive supratentorial tumor. This may cause a palsy of the sixth cranial nerve, even though the tumor is located far from the cranial nerves. Clinical features caused by damage far from the primary site of abnormality sometimes are called false localizing signs. This term derives from the era before neuroimaging studies when clinical examination was the major means of lesion localization. In fact, these are not false signs but rather signs that the intracranial shifts are marked or the intracranial pressure is abnormal.

Pathophysiological Mechanisms and Generating a Differential Diagnosis Once the likely site of the lesion is identified, the next step is to consider all the possible pathophysiological mechanisms that can cause disease, especially in the nervous system and especially in the lesion location postulated (Table 1.2). Reviewing this “medical student” list is an extremely important next step in the process because it allows the clinician to systematically consider all the possible mechanisms of disease and hone down on those most likely to fit the anatomical location and the patient’s symptoms and signs. Once the most likely pathophysiologies are selected, a focused list of diseases or conditions that may be responsible for the patient’s symptoms and signs—the differential diagnosis—can be generated (see Fig. 1.1). The experienced neurologist automatically first considers the most likely pathophysiology and causes, followed by less common causes. The beginner is happy to generate a list of the main causes of the signs and symptoms in whatever order they come to mind. Experience indicates the most likely causes based on specific patient characteristics, the portions of the nervous system affected, and the relative frequency of each disease. An important point is that rare presentations of common diseases are more common than common presentations of rare diseases. Equally important, the neurologist must be vigilant in including in the differential diagnosis less likely disorders that if overlooked can cause significant morbidity and/or mortality. A proper differential diagnosis list should include the most likely causes of the patient’s signs and symptoms as well as the most ominous. Keeping in mind the entire list of pathophysiological mechanisms will ensure that an important entity in the differential diagnosis will not be missed. Sometimes only a single disease is immediately

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CHAPTER 1 Diagnosis of Neurological Disease incriminated, but usually several candidate diseases can be identified. The list of possibilities should take into account both the temporal features of the patient’s symptoms and the pathological processes known to affect the relevant area of the nervous system. For example, in a patient with signs indicating a lesion of the internal capsule, the cause is likely to be stroke if the hemiplegia was of sudden onset. With progression over weeks or months, a more likely cause is an expanding tumor. As another example, in a patient with signs of multifocal lesions whose symptoms have relapsed and remitted over several years, the diagnosis is likely to be multiple sclerosis or multiple strokes (depending on the patient’s age, sex, and risk factors). If symptoms appeared only recently and have gradually progressed, multiple metastases should be considered. Again, the principle of parsimony or Occam’s razor should be applied in constructing the differential diagnostic list. An example is that of a patient with a 3-week history of a progressive spinal cord lesion who suddenly experiences aphasia. Perhaps the patient had a tumor compressing the spinal cord and has incidentally incurred a small stroke. However, the principle of parsimony would suggest a single disease, probably cancer with multiple metastases. Another example is that of a patient with progressive atrophy of the small muscles of the hands for 6 months before the appearance of a pseudobulbar palsy. This patient could have bilateral ulnar nerve lesions and recent bilateral strokes, but amyotrophic lateral sclerosis is more likely. However, nature does not always obey the rules of parsimony, as Hickam’s dictum—that a patient can have multiple coincident unrelated disorders—asserts. As noted earlier, the differential diagnosis generally starts with a list of pathological processes (see Table 1.2) such as a stroke, a tumor, or an abscess. Each pathological process may result from any of several different diseases. Thus a clinical diagnosis of an intracranial mass lesion generates a list of the different types of tumors likely to be responsible for the clinical manifestations in the affected patient, as well as non-neoplastic causes of masses such as abscesses. Similarly, in a patient with a stroke, the clinical history may help to discriminate among hemorrhage, embolism, thrombosis, vascular spasm, and vasculitis. The skilled diagnostician is justly proud of placing the correct diagnosis at the top of the list, but it is more important to ensure that all possible diseases are considered. If a disease is not even considered, it is unlikely to be diagnosed. Treatable disorders should always be kept in mind, even if they have a very low probability. This is especially true if they may mimic more common incurable neurological disorders such as Alzheimer disease or amyotrophic lateral sclerosis.

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Investigations Sometimes the neurological diagnosis can be made without any laboratory or imaging investigations. This is true for a clear-cut case of Parkinson disease, myasthenia gravis, or multiple sclerosis. Nevertheless, even in these situations, appropriate ancillary testing is important documentation for other physicians who will see the patient in the future. In other instances, the cause of the disease will be elucidated only by the use of ancillary tests. These tests may in individual cases include hematological and biochemical blood studies; neurophysiological testing (Chapters 35–39); neuroimaging (Chapters 40–42); organ biopsy; bacteriological and virological studies; and genetic testing. The use of ancillary tests in the diagnosis of neurological diseases is considered more fully in Chapter 34.

MANAGEMENT OF NEUROLOGICAL DISORDERS Not all diseases are curable. However, even if a disease is incurable, the physician should be able to reduce the patient’s discomfort and assist the patient and family in managing the disease. Understanding a neurological disease is a science. Diagnosing a neurological disease is a combination of science and experience. Managing a neurological disease is an art, as illustrated in the chapters that comprise Part III of this book.

THE EXPERIENCED NEUROLOGIST’S APPROACH TO THE DIAGNOSIS OF COMMON NEUROLOGICAL PROBLEMS The skills of a neurologist are learned. Seeing many cases of a disease teaches us which symptoms and signs should be present and—just as important—which should not be present in a given neurological disease. Although there is no substitute for experience and pattern recognition, the trainee can learn the clues used by the seasoned practitioner to reach a correct diagnosis. Part I of this book covers the main symptoms and signs of neurological disease. These chapters describe how an experienced neurologist approaches common presenting problems such as a movement disorder, a speech disturbance, vision loss, or diplopia to arrive at the diagnosis. Part II of this book comprises the major fields of investigation and management of neurological disease. Part III provides a compendium of the neurological diseases themselves with their appropriate diagnoses and management.

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2 Episodic Impairment of Consciousness Daniel Winkel, Dimitri Cassimatis OUTLINE Syncope, 8 History and Physical Examination, 9 Causes of Syncope, 10 Investigations of Patients with Syncope, 13 Seizures, 14 Pathophysiology, 14 History and Physical Examination, 14

Seizure Classification, 14 Absence Seizures, 14 Tonic-Clonic Seizures, 14 Complex Partial Seizures, 15 Investigations of Seizures, 15 Psychogenic Nonepileptic Spells, 15 Miscellaneous Causes of Altered Consciousness, 16

Temporary loss of consciousness may be caused by transient impaired cerebral perfusion (the presumed mechanism for syncope), cerebral ischemia, migraine, epileptic seizures, metabolic disturbances, sudden increases in intracranial pressure (ICP), or sleep disorders. These conditions may be difficult to distinguish from anxiety attacks, psychogenic nonepileptic spells (PNESs), panic disorder, and malingering, which should always be considered. Syncope is defined as an abrupt, transient, complete loss of consciousness, associated with inability to maintain postural tone, with rapid and spontaneous recovery (Shen et al., 2017). Syncope may result from both cardiac and noncardiac causes. Specific causes of a transient impairment in cerebral perfusion include vasovagal episodes (typically a surge in parasympathetic autonomic tone), decreased cardiac output secondary to cardiac arrhythmias, outflow obstruction, hypovolemia, orthostatic hypotension, and decreased venous return. Cerebrovascular disturbances from transient ischemic attacks of the posterior cerebral circulation perfusing the brainstem, or cerebral vasospasm from migraine, subarachnoid hemorrhage, or hypertensive encephalopathy may result in temporary loss of consciousness. Situational syncope may occur in association with cough, micturition, defecation, swallowing, Valsalva maneuver, or diving. These spells are often mediated via a decrease in venous return to the thorax and/or an increase in sympathetic tone. Metabolic disturbances due to hypoxia, drugs, anemia, and hypoglycemia may result in frank syncope or, more frequently, the sensation of an impending faint (presyncope). Absence seizures, generalized tonic-clonic seizures, and complex partial seizures are associated with alterations of consciousness and are usually easily distinguished from syncope by careful questioning. Seizures may be difficult to distinguish from PNESs, panic attacks, and malingering. In children, breath-holding spells, a form of syncope (discussed later under “Miscellaneous Causes of Altered Consciousness”), can cause a transitory alteration of consciousness that may mimic epileptic seizures in this population. Although rapid increases in ICP (which may result from intermittent hydrocephalus, severe head trauma, brain tumors, intracerebral hemorrhage, certain severe metabolic derangements or Reye syndrome) may produce sudden loss of consciousness, affected patients frequently have other neurological manifestations that lead to this diagnosis.

In patients with episodic impairment of consciousness, diagnosis relies heavily on the clinical history described by the patient, and obtaining a detailed history from unaffected observers is often essential to clarifying the diagnosis. Laboratory investigations may also provide useful information. In a minority of patients, a cause for the loss of consciousness may not be established, and these patients may require longer periods of observation. Table 2.1 compares the clinical features of syncope and seizures.

SYNCOPE The pathophysiological basis of syncope is the temporary failure of cerebral perfusion, with a reduction in cerebral oxygen availability. Syncope refers to a symptom complex characterized by lightheadedness, generalized muscle weakness, giddiness, visual blurring, tinnitus, and gastrointestinal (GI) symptoms. The patient may appear pale and feel cold and “sweaty.” The onset of loss of consciousness generally is gradual but may be rapid if related to certain conditions such as a cardiac arrhythmia or in the elderly. The gradual onset may allow patients to protect themselves from falling and injury. Factors precipitating a vasovagal syncopal episode (also known sometimes as a simple faint) include emotional stress, unpleasant visual stimuli, prolonged standing, venipuncture, and pain. Although the duration of unconsciousness is brief, it may range from seconds to minutes. During the faint, the patient may be motionless or display myoclonic jerks but never tonic-clonic movements. Urinary incontinence is uncommon. The pulse is weak and often slow because patients may be briefly bradycardic (from parasympathetic tone) and vasodilated. Breathing may be shallow and the blood pressure barely obtainable. As the fainting episode corrects itself by the patient becoming horizontal, normal color returns, breathing becomes more regular, and the pulse and blood pressure return to normal. After the faint, the patient experiences some residual weakness, but unlike the postictal state, confusion, headaches, and drowsiness are uncommon. Nausea may be noted before the episode and may still be present when the patient regains consciousness. The causes of syncope, which may often overlap, are classified by their pathophysiological mechanism (Box 2.1), but cerebral hypoperfusion is always the common final pathway. Rarely, vasovagal syncope may

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CHAPTER 2 Episodic Impairment of Consciousness

TABLE 2.1

9

Comparison of Clinical Features of Syncope and Seizures

Features

Syncope

Seizure

Relation to posture Time of day Precipitating factors

Common Diurnal Emotion, injury, pain, crowds, heat, exercise, fear, dehydration, coughing, micturition, venipuncture, prolonged standing Pallor Common Often minutes or longer, but can be very brief Rare Minor irregular twitching Rare Rare No Rare No No Common to have low blood pressure and heart rate during event; cardiovascular exam may be completely normal after event unless there is an underlying cardiac disorder Rare (generalized slowing may occur during the event)

No Diurnal or nocturnal Sleep deprivation, drug/alcohol withdrawal, illness, medication nonadherence Cyanosis or normal Rare Brief Common Rhythmic jerks Common (with convulsive seizures) Common Common with convulsive seizures Common Common Occasional Rare

Skin color Diaphoresis Aura or premonitory symptoms Convulsion Other abnormal movements Injury Urinary incontinence Tongue biting Postictal confusion Postictal headache Focal neurological signs Cardiovascular signs

Abnormal findings on EEG

Common

EEG, Electroencephalogram.

BOX 2.1

Syncope

History and Physical Examination

Classification and Etiology of

Arrhythmias: Bradyarrhythmias Tachyarrhythmias Reflex arrhythmias (temporary sinus pause or bradycardia) Decreased cardiac output: Outflow obstruction Inflow obstruction Cardiomyopathy Hypovolemic Hypotensive: Vasovagal attack Drugs Dysautonomia Cerebrovascular: Carotid disease Vertebrobasilar disease Vasospasm Takayasu disease Metabolic: Hypoglycemia Anemia Anoxia Hyperventilation Multifactorial: Vasovagal (vasodepressor) attack Cardiac syncope Situational: cough, micturition, defecation, swallowing, diving, Valsalva maneuver

have a genetic component suggestive of autosomal dominant inheritance (Klein et al., 2013). Wieling et al. (2009) reviewed the clinical features of the successive phases of syncope, as discussed earlier.

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The history and physical examination are the most important components of the initial evaluation of syncope. Significant age and sex differences exist in the frequency of the various types of syncope. Syncope occurring in children and young adults is most frequently due to hyperventilation or vasovagal (vasodepressor) attacks and less frequently due to congenital heart disease (Lewis and Dhala, 1999). Fainting associated with benign tachycardias without underlying organic heart disease also may occur in children. Syncope due to basilar migraine is more common in young females. Although vasovagal syncope can occur in older patients (Tan and Perry, 2008), when repeated syncope begins in later life, organic disease of the cerebral circulation or cardiovascular system usually is responsible and requires exhaustive investigation. A thorough history is the most important step in establishing the cause of syncope. The patient’s description usually establishes the diagnosis. The neurologist should always obtain as full a description as possible of the first faint. The clinical features should be established, with emphasis on precipitating factors, posture, type of onset of the faint (including whether it was abrupt or gradual), position of head and neck, the presence and duration of preceding and associated symptoms, duration of loss of consciousness, rate of recovery, and sequelae. If possible, question an observer about clonic movements, color changes, diaphoresis, pulse, respiration, urinary incontinence, and the nature of recovery. Be certain to ask about any prior events, and gather these same details for each event that the patient recalls. Cardiac syncope is defined as syncope caused by bradycardia, tachycardia, or hypotension due to low cardiac index, blood flow obstruction, vasodilation, or acute vascular dissection (Shen et al., 2017). Cardiac syncope should be suspected in patients with known cardiac disease. Clues in the history that suggest cardiac syncope include a history of palpitations or a fluttering sensation in the chest before loss of consciousness. These symptoms are common in arrhythmias but do not definitively establish that diagnosis as the cause for the syncope. In vasodepressor syncope and orthostatic hypotension,

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preceding symptoms of lightheadedness are common. Episodes of cardiac syncope generally are briefer than vasodepressor syncope, and the onset usually is rapid. Episodes due to cardiac arrhythmias occur independently of position, whereas in vasodepressor syncope and syncope due to orthostatic hypotension the patient usually is standing. Attacks of syncope precipitated by exertion suggest a cardiac etiology. Exercise may induce arrhythmic syncope or syncope due to decreased cardiac output secondary to blood flow obstruction, such as may occur with hypertrophic cardiomyopathy with dynamic outflow obstruction, or with aortic or subaortic stenosis. Exercise syncope also may be due to cerebrovascular disease, aortic arch disease, congenital heart disease, severe stenosis of any of the cardiac valves, pulseless disease (Takayasu disease, a type of vasculitis), pulmonary hypertension, anemia, hypoxia, and hypoglycemia. A family history of sudden cardiac death, especially in females, suggests the long QT syndrome. Postexercise syncope may be secondary to orthostasis in the setting of dilated vascular beds in the large muscles (cardiac output may normalize faster than systemic vascular resistance), vasovagal syncope brought on by relative hypovolemia (in a setting of dilated vasculature), or autonomic dysfunction. A careful and complete medical and medication history is mandatory to determine whether prescribed drugs have induced either orthostatic hypotension or cardiac arrhythmias. To avoid missing a significant cardiac disorder, one should always consider a comprehensive cardiac evaluation in patients with exercise-related syncope. Particularly in the elderly, cardiac syncope must be distinguished from more benign causes because of increased risk of sudden cardiac death (Anderson and O’Callaghan, 2012). The neurologist should inquire about the frequency of attacks of loss of consciousness and the presence of cerebrovascular or cardiovascular symptoms between episodes. Question the patient whether all episodes are similar, because some patients experience more than one type of attack. In the elderly, syncope may cause unexplained falls lacking prodromal symptoms. With an accurate description of the attacks and familiarity with clinical features of various types of syncope, the physician will correctly diagnose most patients (Brignole et al., 2006; Shen et al., 2004), but confirmatory testing to rule in, or to exclude, some high-risk diagnoses may be required. Features that distinguish syncope from seizures and other alterations of consciousness are discussed later in the chapter. After a complete history, the physical examination is of next importance. Examination during the episode is very informative but frequently impossible unless syncope is reproducible by a Valsalva maneuver or by recreating the circumstances of the attack, such as by position change. In the patient with suspected cardiac syncope, pay particular attention to the vital signs and determination of supine and erect blood pressure. Normally, with standing, the systolic blood pressure is stable or rises and the pulse rate may increase. An orthostatic drop in blood pressure greater than 15 mm Hg may suggest autonomic dysfunction. Assess blood pressure in both arms when suspecting cerebrovascular disease, subclavian steal, or Takayasu arteritis. During syncope due to a cardiac arrhythmia, a heart rate faster than 140 beats/ min often indicates that the rhythm is not sinus tachycardia (may be a supraventricular tachycardia, an ectopic atrial or ventricular tachycardia, or atrial fibrillation or flutter), whereas a bradycardia with heart rate of less than 40 beats/min suggests complete atrioventricular (AV) block or a prolonged sinus pause. An irregular pulse indicates possible atrial fibrillation but may also be seen with frequent premature atrial or ventricular contractions, and with intermittent AV block. Vagal maneuvers, which include Valsalva and cold water to the face, sometimes terminate a supraventricular tachycardia. Carotid sinus massage may also be effective, but this maneuver is not advisable in the acute setting because of the risk of cerebral embolism from potential

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atheroma in the carotid artery wall. In contrast, an ectopic atrial or ventricular tachycardia will usually not be terminated by vagal maneuvers. It is recommended that all patients with syncope undergo a resting electrocardiogram as part of their initial evaluation (Shen et al., 2017). All patients with syncope should also undergo cardiac auscultation for the presence of cardiac murmurs and abnormalities of the heart sounds. Possible murmurs of concern include aortic stenosis, hypertrophic cardiomyopathy with outflow tract obstruction, and mitral valve stenosis. An intermittent posture-related murmur may be associated with an atrial myxoma. A systolic click and late systolic murmur of mitral regurgitation in a young person suggests mitral valve prolapse. A pericardial rub suggests pericarditis. The finding of a murmur, rub, or abnormal click in a patient with syncope should prompt the physician to order an echocardiogram. All patients should undergo observation of the carotid and jugular venous pulses and auscultation of the neck. The degree of aortic stenosis may be reflected at times in a delayed or weakened carotid upstroke. Carotid, ophthalmic, and supraclavicular bruits suggest underlying cerebrovascular disease. Jugular venous distention suggests congestive heart failure or other abnormal filling of the right heart, whereas a very low jugular venous pressure suggests hypovolemia. Carotid sinus massage should be avoided in patients with carotid bruits but may be useful in patients suspected of having carotid sinus syncope. It is important to keep in mind that up to 25% of asymptomatic persons may have some degree of carotid sinus hypersensitivity. Carotid massage should be avoided in patients with suspected cerebrovascular disease, even if they have no carotid bruit, and when performed should be under properly controlled conditions with electrocardiographic (ECG) and blood pressure monitoring. The response to carotid massage may be vasodepressor, cardioinhibitory, mixed, or minimal.

Causes of Syncope Cardiac Arrhythmias

Both bradyarrhythmias and tachyarrhythmias may result in syncope, and abnormalities of cardiac rhythm due to dysfunction from the sinoatrial (SA) node to the Purkinje network may be involved. Always consider arrhythmias in all cases in which an obvious alternative mechanism is not established. Syncope due to cardiac arrhythmias generally occurs more quickly than syncope from other causes. Cardiac syncope may occur in any position, is occasionally exercise induced, and may occur in both congenital and acquired forms of heart disease. Although palpitations sometimes occur during arrhythmias, others are unaware of any cardiac symptoms. Syncopal episodes secondary to cardiac arrhythmias may be more prolonged than benign syncope and often occur with less warning. Patients may injure themselves significantly during their fall. The most common arrhythmias causing syncope are AV block, SA block, and paroxysmal supraventricular and ventricular tachyarrhythmias. AV block describes disturbances of conduction occurring in the AV conducting system, which include the AV node to the bundle of His and the Purkinje network. SA block describes a failure of consistent pacemaker function of the SA node. Paroxysmal tachycardia refers to a rapid heart rate that comes on intermittently. It may be secondary to an ectopic focus or reentrant loop outside the SA node but above the ventricle (supraventricular), or it may be from a source below the AV node (ventricular). In patients with implanted pacemakers, syncope can occur because of pacemaker malfunction.

Atrioventricular Block AV block is probably the most common cause of arrhythmic cardiac syncope. The term Stokes-Adams attack describes disturbances

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CHAPTER 2 Episodic Impairment of Consciousness of consciousness occurring in association with a complete AV block. Complete AV block occurs primarily in elderly patients and is often also seen in patients with a history of aortic valve disease. The onset of a Stokes-Adams attack generally is sudden, although a number of visual, sensory, and perceptual premonitory symptoms may be experienced. During the syncopal attack, the pulse disappears and no heart sounds are audible. The patient is pale and, if standing, falls down, often with resultant injury. If the attack is sufficiently prolonged, respiration may become labored, and urinary incontinence and clonic muscle jerks may occur. Prolonged confusion and neurological signs of cerebral ischemia may be present. Regaining of consciousness generally is rapid. The clinical features of complete AV block include a slow pulse and elevation of the jugular venous pressure, sometimes with cannon waves. The first heart sound is of variable intensity, and heart sounds related to atrial contractions may be audible. An ECG confirming the diagnosis demonstrates independence of atrial P waves and ventricular QRS complexes. During Stokes-Adams attacks, the ECG generally shows ventricular standstill or a very slow ventricular escape rhythm, but ventricular fibrillation or tachycardia also may occur.

Sinoatrial Block SA block may result in dizziness, lightheadedness, and syncope. It is most frequent in the elderly. Palpitations are common, and the patient appears pale. Patients with SA node dysfunction frequently have other conduction disturbances, and certain drugs (e.g., verapamil, digoxin, beta-blockers) may further impair SA node function. On examination, the patient’s pulse may be regular between attacks. During an attack, the pulse may be slow or irregular, and any of a number of rhythm disturbances may be present.

Paroxysmal Tachycardia Supraventricular tachycardias include atrial fibrillation with a rapid ventricular response, atrial flutter, AV nodal reentry, and the WolffParkinson-White syndrome (AV reentry involving an accessory pathway). These arrhythmias may suddenly reduce cardiac output enough to cause syncope. Ventricular tachycardia may result in syncope if the heart rate is sufficiently fast, and ventricular fibrillation will almost always result in nearly immediate syncope. Ventricular arrhythmias are more likely in the elderly and in patients with cardiac disease. Ventricular fibrillation may be part of the long QT syndrome, which has a cardiac-only phenotype or may be associated with congenital sensorineural deafness in children. In most patients with this syndrome, episodes begin in the first decade of life, but onset may be much later. Exercise may precipitate an episode of cardiac syncope. Long QT syndrome may be congenital or acquired and sometimes is misdiagnosed in adults as epilepsy. Acquired causes include cardiac ischemia, mitral valve prolapse, myocarditis, and electrolyte disturbances; there are also many drugs that can prolong the QT. In the short QT syndrome, signs and symptoms are highly variable, ranging from complete absence of clinical manifestations to recurrent syncope to sudden death. The age at onset often is young, and affected persons frequently are otherwise healthy. A family history of sudden death in a patient with a short QT may indicate a familial short QT syndrome inherited as an autosomal dominant mutation. The ECG demonstrates a short QT interval and a tall and peaked T wave, and electrophysiological studies may induce ventricular fibrillation. Brugada syndrome may produce syncope as a result of ventricular tachycardia or ventricular fibrillation (Brugada et al., 2000). The ECG in Brugada syndrome may or may not show a typical Brugada pattern at rest (i.e., an incomplete right bundle-branch block in leads V1 and V2 and significant downsloping ST elevation leading to inverted T waves in those two leads).

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Reflex Cardiac Arrhythmias A hypersensitive carotid sinus may be a cause of syncope in the elderly, most frequently men. Syncope may result from a reflex sinus bradycardia, sinus arrest, or AV block; peripheral vasodilatation with a fall in arterial pressure; or a combination of both. Although 10% of the population older than 60 years of age may have a hypersensitive carotid sinus, not all such patients experience syncope. Accordingly, consider this diagnosis only when the clinical history is compatible. Carotid sinus syncope may be initiated by wearing a tight collar, by rapidly turning the head (including when patients do so on their own), or by carotid sinus massage on clinical examination. When syncope occurs, the patient usually is upright, and the duration of the loss of consciousness generally is a few minutes. On regaining consciousness, the patient is mentally clear. Unfortunately, no accepted diagnostic criteria exist for carotid sinus syncope, and the condition is likely overdiagnosed. Syncope in certain patients can be induced by unilateral carotid massage or compression; however, in those with atherosclerotic carotid disease, this can sometimes cause partial or complete occlusion of the ipsilateral carotid artery or release of atheromatous emboli and subsequent stroke. Because of these risks, carotid artery massage is contraindicated in those with known or suspected carotid atherosclerotic disease. The rare syndrome of glossopharyngeal neuralgia is characterized by intense paroxysmal pain in the throat and neck accompanied by bradycardia or asystole, severe hypotension, and, if prolonged, seizures. Episodes of pain may be initiated by swallowing but also by chewing, speaking, laughing, coughing, shouting, sneezing, yawning, or talking. The episodes of pain always precede the loss of consciousness (see Chapter 20). Rarely, cardiac syncope may be due to bradyarrhythmias consequent to vagus nerve irritation caused by esophageal diverticula, tumors, or aneurysms in the region of the carotid sinus or by mediastinal masses or gallbladder disease.

Decreased Cardiac Output Syncope may occur as a result of a sudden and marked decrease in cardiac output. Causes are both congenital and acquired. Tetralogy of Fallot, the most common congenital malformation causing syncope, does so by producing hypoxia due to right-to-left shunting. Other congenital conditions associated with cyanotic heart disease also may cause syncope. Ischemic heart disease and myocardial infarction (MI), aortic stenosis, hypertrophic cardiomyopathy with outflow tract obstruction, pulmonary hypertension, pulmonic valve stenosis, acute massive pulmonary embolism, atrial myxoma, and cardiac tamponade may sufficiently impair cardiac output to cause syncope. Exercise-induced or effort syncope may occur in aortic or subaortic stenosis and other states in which there is limited cardiac output and associated peripheral vasodilatation induced by the exercise. Exercise-induced cardiac syncope and exercise-induced cardiac arrhythmias may be related. In patients with valvular heart disease, the cause of syncope may be related to flow through the valve or to arrhythmias. Syncope in valvular disease may also be due to reduced cardiac output secondary to myocardial failure, to mechanical prosthetic valve malfunction, or to thrombus formation at a valve. Mitral valve prolapse generally is a benign condition, but, rarely, cardiac arrhythmias can occur. The most significant arrhythmias are ventricular. In atrial myxoma or with massive pulmonary embolism, a sudden drop in left ventricular output may occur. In atrial myxoma, syncope frequently is positional and occurs when the tumor falls into the AV valve opening during a change in position of the patient, thereby causing obstruction of the ventricular inflow. Decreased cardiac output also may be secondary to conditions causing an inflow obstruction or reduced venous return. Such conditions include superior and inferior vena cava obstruction, tension pneumothorax, constrictive cardiomyopathies, constrictive pericarditis, and

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cardiac tamponade. Patients may also inadvertently cause reduced venous return and hypotension during a prolonged coughing fit or breath hold. Syncope associated with aortic dissection may be due to cardiac tamponade but also may be secondary to hypotension, obstruction of cerebral circulation, or a cardiac arrhythmia.

Hypovolemia Acute blood loss, usually due to GI tract bleeding, may cause weakness, faintness, and syncope if sufficient blood is lost. Blood volume depletion by dehydration may cause faintness and weakness, but true syncope is uncommon except when combining dehydration and exercise. Both anemia and hypovolemia may predispose a patient to vasovagal symptoms and vasovagal syncope when standing upright.

Hypotension Several conditions cause syncope by producing a fall in arterial pressure. Cardiac causes were discussed earlier. The common faint (synonymous with vasovagal or vasodepressor syncope) is the most frequent cause of a transitory fall in blood pressure resulting in syncope. It often is recurrent, tends to occur in relation to emotional stimuli, and may affect 20%–25% of young people. Less commonly, it occurs in older patients with cardiovascular disease. The common faint may or may not be associated with bradycardia. The patient experiences impairment of consciousness, with loss of postural tone. Acutely, signs of autonomic hyperactivity are common, including pallor, diaphoresis, nausea, and dilated pupils. After recovery, patients may have persistent pallor, sweating, and nausea; if they get up too quickly, they may black out again. Presyncopal symptoms of lethargy and fatigue, nausea, weakness, a sensation of an impending faint, yawning, ringing in the ears, and blurred or tunnel vision may occur. It is more likely to occur in certain circumstances such as in a hot crowded room, especially if the affected person is volume-depleted and standing for a prolonged period, although it may still occur when sitting upright. Venipuncture, the sight of blood, or a sudden painful or traumatic experience may precipitate syncope. When the patient regains consciousness, there usually is no confusion or headache, although weakness is frequent. As in other causes of syncope, if the period of cerebral hypoperfusion is prolonged, urinary incontinence and a few clonic movements may occur (convulsive syncope). Orthostatic syncope occurs when autonomic factors that compensate for the upright posture are inadequate. This can result from a variety of clinical disorders. Blood volume depletion or venous pooling may cause syncope when the affected person assumes an upright posture. Orthostatic hypotension resulting in syncope also may occur with drugs that impair sympathetic nervous system function. Diuretics, antihypertensive medications, nitrates, arterial vasodilators, sildenafil, calcium channel blockers, monoamine oxidase inhibitors, phenothiazines, opiates, l-dopa, alcohol, and tricyclic antidepressants all may cause orthostatic hypotension. Patients with postural orthostatic tachycardia syndrome (POTS) frequently experience orthostatic symptoms without orthostatic hypotension, but syncope can occur occasionally. Data suggest that there is sympathetic activation in this syndrome (Garland et al., 2007). Autonomic nervous system dysfunction resulting in syncope due to orthostatic hypotension may be a result of primary autonomic failure due to Shy-Drager syndrome (multiple system atrophy) or Riley-Day syndrome. Neuropathies that affect the autonomic nervous system include those of diabetes mellitus, amyloidosis, Guillain-Barré syndrome, acquired immunodeficiency syndrome (AIDS), chronic alcoholism, hepatic porphyria, beriberi, autoimmune subacute autonomic neuropathy, and small fiber neuropathies. Rarely, subacute combined degeneration, syringomyelia, and other spinal cord lesions may damage the descending sympathetic

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pathways, producing orthostatic hypotension. Accordingly, conditions that affect both the central and peripheral baroreceptor mechanisms may cause orthostatic hypotension (Benafroch, 2008).

Cerebrovascular Ischemia Syncope occasionally may result from reduction of cerebral blood flow in either the carotid or vertebrobasilar system in patients with extensive occlusive disease. Most frequently, the underlying condition is atherosclerosis of the cerebral vessels, but reduction of cerebral blood flow due to cerebral embolism, mechanical factors in the neck (e.g., severe osteoarthritis), and arteritis (e.g., Takayasu disease or cranial arteritis) may be responsible. In the subclavian steal syndrome, a very rare impairment of consciousness is associated with upper extremity exercise and resultant diversion of cerebral blood flow to the peripheral circulation. In elderly patients with cervical skeletal deformities, certain head movements such as hyperextension or lateral rotation can result in syncope secondary to vertebrobasilar arterial ischemia. In these patients, associated vestibular symptoms are common. Occasionally, cerebral vasospasm secondary to basilar artery migraine or subarachnoid hemorrhage may be responsible. Insufficiency of the cerebral circulation frequently causes other neurological symptoms, depending on the circulation involved. Reduction in blood flow in the carotid circulation may lead to loss of consciousness, lightheadedness, giddiness, and a sensation of an impending faint. Reduction in blood flow in the vertebrobasilar system also may lead to loss of consciousness, but dizziness, lightheadedness, drop attacks without loss of consciousness, and bilateral motor and sensory symptoms are more common. However, dizziness and lightheadedness alone are not symptoms of vertebrobasilar insufficiency. Syncope due to compression of the vertebral artery during certain head and neck movements may be associated with episodes of vertigo, disequilibrium, or drop attacks. Patients may describe blackouts on looking upward suddenly or on turning the head quickly to one side. In general, symptoms persist for several seconds after the movement stops. In Takayasu disease, major occlusion of blood flow in the carotid and vertebrobasilar systems may occur; in addition to fainting, other neurological manifestations are frequent. Pulsations in the neck and arm vessels usually are absent, and blood pressure in the arms is unobtainable. The syncopal episodes characteristically occur with mild or moderate exercise and with certain head movements. Cerebral vasospasm may result in syncope, particularly if the posterior circulation is involved. In basilar artery migraine, usually seen in young women and children, a variety of brainstem symptoms also may be experienced, and it is associated with a pulsating headache. The loss of consciousness usually is gradual, but a confusional state may last for hours.

Metabolic Disorders A number of metabolic disturbances, including hypoglycemia, anoxia, and hyperventilation-induced alkalosis, may predispose affected persons to syncope, but usually only lightheadedness and dizziness are experienced. The abruptness of onset of loss of consciousness depends on the acuteness and reversibility of the metabolic disturbances. Syncope due to hypoglycemia usually develops gradually. The patient has a sensation of hunger; there may be a relationship to fasting, a history of diabetes mellitus, and a prompt response to ingestion of food. Symptoms are unrelated to posture but may increase with exercise. During the syncopal attack, no significant change in blood pressure or pulse occurs. Hypoadrenalism may give rise to syncope by causing orthostatic hypotension. Disturbances of calcium, magnesium, and potassium metabolism are other rare causes of syncope. Anoxia may produce syncope because of the lack of oxygen or through the production of a vasodepressor type of syncope. A feeling of lightheadedness is common, but true syncope is less common. Patients with underlying cardiac or pulmonary disease are susceptible. In patients

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CHAPTER 2 Episodic Impairment of Consciousness with chronic anemia or certain hemoglobinopathies that impair oxygen transport, similar symptoms may occur. Syncopal symptoms may be more prominent with exercise or physical activity. Hyperventilation-induced syncope usually has a psychogenic origin. During hyperventilation, the patient may experience paresthesia of the face, hands, and feet, a buzzing sensation in the head, lightheadedness, giddiness, blurring of vision, mouth dryness, and occasionally tetany. Patients often complain of tightness in the chest and a sense of panic. Symptoms can occur in the supine or erect position and are gradual in onset. Rebreathing into a paper bag relieves the symptoms. During hyperventilation, a tachycardia may be present, but blood pressure generally remains normal.

Miscellaneous Causes of Syncope More than one mechanism may be responsible in certain types of syncope. Both vasodepressor and cardioinhibitory factors may be operational in common presentations of vasovagal syncope. In cardiac syncope, a reduction of cardiac output may be due to a single cause such as obstruction to inflow or outflow or a cardiac arrhythmia, but multiple factors are frequent. Situational syncope, such as is associated with cough (tussive syncope) and micturition, are special cases of reflex syncope. In cough syncope, loss of consciousness occurs after a paroxysm of severe coughing. This is most likely to occur in obese men, usually smokers or patients with chronic bronchitis. The syncopal episodes occur suddenly, generally after repeated coughing but occasionally after a single cough. Before losing consciousness, the patient may feel lightheaded. The face often becomes flushed secondary to congestion, and then pale. Diaphoresis may be present, and loss of muscle tone may occur. Syncope generally is brief, lasting only seconds, and recovery is rapid. Several factors probably are operational in causing cough syncope. The most significant is blockage of venous return by raised intrathoracic pressure. In weight-lifting syncope, a similar mechanism is operational. Micturition syncope most commonly occurs in men during or after micturition, usually after arising from bed in the middle of the night to urinate in the erect position. There may be a history of drinking alcohol before going to bed. The syncope may result from sudden reflex peripheral vasodilatation caused by the release of intravesicular pressure and bradycardia. The relative peripheral vasodilatation from recent alcohol use and a supine sleeping position is contributory because blood pressure is lowest in the middle of the night. The syncopal propensity may increase with fever. Rarely, micturition syncope with headache may result from a pheochromocytoma in the bladder wall. Defecation syncope is uncommon, but it probably shares the underlying pathophysiological mechanisms responsible for micturition syncope. Convulsive syncope is an episode of syncope of any cause that is sufficiently prolonged to result in a few clonic jerks; the other features typically are syncopal and should not be confused with epileptic seizures. Other causes of situational syncope include diving and the postprandial state. Syncope during sexual activity may be due to neurocardiogenic syncope, coronary artery disease, or the use of erectile dysfunction medications. Rare intracranial causes of syncope include intermittent obstruction to cerebrospinal fluid (CSF) flow such as with a third ventricular mass. Rarely, syncope can occur with Arnold-Chiari malformations, but these patients usually have other symptoms of brainstem dysfunction.

Investigations of Patients with Syncope In the investigation of the patient with episodic impairment of consciousness, the diagnostic tests performed depend on the initial differential diagnosis. It is best to individualize investigations, but some measurements such as hematocrit, blood glucose, and ECG are always appropriate. A resting ECG may reveal an abnormality of cardiac

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rhythm or conduction or suggest the presence of underlying ischemic or congenital heart disease. In the patient suspected of cardiac syncope, a chest radiograph may show evidence of cardiac hypertrophy, valvular heart disease, or pulmonary hypertension. Other noninvasive investigations that may be helpful include echocardiography, exercise stress testing, radionuclide cardiac scanning, prolonged Holter monitoring for the detection of cardiac arrhythmias, and cardiac magnetic resonance imaging (MRI). Echocardiography is useful in the diagnosis of valvular heart disease, cardiomyopathy, atrial myxoma, prosthetic valve dysfunction, pericardial effusion, aortic dissection, and congenital heart disease. Holter monitoring detects twice as many ECG abnormalities as those discovered on a routine ECG and may disclose an arrhythmia at the time of a syncopal episode. Holter monitoring typically for a 24-hour period is usual, although longer periods of recording may be required, typically up to 30 days. Implantable loop recorders can provide long-term rhythm monitoring in patients suspected of having a seldom but highly symptomatic cardiac arrhythmia (Krahn et al., 2004). Exercise testing and electrophysiological studies are useful in selected patients. Exercise testing may be useful in detecting coronary artery disease, and exercise-related syncopal recordings may help to localize the site of conduction disturbances. Exercise testing should be considered in anyone with a history of exertional symptoms. Consider tilt-table testing in patients with unexplained syncope in high-risk settings or with recurrent faints in the absence of heart disease (Kapoor, 1999). Falsepositives occur, and 10% of healthy persons may faint during the test. Tilt testing frequently uses pharmacological agents such as nitroglycerin or isoproterenol, which increase sensitivity but decrease specificity. The specificity of tilt-table testing is approximately 90%, but the sensitivity differs in different patient populations. In patients suspected to have syncope due to cerebrovascular causes, noninvasive diagnostic studies including Doppler flow studies of the cerebral vessels and MRI or magnetic resonance angiography may provide useful information. The American Academy of Neurology recommends that carotid imaging not be performed unless there are other focal neurological symptoms (Langer-Gould et al., 2013). Cerebral angiography is sometimes useful. Electroencephalography (EEG) is useful in differentiating syncope from epileptic seizure disorders. EEG should be obtained only when a seizure disorder is suspected and generally has a low diagnostic yield (Poliquin-Lasnier and Moore, 2009). A systematic evaluation can establish a definitive diagnosis in 98% of patients (Brignole et al., 2006). Neurally mediated (vasovagal or vasodepressor) syncope was found in 66% of patients, orthostatic hypotension in 10%, primary arrhythmias in 11%, and structural cardiopulmonary disease in 5%. Initial history, physical examination, and a standard ECG established a diagnosis in 50% of patients. A risk score such as the San Francisco Syncope Rule (SFSR) can help to identify patients who need urgent referral. The presence of cardiac failure, anemia, abnormal ECG, or systolic hypotension helps to identify these patients (Parry and Tan, 2010). A systematic review of the SFSR accuracy (Saccilotto et al., 2011) found that the rule cannot be applied safely to all patients and should only be applied to patients for whom no cause of syncope is identified. The rule should be used only in conjunction with clinical evaluation, particularly in elderly patients. The Risk Stratification of Syncope in the Emergency Department (ROSE) study is another risk stratification evaluation of patients who present to the emergency department (Reed et al., 2010). Independent predictors of 1-month serious outcome were elevated brain natriuretic peptide concentration, positive fecal occult blood, hemoglobin of 90 g/L or less, oxygen saturation of 94% or less, and Q wave on the ECG. Although these risk scores can be used, there has been limited external validation, and there is no evidence to support that their use leads to better clinical outcomes than with unstructured clinical judgment (Shen et al., 2017).

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Common Neurological Problems

In summary, the initial and most important parts of the evaluation of a patient with syncope are a detailed history from the patient and any witnesses of the syncopal event, followed by a thorough physical examination with a focus on the neurological and cardiovascular findings. It is recommended that all patients receive an ECG as part of an initial syncope evaluation. It is reasonable for most patients to undergo at least limited laboratory testing in the acute setting to rule out anemia and hypoglycemia. Beyond this, imaging and laboratory testing should be individualized and may not be necessary if the history and physical are highly suggestive of vasovagal syncope and if the exam and ECG show no concerning findings. In 2017 the American College of Cardiology, American Heart Association, and the Heart Rhythm Society released a joint guideline on the evaluation and management of patients with syncope that may further guide the clinician in the care of these patients (Shen et al., 2017).

SEIZURES Seizures can cause sudden, unexplained loss of consciousness in a child or an adult (see Chapter 100). Seizures and syncope are distinguishable clinically, and one should be familiar with the pathophysiology and clinical features for both.

Pathophysiology Epilepsy is the syndrome of recurrent unprovoked seizures. It is broadly dichotomized into generalized and partial (also known as focal). Generalized epilepsies are characterized by seizures that involve both hemispheres at onset rather than by electrographic spread. They are typically genetically predisposed and tend to manifest in childhood and adolescence in the form of discrete epilepsy syndromes (e.g., childhood absence epilepsy, juvenile myoclonic epilepsy). In contrast, partial or focal epilepsies are characterized by focal-onset seizures that may or may not secondarily generalize (i.e., propagate to various parts of the brain). These are often termed “localization related” or symptomatic due to the known local pathology (e.g., tumor, gliosis, abscess) that serves as an epileptogenic focus. If the pathology is suspected but not visualized, the term cryptogenic is instead used.

History and Physical Examination The most definitive way to diagnose epilepsy and the seizure type is clinical observation of the seizure, although this often is not possible, except when seizures are frequent. The history of an episode, as obtained from the patient and an observer, is of paramount importance. The neurologist should obtain a family history and should inquire about birth complications, central nervous system (CNS) infection, head trauma, and previous febrile seizures because they all may have relevance. The neurologist should obtain a complete description of the episode and inquire about any warning before the event, possible precipitating factors, and other neurological symptoms that may suggest an underlying structural cause. Important considerations are the age at onset, frequency, and diurnal variation of the events. Seizures generally are brief and have stereotypical patterns, as described previously. With complex partial seizures and tonic-clonic seizures, a period of postictal confusion is highly characteristic and is much slower to resolve than the typical postsyncopal confusion. Unlike some types of syncope, seizures are unrelated to posture and generally last longer. In a tonic-clonic seizure, cyanosis frequently is present, pallor is uncommon, and breathing may be stertorous. In children with autonomic seizures (Panayiotopoulos syndrome) syncope-like epileptic seizures can occur, although usually accompanied by other features that help to clarify the diagnosis (Koutroumanidis et al., 2012). Tonic-clonic and complex partial seizures may begin at any age, although young infants may not demonstrate the typical features because

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of incomplete development of the nervous system; specifically, the lack of CNS myelination in infants leads to more migratory jerking rather than the synchronous jerking seen with tonic-clonic seizures in children and adults. The neurological examination may reveal an underlying structural disturbance responsible for the seizure disorder. Perinatal trauma may result in asymmetries of physical development, cranial bruits may indicate an arteriovenous malformation, and space-occupying lesions may result in papilledema or in focal motor, sensory, or reflex signs. In the pediatric age group, mental retardation occurs in association with birth injury or metabolic defects. The skin should be examined for abnormal pigment changes and other dysmorphic features characteristic of some of the neurodegenerative disorders. If examination occurs immediately after a suspected tonic-clonic seizure, the neurologist should search for abnormal signs such as focal motor weakness (“Todd paralysis”) and reflex asymmetry and for pathological reflexes such as a Babinski sign. Such findings may help to confirm that the attack was a seizure and suggest a possible lateralization or location of the seizure focus.

SEIZURE CLASSIFICATION Seizure classification is based on their functional distribution and on the structural neuroanatomy of the brain (see Chapter 100). The location and extent of a seizure’s involvement is reflected in its clinical manifestation, termed its semiology.

Absence Seizures The onset of absence seizures is usually between the ages of 5 and 15 years, and a family history of seizures is present in 20%–40% of patients. The absence seizure is a well-defined clinical and electrographic event. The essential feature is an abrupt, brief episode of decreased awareness without any warning, aura, or postictal symptoms. At the onset of the absence seizure, there is an abrupt interruption of activity, or behavioral arrest. A simple absence seizure is characterized clinically only by an alteration of consciousness. Characteristic of a complex absence seizure is an alteration of consciousness and other signs such as minor motor automatisms (repetitive purposeless movements), most often fluttering of the eyelids. During a simple absence seizure, the patient remains immobile, breathing is normal, skin color remains unchanged, postural tone is not lost, and no motor manifestations occur. After the seizure, the patient immediately resumes the previous activities and may be unaware of the attack. An absence seizure generally lasts 10–15 seconds, but it may be shorter or as long as 40 seconds. Complex absence seizures have additional manifestations such as diminution of postural tone that may cause the patient to fall, an increase in postural tone, minor clonic movements of the facial musculature or extremities, minor face or extremity automatisms, or autonomic phenomena such as pallor, flushing, tachycardia, piloerection, mydriasis, or urinary incontinence. If absence seizures are suspected, office diagnosis is frequently possible by having the patient hyperventilate for 3–4 minutes, which often, although not always, induces an absence seizure.

Tonic-Clonic Seizures The tonic-clonic seizure is the most dramatic manifestation of epilepsy and is characterized by motor activity and loss of consciousness. Tonicclonic seizures may be the only manifestation of epilepsy or may be associated with other seizure types. In a primary generalized tonic-clonic seizure, the affected person generally experiences no warning or aura, although a few myoclonic jerks may occur in some patients. The seizure begins with a tonic phase, during which there is sustained muscle contraction lasting 10–20 seconds. Following this phase is a clonic phase

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CHAPTER 2 Episodic Impairment of Consciousness characterized by recurrent synchronous muscle contractions or rhythmic jerking. During a tonic-clonic seizure, a number of autonomic changes may be present, including an increase in blood pressure and heart rate, apnea, mydriasis, urinary or fecal incontinence, piloerection, cyanosis, and diaphoresis. Injury may result from a fall, shoulder dislocation, or tongue biting. In the postictal period, consciousness returns quite slowly, and the patient may remain lethargic and confused for a variable period. The patient may remain somnolent and wish to sleep for many hours. Pathologically brisk reflexes may be elicitable. Some generalized motor seizures with transitory alteration of consciousness may have only tonic or only clonic components. Tonic seizures consist of an increase in muscle tone, and the alteration of consciousness generally is brief. Clonic seizures have a brief impairment of consciousness and bilateral clonic movements. Recovery may be rapid, but if the seizure is more prolonged, a postictal period of confusion may be noted.

Complex Partial Seizures In a complex partial seizure, the first seizure manifestation may be an alteration of consciousness, but the patient frequently experiences an aura or warning symptom. The seizure may have a simple partial onset that may include motor, sensory, visceral, or psychic symptoms. The patient initially may experience hallucinations or illusions, affective symptoms such as fear or depression, cognitive symptoms such as a sense of depersonalization or unreality, or aphasia. The particular symptoms are tightly correlated to the neuroanatomy of the seizure onset zone and eventually the extent of propagation. The complex partial seizure generally lasts 1–2 minutes but may be shorter or longer. If it propagates widely, it may become secondarily generalized and evolve into a tonic-clonic convulsion. During a complex partial seizure, automatisms, generally more complex than those in absence seizures, may occur. The automatisms may involve continuation of the patient’s activity before the onset of the seizure, or they may be new motor acts. Such automatisms are variable but frequently consist of oral automatisms (chewing or swallowing movements, lip smacking) or automatisms of the extremities, including fumbling with objects, walking, or trying to stand up. The duration of the postictal period after a complex partial seizure is variable, with a gradual return to normal consciousness and normal response to external stimuli. Table 2.2 provides a comparison of absence seizures and complex partial seizures.

Investigations of Seizures In the initial investigations of the patient with tonic-clonic or complex partial seizures, one should perform a complete blood cell count, urinalysis, biochemical screening, and determinations of blood glucose level and serum calcium concentration. Laboratory investigations generally are not helpful in establishing a diagnosis of absence seizures. In infants and children, consider biochemical screening for amino acid disorders. CSF examination is not necessary in every patient with a seizure disorder and should be reserved for those in whom a recent seizure may relate to an acute CNS infection. MRI is the imaging modality of choice for the investigation of patients with suspected seizures. It is superior to computed tomography and increases the yield of focal structural disturbances. EEG provides laboratory support for a clinical impression and helps to classify the type of seizure. Epilepsy is a clinical diagnosis; therefore an EEG cannot confirm the diagnosis with certainty unless the patient has a clinical event during the recording. Normal findings on the EEG do not exclude epilepsy, and minor nonspecific abnormalities do not confirm epilepsy. Some patients with clinically documented seizures show no abnormality even after serial or prolonged EEG recordings, including with special activation techniques. The EEG is most frequently helpful

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Comparison of Absence and Complex Partial Seizures

TABLE 2.2

Feature

Absence Seizure

Neurological status

Normal

Complex Partial Seizure

May have positive history or examination Childhood or adolescence Any age No Common Abrupt Gradual Seconds Typically 1–2 minutes Simple More complex Common Uncommon

Age at onset Aura or warning Onset Duration Automatisms Provocation by hyperventilation Termination Postictal phase Frequency

Abrupt No Possibly multiple seizures per day Electroencephalogram 3 Hz generalized spikeand-wave Neuroimaging

Usually normal findings

Gradual Confusion, fatigue Occasional Focal epileptic discharges or focal slowing May demonstrate focal lesions

in the diagnosis of absence seizures. EEG supplemented with simultaneous video monitoring may document events of loss or alteration of consciousness, allowing for a strict correlation between EEG changes and the clinical manifestations in question. Video EEG is also is useful in distinguishing epileptic seizures from nonepileptic phenomena. In most patients, an accurate diagnosis requires only a carefully taken clinical history, physical examination, and the aforementioned investigations. Others present a diagnostic dilemma and may require more extensive and invasive testing.

Psychogenic Nonepileptic Spells Nonepileptic spells are paroxysmal episodes of altered behavior that superficially resemble epileptic seizures but lack the expected EEG epileptic changes (Ettinger et al., 1999). However, 10%–20% of patients with nonepileptic spells also experience epileptic seizures and vice versa. In such cases, carefully determining semiological differences among the spell types is important when the spells are ongoing despite seemingly appropriate interventions. A diagnosis often is difficult to establish based on the initial history alone. Establishing the correct diagnosis often requires observation of the patient’s clinical episodes, but complex partial seizures of frontal lobe origin may be difficult to distinguish from nonepileptic spells. Most frequently, they superficially resemble tonic-clonic seizures, with whole-body shaking and unresponsiveness. They generally are abrupt in onset, typically occur in the presence of other people, and do not occur during sleep. Motor activity is uncoordinated, but urinary incontinence and physical injury are uncommon. Nonepileptic spells tend to be more prolonged than tonic-clonic seizures. Pelvic thrusting and back arching are common. Eye closure is common in nonepileptic spells, whereas the eyes tend to be open in epileptic seizures (Chung et al., 2006). During and immediately after the spell, the patient may not respond to verbal or painful stimuli. Cyanosis does not occur, and focal neurological signs and pathological reflexes are absent. PNES syncope without prominent motor activity can resemble. These spells are not uncommon and are often referred to as psychogenic pseudosyncope (Tannemaat et al., 2013). The apparent loss of consciousness in these patients may be longer than in syncope. The

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PART I

Common Neurological Problems

diagnosis can be distinguished from syncope if tilt-table testing fails to document a decrease in heart rate or blood pressure. In the patient with known epilepsy, consider the diagnosis of nonepileptic spells when previously controlled seizures become medically refractory. The patient should undergo psychological assessments because most affected persons are found to have specific psychiatric disturbances. In this patient group, a high frequency of hysteria, depression, anxiety, somatoform disorders, dissociative disorders, and personality disturbances is recognized. A history of physical or sexual abuse is also more prevalent in patients with PNESs. At times, a secondary gain is identifiable, although the absence of an identified gain or trigger should not preclude the diagnosis. In some patients with PNESs, the clinical episodes frequently precipitate by suggestion, by certain clinical tests such as hyperventilation and photic stimulation, and by placebo procedures such as intravenous saline infusion, tactile (vibration) stimulation, or pinching the nose to induce apnea. Hyperventilation and photic stimulation also may induce epileptic seizures, but their clinical features usually are distinctive. Some physicians avoid the use of placebo procedures because of the potential for an adverse effect on the doctor-patient relationship (Parra et al., 1998). Findings on the EEG in patients with PNESs are normal during the clinical episode, demonstrating no evidence of an ictal process. However, it is important to note that a number of organic conditions may present with similar behavioral and motor symptoms and a nonepileptiform EEG (Caplan et al., 2011). These may include conditions such as frontal lobe seizures, limb-shaking transient ischemic attacks, and paroxysmal dyskinesias, and a careful clinical history and adjunct testing are paramount. With the introduction of long-term ambulatory EEG monitoring, correlating the episodic behavior of a patient with the EEG tracing is possible, and PNESs are distinguishable from epileptic seizures. Table 2.3 compares the features of PNES with those of epileptic seizures. Although several procedures are used to help distinguish epileptic seizures from PNESs, none of these procedures have both high sensitivity and high specificity. No procedure attains the reliability of EEGvideo monitoring, which remains the standard diagnostic method for distinguishing between the two (Cuthill and Espire, 2005).

MISCELLANEOUS CAUSES OF ALTERED CONSCIOUSNESS In children, alteration of consciousness may accompany breath-holding spells and metabolic disturbances. Breath-holding spells and seizures are easily distinguished. Most spells start at 6–28 months of age, but they may occur as early as the first month of life; they usually disappear by 5 or 6 years of age. Breath-holding spells may occur several times per day and appear as either cyanosis or pallor. The trigger for cyanotic breath-holding spells is usually a sudden injury or fright, anger, or frustration. The child initially is provoked, cries vigorously for a few breaths, and stops breathing in expiration, whereupon cyanosis rapidly develops. Consciousness is lost because of hypoxia. Although stiffening, a few clonic movements, and urinary incontinence occasionally are observed, these episodes can be clearly distinguished from epileptic seizures by the history of provocation and by noting that the apnea and cyanosis occur before any alteration of consciousness. In these children, findings on the neurological examination and the EEG are normal. The provocation for pallid breath-holding is often a mild painful injury or a startle. The infant cries initially and then becomes pale and loses consciousness. As in the cyanotic type, stiffening, clonic movements, and urinary incontinence may rarely occur. In the pallid infant syndrome, loss of consciousness is secondary to excessive vagal tone, resulting in bradycardia and subsequent cerebral ischemia, as in a vasovagal attack.

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Comparison of Psychogenic and Epileptic Seizures

TABLE 2.3 Attack Feature

Psychogenic Seizure

Epileptic Seizure

Stereotypy of attack Onset or progression Duration Diurnal variation Injury

Often variable Gradual May be prolonged Daytime Rare

Tongue biting

Rare (typically tip of tongue)

Stereotypical More rapid Typically 1–2 minutes Nocturnal or daytime Can occur with tonic-clonic seizures Can occur with tonic-clonic seizures (lateral tongue or inside of cheek) Rare (eyes typically open) Frequent Tonic-clonic seizures may have ictal cry at onset Typically unilateral rhythmic jerking, dystonic posturing of a limb, or synchronous tonic-clonic activity Rare

Ictal eye closure Common Urinary incontinence Rare Vocalization May occur; variable (often crying, moaning) Motor activity Prolonged, uncoordinated; pelvic thrusting, back arching

Prolonged loss of muscle tone Postictal confusion

Common

Postictal headache Postictal crying Relation to medication changes Relation to menses in women Triggers

Rare Common Unrelated

Common (several minutes, often fatigued for hours desiring sleep) Common Rare Usually related

Uncommon

Occasionally increased

Emotional disturbances

Sleep deprivation, illness, medication nonadherence Less frequent

Rare

Frequency of attacks More frequent, up to daily Interictal EEG Normal findings Reproduction of Sometimes attack by suggestion Ictal EEG findings Normal Presence of second- Common ary gain Presence of others Frequently Psychiatric disturVery common (though not bances always apparent)

Frequently abnormal No

Abnormal Uncommon Variable Variable

EEG, Electroencephalogram.

Breath-holding spells do not require treatment, but when intervention is required, levetiracetam (Keppra) is effective for prophylaxis at ordinary anticonvulsant doses. Several pediatric metabolic disorders may have clinical manifestations of alterations of consciousness, lethargy, or seizures (see Chapter 90). The complete reference list is available online at https://expertconsult. inkling.com/.

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3 Falls and Drop Attacks Bernd F. Remler, Hatim Attar OUTLINE Falls and Drop Attacks—Introduction, 17 Drop Attacks With Loss of Consciousness, 17 Syncope, 17 Seizures, 18 Drop Attacks Without Loss of Consciousness, 18 Transient Ischemic Attacks, 18 Third Ventricular and Posterior Fossa Abnormalities, 18 Otolith Crisis, 19

Falls, 19 Neuromuscular Disorders and Myelopathy, 19 Other Cerebral or Cerebellar Disorders, 19 Cryptogenic Falls in the Middle-Aged, 19 Aging, Neurodegeneration, and the Neural Substrate of Gait and Balance, 20

FALLS AND DROP ATTACKS—INTRODUCTION

What were the circumstances of the fall and has the patient fallen before? Did the patient lose consciousness? If so, for how long? Did lightheadedness, vertiginous sensations, or palpitations precede the event? Is there a history of a seizure disorder, startle sensitivity, excessive daytime sleepiness, or falls precipitated by strong emotions? Does the patient have headaches or migraine attacks associated with weakness? Does the patient have vascular risk factors, and were there previous symptoms suggestive of transient ischemic attacks (TIAs)? Are there symptoms of sensory loss, limb weakness, or stiffness? Is there a history of visual impairment, hearing loss, vertigo, or tinnitus? The neurological examination identifies predisposing functional deficits. However, in the case of drop attacks, the examination is often normal, posing a diagnostic challenge. In such patients, neuroimaging is necessary. Further workup is tailored to the clinical circumstance and may include vascular imaging, cardiac and autonomic studies, electroencephalogram (EEG), nocturnal polysomnography, and, rarely, genetic and metabolic testing when related conditions are suspected. Psychogenic disorders of station and gait need to be considered in patients who frequently experience near falls without injuries.

Falling in childhood is part of growing up and usually medically insignificant, unless a serious childhood illness contributes. With advancing age, the potential for injury and other complications increases, and falling eventually develops into a dangerous burden for the elderly and the neurologically impaired. Quality of life can be severely affected by associated morbidity, immobilization, fear of falling (FOF), and growing dependency. Despite improved understanding of falls and their prevention, they remain a leading public health problem. The 2014 Behavioral Risk Factor Surveillance System (BRFSS) estimated that more than a fourth of adults older than 65 years have fallen, resulting in 29 million annual falls, more than 7 million injuries, and 800,000 hospital admissions in the United States. The corresponding cost to Medicare alone exceeded $31 billion and $50 billion for all medical care (Centers for Disease Control and Prevention, 2017, August 17). Fall-related injuries belong to the 20 most costly medical conditions. Clinically, a large number of etiologies of falls have to be considered. A useful initial approach is to determine whether a patient has suffered a drop attack or an accidental fall. In this discussion the term drop attack describes a sudden fall occurring without a prodrome that may or may not be associated with loss of consciousness and cannot be prevented by assistive devices. In contrast, falls reflect an inability to remain upright during a postural challenge. Potential etiologies of drop attacks include cardiac, epileptic, vascular, sleep, and vestibular disorders, as well as congenital brain abnormalities and intracranial masses. In neurological practice, falling is most commonly associated with chronic disorders such as neuropathies, stroke, multiple sclerosis (MS), parkinsonism, and dementia. Affected patients have impaired control of stability and gait due to functional declines in neuromuscular, sensory, vestibulocerebellar, and cognitive systems. Finally, the elderly, with their inevitable infirmities and accumulating functional deficits, frequently fall. These associations permit a classification of falls and drop attacks, as presented in Box 3.1. As is true for most neurological presentations, the medical history is essential in establishing the likely etiology of a patient’s fall. Aside from gender, age, medications, and neurological conditions, which all affect fall risk, answers to the following questions should be sought:

DROP ATTACKS WITH LOSS OF CONSCIOUSNESS Syncope The manifestations and causes of syncope are described in Chapter 2. Severe ventricular arrhythmias and hypotension lead to cephalic ischemia and falling. With sudden-onset third-degree heart block (Stokes-Adams attack), the patient loses consciousness and falls without warning. Other causes of decreased cardiac output, such as bradyarrythmias or tachyarrhythmias, are believed to be associated with prodromal faintness. However, reliance on history to determine a cardiac etiology of a fall may be inadequate because elderly patients with sick sinus syndrome can be amnestic for presyncopal symptoms. When occurring in young athletes, exertional drop attacks indicate the presence of potentially life-threatening structural heart disease, including

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Drops

PART I

Common Neurological Problems

DROP ATTACKS WITHOUT LOSS OF CONSCIOUSNESS

Causes and Types of Falls and

Transient Ischemic Attacks

Drop Attacks With loss of consciousness: Syncope Seizures Without loss of consciousness: Transient ischemic attacks: Vertebrobasilar insufficiency Anterior cerebral artery ischemia Third ventricular and posterior fossa tumors Chiari malformation Otolithic crisis Cataplexy

Drop attacks secondary to TIAs are sudden falls occurring without warning or obvious explanation such as tripping. Loss of consciousness either does not occur or is only momentary; the sensorium and lower limb strength are intact immediately or shortly after the patient hits the ground. Between episodes the neurological examination should not reveal lower limb motor or sensory dysfunction. The vascular distributions for drop attacks from TIAs are the posterior circulation and the anterior cerebral arteries.

Vertebrobasilar Insufficiency Drop attacks caused by posterior circulation insufficiency result from transient ischemia to the corticospinal tracts or the paramedian reticular formation. They are rarely an isolated manifestation of vertebrobasilar insufficiency, because most patients have a history of TIAs that include the more common signs and symptoms of vertigo, diplopia, ataxia, weakness, and hemisensory loss. Occasionally, however, a drop attack is the ominous precursor of severe neurological deficits due to progressive thrombosis of the basilar artery and may precede permanent ischemic damage only by hours. Aside from embolism and focal stenosis in the posterior circulation, vertebrobasilar insufficiency can also be caused by the subclavian steal syndrome (Osiro S 2012).

Falls Neuromuscular disorders (neuropathy, radiculopathy, and myopathy) Cerebral or cerebellar disorders Cryptogenic falls in the middle-aged Aging, neurodegeneration, and the neural substrate of gait and balance: Fear of falling Basal ganglia disorders: Parkinson disease Progressive supranuclear palsy and other parkinsonian syndromes The aged state

Anterior Cerebral Artery Ischemia

aortic stenosis or right ventricular dysplasia, among others. A large atrial myxoma can present in the same manner. Cerebral hypoperfusion due to peripheral loss of vascular tone (orthostasis) is usually identifiable by a presyncopal syndrome of progressive lightheadedness, faintness, dimming of vision, and “rubbery”-feeling legs, but even in the context of positive tilt-table testing, up to 37% of patients report a clinically misleading symptom of true, “cardiogenic” vertigo (Newman-Toker et al., 2008). Vertigo and downbeat nystagmus may also occur with asystole (Choi et al., 2010).

Seizures Epileptic drop attacks are caused by several mechanisms, including asymmetrical tonic contractions of limb and axial muscles, loss of tone of postural muscles (atonic seizures), and seizure-related cardiac arrhythmias. Video-EEG monitoring of epileptic patients with a history of falls permits characterization of the various motor phenomena that cause loss of posture. Pediatric epileptic encephalopathy syndromes (e.g., Lennox-Gastaut syndrome and Dravet syndrome, as well as the myoclonic epilepsies) frequently present as drop attacks. A tilt-table test should be considered in children and adolescents to avoid overdiagnosing epilepsy (Sabri, Mahmodian, and Sadri, 2006). Epileptic drops in young patients with epileptic encephalopathy syndromes can be reduced with vagal nerve stimulation in some, as well as with clobazam, rufinamide (VanStraten and Ng, 2012) and cannabidiol oil (Thiele et al., 2018). Medically refractory cases may show improved control of epileptic drops, as well as developmental gains after callosotomy (Ueda, Sood, Asano, Kumar, and Luat, 2017). Falling as a consequence of the tonic axial component of startle-induced seizures may be controllable with lamotrigine. Paradoxically, some antiseizure drugs can precipitate epileptic drop attacks, such as carbamazepine in Rolandic epilepsy. In patients with a history of stroke, falling may be falsely attributed to motor weakness rather than to new-onset seizures. Destabilizing extensor spasms of spasticity can also be difficult to distinguish from focal seizures.

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Anterior cerebral artery (ACA) ischemia causes drop attacks by impairing perfusion of the parasagittal premotor and motor cortex controlling the lower extremities. Origination of both ACAs from the same root occurs in approximately 20% of the population and predisposes to ischemic drop attacks from a single embolus. Paraparesis and even tetraparesis can result from simultaneous infarctions in bilateral anterior cerebral artery (ACA) territories (Kang and Kim, 2008). Limbshaking TIAs can be associated with drop attacks and occur in the context of the same vascular variant described earlier (Gerstner, Liberato, and Wright, 2005). Rare cases of drop attacks arising in the context of carotid dissection (Casana et al., 2011) and frontal arteriovenous (AV) fistulas (Oh, Yoon, Kim, and Shim, 2011) have been described.

Third Ventricular and Posterior Fossa Abnormalities Drop attacks can be a manifestation of colloid cysts of the third ventricle, Chiari malformation (“Chiari drop attack”), or mass lesions within the posterior fossa. With colloid cysts, unprovoked falling is the second most common symptom, after position-induced headaches. This history may be the only clinical clue to the diagnosis because the neurological examination can be entirely normal. Pineal cysts are also an occasional cause of drop attacks by producing a sudden rise in cerebrospinal fluid (CSF) pressure with position-dependent obstruction (“ball valve effect”) of the ventricular system (Fernandez-Miranda, 2018). Drop attacks occur in 2%–3% of patients with Chiari malformation and can be associated with loss of consciousness. They often resolve after decompression surgery (Straus, Foster, Zimmerman, and Frim, 2009). Posterior fossa arachnoid cysts are common but only occasionally associated with tonsillar ectopia. This combination of anomalies has also been reported to cause drop attacks (Killeen, Tromop, Alexander, and Wickremesekera, 2013). Drops induced by rapid head turning were considered pathognomonic of cysticercosis of the fourth ventricle in the early twentieth century (Brun sign). The contemporary maneuver of cervical spine manipulation is rarely associated with a drop attack (Sweeney and Doody, 2010). Patients who experience sudden drop attacks in the context of intracranial mass lesions such

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CHAPTER 3 Falls and Drop Attacks as parasagittal meningiomas, posterior fossa and foramen magnum tumors, and subdural hematomas usually have baseline abnormalities of gait and strength. Falling may occur consequent to these impairments rather than to acute loss of muscle tone.

Otolith Crisis During attacks of vertigo, patients often lose balance and fall. Approximately one in five patients with peripheral vestibular disorders experience drop attacks (Tomanovic and Bergenius, 2010). Meniere disease (see Chapter 22) may be complicated by “vestibular drop attacks”—Tumarkin otolithic crisis (Tumarkin, 1936)—in approximately 6% of patients. Presumably, stimulation of otolith receptors in the saccule triggers inappropriate postural reflex adjustments via vestibulospinal pathways, resulting in falls without accompanying vertigo. Affected patients report feeling as if, without warning, they are being thrown to the ground. They may fall straight down or be propelled in any direction (Chen, Zhang, Zhang, and Tumarkin, 2020). One patient reported suddenly seeing and feeling her legs moving forward in front of her as she did a spontaneous backflip (personal communication Dr. R.B. Daroff). Vestibular drop attacks may also occur in elderly patients with unilateral vestibulopathies who do not satisfy diagnostic criteria for Meniere disease (H. Lee, Yi, Lee, Ahn, and Park, 2005).

Cataplexy Cataplexy, the sudden loss of lower limb tone, is part of the tetrad of narcolepsy that also includes excessive daytime sleepiness, hypnagogic hallucinations, and sleep paralysis (see Chapter 101). Consciousness is preserved during a cataplectic attack, and the attack may vary in severity from slight lower limb weakness to generalized and complete flaccid paralysis with abrupt falling. Once on the ground, the patient is unable to move but continues to breathe. The attacks usually last less than 1 minute, only rarely exceeding several minutes in duration. Cataplectic attacks are provoked by strong emotion and associated with laughter, anger, surprise, or startle. Occasionally they interrupt or follow sexual orgasm. Cataplexy is rarely diagnosed in children, but a characteristic “cataplectic facies” with repetitive mouth opening, partial ptosis, and tongue protrusion has been described (Pillen, Pizza, Dhondt, Scammell, and Overeem, 2017). During the cataplectic attack, electromyographic silence in antigravity muscles is seen, and deep tendon reflexes and the H-reflex cannot be elicited. Cataplexy occurs in the absence of narcolepsy when associated with cerebral disease (symptomatic cataplexy), as in Niemann-Pick disease, Norrie disease, brainstem lesions, or as a paraneoplastic disorder (Farid et al., 2009). It can rarely occur as an isolated problem in normal individuals who have a family history of narcolepsy.

19

sensory tracts traverse the cord. This is particularly true for multiple sclerosis patients with gait and balance dysfunction, of whom at least half fall once or more a year (Cameron and Nilsagard, 2018). Multiple sclerosis patients older than 55 years have a high rate of injurious falls (Peterson, Cho, von Koch, and Finlayson, 2008), and FOF is common in this group (Kalron and Achiron, 2014). However, even elderly multiple sclerosis patients can attain marked reductions in fall risk with home-based balance and strength training (Sosnoff, Finlayson, McAuley, Morrison, and Motl, 2014).

Stroke Strokes present with any combination of neurological deficits that predispose to falls in the acute and chronic state: weakness, ataxia, sensory deafferentation, hemianopsia, diplopia, anosognosia, hemineglect, vestibular tilting, and acquired gait abnormalities (Chen, Novak, and Manor, 2014) are obvious risk enhancing factors. Poststroke depression and immobilization further aggravate this risk, which is at least twice as high in stroke patients compared with age-matched controls. The majority of falls occur within the home environment and come with a high risk (>70%) of injuries (Schmid et al., 2013). The poststroke risk of a hip fracture is doubled and is particularly high in women within 3 months of the ischemic event (Pouwels et al., 2009). Concerns for such injuries have increased prevention efforts but have also provoked restrictions on patient mobility in acute care and rehabilitation facilities (Inouye, Brown, and Tinetti, 2009), because falls typically occur when patients attempt to get out of bed, stand up, or walk. Fortunately, concerted efforts have yielded significant reductions of fall and injury incidence in such institutions (Services, 2014, May 7).

Other Cerebral or Cerebellar Disorders

FALLS

Metabolic encephalopathies may cause a characteristic transient loss of postural tone (asterixis). If this is extensive and involves the axial musculature, episodic loss of the upright posture can mimic drop attacks in patients with chronic uremia. Cerebellar disease causes truncal instability and represents a prime cause of falling. Patients with degenerative cerebellar ataxias (see Chapter 23) have a 50% incidence of falls in any 3-month period of observation, which correlates with increased gait variability (Schniepp et al., 2014). Episodic ataxia syndromes and familial hemiplegic migraine are also associated with recurrent falls (Black, 2006). Severe attacks of hyperekplexia, a familial disorder of increased startle sensitivity, manifest with generalized hypertonia that can lead to uncontrollable falls. Effective prevention with clonazepam or valproate is available. Beneficial treatment can also be offered to properly diagnosed patients with normal-pressure hydrocephalus (see Chapter 88); ventriculoperitoneal shunting leads to dramatic improvement of gait and decreased risk of falls, albeit in a temporally limited manner.

Neuromuscular Disorders and Myelopathy

Cryptogenic Falls in the Middle-Aged

All conditions causing sensory and motor impairment in the lower limbs predispose to falls. Leg weakness, especially of the proximal type, and delayed sensory signals from the lower limbs lead to characteristic gait abnormalities in neuropathies (Wuehr et al., 2014). In diabetics, coexisting retinopathy and vestibulopathy further enhance the fall risk (Gioacchini et al., 2018). The multiple causes of neuropathy and myopathy are discussed in Chapters 106 and 109. Additional disorders increasing fall risk include lumbosacral radiculopathies, myelopathies, channelopathies associated with intermittent weakness, and neuromuscular transmission disorders. Falling may herald the onset of acute polyneuropathies such as Guillain-Barré syndrome. Patients with spinal cord disease (see Chapter 27) are at particularly high risk of falling because all descending motor and cerebellar tracts and ascending

A diagnostic enigma is the occurrence of falls of unknown etiology among a subset of women older than 40 years of age. The fall usually is forward and occurs without warning during walking. The knees are often bruised (Thijs, Bloem, and van Dijk, 2009). Affected women report no loss of consciousness, dizziness, or even a sense of imbalance. They are convinced that they have not tripped but that their legs suddenly gave way. Gait is normal after the fall. This condition is estimated to affect 3% of women and develops after the age of 40 in the majority of patients. Originally described as a disorder of unknown causality, more recent inquiry into the frequency of falls in middle-aged and older women in the general population has elicited fall frequencies from 8% in women in their 40s to 47% in their 70s. Age and number of comorbidities such as diabetes and neuropathies are most predictive of

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Common Neurological Problems

falling (Nitz and Choy, 2008). Vestibular dysfunction of variable severity is also unexpectedly common and can be seen in 35% of individuals older than 40 years. Symptomatic (dizzy) patients have a 12-fold increase in the odds of falling (Agrawal, Carey, Della Santina, Schubert, and Minor, 2009). Fibromyalgia is associated with vestibular symptoms and an increased fall frequency (Jones, Horak, Winters-Stone, Irvine, and Bennett, 2009), as are migraine (Carvalho et al., 2018), poor sleep (Cauley et al., 2018), lower limb joint and foot problems (Afrin et al., 2018), and obesity (Ylitalo and Karvonen-Gutierrez, 2016). Indeed, obesity is associated with impaired dynamic balance functions already at a young age (do Nascimento, Silva, Dos Santos, de Almeida Ferreira, and de Andrade, 2017). When combined with sarcopenia, a clinically significant loss of muscle bulk and strength that can arise at any age throughout adulthood, the negative impact of obesity on mobility and associated FOF is magnified. Although beneficial in many regards, bariatric surgery has, unfortunately, been shown to increase the risk of fall-related, serious injuries (Carlsson et al., 2018). These observations indicate that risk factors for falls are prevalent already in middle age and correlate with falling later in life.

Aging, Neurodegeneration, and the Neural Substrate of Gait and Balance Significant alterations in quantitative gait characteristics (Chong, Chastan, Welter, and Do, 2009) evolve with advancing age, even in healthy individuals. It is estimated that by the age of 65, only 1 in 10 persons show gait abnormalities, but by the age of 85, only 1 in 10 have a normal gait. In the future, standardized measurement of gait speed could be included in the routine clinical assessment of the elderly, akin to a “vital sign” because slow speed (≤0.6 m/sec) has strong predictive power for all-cause mortality (Cummings, Studenski, and Ferrucci, 2014). Modern imaging methods are beginning to reveal the cerebral circuitry and brain centers supporting gait and balance. The midbrain contains a locomotor region within its reticular formation that includes the cholinergic pedunculopontine nucleus (PPN) and the cuneiform nucleus (CN). They are poorly delineated anatomically, but mesencephalic gray matter shows atrophy on magnetic resonance imaging (MRI) morphometry in non–dopa-responsive parkinsonism associated with gait and balance deficits (Sebille et al., 2019). The noradrenergic locus coeruleus is coactivated with the PPN (Benarroch, 2013) along with extensive pyramidal, extrapyramidal, and transcallosal networks. Cognitive circuitry in the frontal lobe and in the temporoparietal cortex (Takakusaki, 2017) is also involved in gait and balance functions, explaining the link between declining stability and cognition in the elderly, sometimes described as “brain failure.” As expected, this is accelerated by subcortical white matter ischemic changes and neurodegenerative disorders (Montero-Odasso and Hachinski, 2014; Srikanth et al., 2010). For instance, patients with mild cognitive impairment (MCI) have a nearly threefold prevalence of gait abnormalities compared with healthy older adults (Allali and Verghese, 2017), and specific spatiotemporal gait features correlate with an increased risk of falls in dementia (Modarresi, Divine, Grahn, Overend, and Hunter, 2018). A clinically useful correlate of the parallel involvement of cognitive and locomotor pathways in the elderly is the failure of dual task execution when walking. Reduction of step length or stoppage when talking (“stops walking while talking”) is a reliable indicator of an increased fall risk in the elderly (Ayers, Tow, Holtzer, and Verghese, 2014).

Fear of Falling FOF is a common and serious complication in patients with a history of falls and can also affect those at increased risk for falling. By itself, FOF increases the likelihood of such events, subsequent immobilization,

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and progression toward endstage disability. It is not limited to the elderly who have suffered injuries. FOF is prevalent among diabetics (Hewston and Deshpande, 2018), migraineurs (Carvalho et al., 2018), obese patients (Neri et al., 2017), and those with depression and sarcopenia (Gadelha et al., 2018). It tends to affect female patients more severely. Older adults should be queried about possible fear of outdoor falling, because their perceptions about the neighborhood environment can lead to self-imposed mobility restrictions (S. Lee et al., 2018). FOF and its advancing severity in patients with recurrent falls is reliably assessed with the Falls Efficacy Scale-I (Gazibara et al., 2019). Brain mechanisms underlying FOF may relate to hypometabolism in the L supplementary motor area, a brain region involved in motor planning (Sakurai et al., 2017). FOF is augmented by underlying anxiety and may evolve into a specific phobia (basiphobia) in some patients (Grenier et al., 2019). Intervention in the form of structured exercise and cognitive behavioral therapy can alleviate the adverse effects of FOF (Wetherell et al., 2018; Liu, Ng, Chung, and Ng, 2018).

Basal Ganglia Disorders Parkinson disease. Nearly all patients with Parkinson disease (PD) fall over the course of their illness and suffer twice as many fractures as age-matched controls. The fall risk increases with multiple factors, including disease duration, depression, cognitive impairment, treatment-related motor fluctuation, sedating drug use, coexisting rapid eye movement (REM) sleep behavior disorder (RBD) and, especially, cardiovascular autonomic dysfunction with orthostatic hypotension (Romagnolo et al., 2019). In addition, some patients may, without warning, drop directly to the ground. This is most commonly related to dopamine-induced motor fluctuations, particularly peak-dose dyskinesias and off periods (see Chapter 96). Freezing of gait (FOG), another fall-promoting feature of PD, shares a pathophysiological link with RBD because both conditions are associated with changes in the mesencephalic locomotor and balance centers (PPN and locus coeruleus) (Videnovic et al., 2013). FOG further correlates with dysfunction in cholinergic striatal pathways (Bohnen et al., 2019), while cholinergic dysinnervation of cortex relates to slowing of gait in PD (Bohnen et al., 2013). Dopamine substitution and deep brain stimulation (DBS) in PD patients improve gait characteristics but have less effect on axial locomotive components (Chastan et al., 2009), such as vertical breaking, which corresponds with an individual’s ability to control falling. This appears to depend on nondopaminergic pathways, because PD patients who fall demonstrate cholinergic hypofunction, whereas nigrostriatal dopaminergic activity is the same as in nonfallers. Degeneration of the cholinergic PPN appears to be a key factor for impaired postural control in PD. These findings offer an explanation why standard DBS targeting the subthalamic nucleus does not diminish fall risk (Hausdorff, Gruendlinger, Scollins, O’Herron, and Tarsy, 2009) and may actually contribute to an increased fall incidence (Parashos, Wielinski, Giladi, Gurevich, and National Parkinson Foundation Quality Improvement Initiative, 2013). DBS of the PPN has yielded variable results with regard to improvement of gait and postural instability (Thevathasan et al., 2012). Although central mechanisms of gait and balance dysfunction predominate in falling PD patients, there is evidence that proprioceptive functions in the lower extremities also may be impaired, augmenting the fall risk (Teasdale, Preston, and Waddington, 2017). Consensus recommendations for fall assessment and prevention in PD patients have been published (van der Marck et al., 2014). However, falling still remains intractable in many PD patients, and prevention programs have demonstrated only limited and transient benefit.

Progressive supranuclear palsy and other parkinsonian syndromes. Progressive supranuclear palsy (PSP) (see Chapter 96)

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CHAPTER 3 Falls and Drop Attacks manifests with parkinsonian features, axial rigidity, spasticity, and ophthalmoparesis. Falling affects all patients early in the course of the illness (Williams, Watt, and Lees, 2006) and is more likely in the backward direction than in those with PD, even with equivalent functional impairment. MRI tractography demonstrates overlapping but also differential involvement of brain circuitry in PD, in parkinsonism, and in normal elderly (Chan et al., 2014). RBD (see Chapter 101) is a precursor of PSP and an underrecognized cause of nocturnal falls. Clonazepam is commonly effective in the treatment of this parasomnia. Mechanisms similar to those described with PD and PSP contribute to falls in other parkinsonian syndromes, including multiple system atrophy, corticobasal ganglionic degeneration, and Lewy body disease (see Chapter 96). Falls are highly prevalent in the latter disorder because of the added cognitive dimension of neurological disability.

TABLE 3.1

Medical Conditions Associated with an Increased Risk of Falls History of falls

Orthostatic hypotension

Diabetes and other metabolic disorders Carotid sinus hypersensitivity Ischemic heart disease/heart failure

Low testosterone*

Persistent atrial fibrillation

Hearing and vision impairment

Cancer and chemotherapy

New spectacle lens prescription

Obesity

Smoking†

Low level of physical activity, apathy

UTI/ incontinence

Sarcopenia

Polypharmacy‡

COPD

Depression

Frailty

Fear of falling

Aged State

Migraine

Stressful life events*

Most patients presenting to neurologists with a complaint of falling are elderly and chronically impaired. Approximately one-third of persons older than 65 years fall at least once every year (Centers for Disease and Prevention, 2008). As the likelihood of falling increases with age, so does the severity of injury. Next to fractures, falls are the single most disabling condition leading to admission to long-term care facilities. The increased risk of injuries and fractures with falling is explained by a declining ability to absorb fall energy with the upper extremities (Sran, Stotz, Normandin, and Robinovitch, 2010), the diminishing size of soft-tissue pads around joints (in particular the hips), and osteoporosis. As would be expected, elderly in sheltered accommodations have the highest frequency of falls, affecting up to 50% every year. Many of these patients fall repeatedly, with women bearing a higher risk than men. Women also experience more FOF and fractures after falling, whereas men are more likely to suffer traumatic brain injury (TBI) and die as a result. Additional gender differences exist in regards to fall circumstances. Men in long-term care facilities are more prone to fall from loss of support from an object and while rising from the seated position. Women are more likely to fall when walking (Yang et al., 2018). The high prevalence of anticoagulant and antiplatelet use in the elderly raises concern about the risk of intracranial bleeding in fall-related TBI. Paradoxically, low-dose aspirin may be protective (Gangavati et al., 2009) but can also cause delayed intracranial bleeding within 12–24 hours after head trauma (Tauber, Koller, Moroder, Hitzl, and Resch, 2009). The presence of an intracranial hemorrhage in conjunction with warfarin use indicates an increased risk for further clinical deterioration, even if the patient is awake upon admission (Howard et al., 2009). Recurrent falls while on anticoagulation do not appear to be associated with an increased bleeding risk, but there is a much greater risk of death if an intracranial hemorrhage or another bleeding injury in a solid organ has occurred (Chiu, Jean, Fleming, and Pei, 2018). In very old patients, falls constitute the leading cause of injury-related deaths, with TBI causing at least one-third of 15,000+ fall-related fatalities every year. Complications of hip fractures cause most of the other fatalities (Deprey, 2009). The normal aging process is associated with a decline in multiple physiological functions that diminish the ability to compensate for challenges to the upright posture. Decreased proprioception (Suetterlin and Sayer, 2014), sarcopenia (Schaap, van Schoor, Lips, and Visser, 2018), orthopedic conditions, obesity (Follis et al., 2018), cardiovascular disturbances, deteriorating visual and vestibular functions (Liston et al., 2014), cognitive impairment, and failing postural reflexes (presbyastasis) (P. Y. Lee, Gadareh, and Bronstein, 2014) accrue to increase the risk of falling. Table 3.1 contains a steadily growing list of medical conditions that have been shown to increase falling risk in the elderly. Neurological conditions are not listed because all

Musculoskeletal pain/rheumatological disease

Elder abuse

Orthopedic/foot problems

Schizophrenia

Sleep apnea and other sleep disorders

Vestibular dysfunction

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Delirium COPD, Chronic Obstructive Pulmonary Disease; UTI, Urinary Tract Infection. *Associated with falling in men. †Associated with falling in women. ‡Benzodiazepines, psychotropic (antidepressants), and other centrally acting drugs (opioids, antiseizure agents, opioid analgesics, hypnotics). Antiarrhythmics; antihypertensives, especially after the onset of treatment.

impairments of motor, cerebellar, sensory, and cognitive functions augment a patient’s susceptibility to fall. The clinical evaluation aims to determine the fall mechanism and to identify predisposing medical conditions and correctable risk factors. In the absence of an overt explanation for falls, a syncopal event for which the patient may be amnestic becomes more likely. Orthostatic hypotension (Shaw and Claydon, 2014) and blood pressure drops associated with head turning (Schoon et al., 2013) are important contributors to falls but require a detailed evaluation of autonomic functions for adequate diagnosis. However, definitions of orthostasis vary significantly and diminish the relevance of an incidental measurement (Saedon, Tan, and Frith, 2018). A greater than 25% diastolic blood pressure drop is strongly correlated with previous falls, whereas a greater than 25% systolic drop correlates with orthostatic symptoms (Hartog et al., 2017). The implications of severe orthostatic blood pressure dysregulation are dire: failure of recovery of systolic blood pressure to at least 80% after 1 minute of standing is a strong predictor of mortality in elderly who fall (Lagro et al., 2014). The immense burden of falling to patients and society necessitates recognition of an increased risk of future falls. Detailed practice parameters and guidelines have been published (Society, 2010; Thurman, Stevens, Rao, and Quality Standards Subcommittee of the American Academy of, 2008). Intervention for falling elders requires a multifaceted approach (Society, 2010; Tinetti and Kumar, 2010). Depending on the clinical situation, this may include provision of assistive devices (orthotics, canes, and walkers), treatment of orthostasis or cardiac dysrhythmias, and modification of environmental hazards identified during home visits. All unnecessary medications that increase the risk of falls, especially sedatives, antihypertensives, and hypnotics, should be discontinued. High-risk behavior such as the use of ladders and moving about at low levels of illumination is discouraged, and women are advised to

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wear sturdy low-heeled shoes. Balance training such as tai chi and exercises aimed at improving strength and endurance diminish fall rates. Behavioral intervention for the development of FOF after such events can be effective and is strongly encouraged. Further useful interventions in the long term include vitamin D substitution (>800 international units (IU)/day), improvement of vision with cataract surgery (Foss et al., 2006), and statin treatment for prevention of osteoporotic fractures. However, none of these measures abolish the risk of falling, and even well-intended interventions may be associated with an increased fall risk. Unexpectedly, this was shown in patients who received new prescription eyeglasses (Campbell, Sanderson, and Robertson, 2010) and for the convenient annual dosing of 500,000 IU of vitamin D, which not only enhanced the risk of falls but also fractures (Sanders et al., 2010). Use of walkers is associated with the highest fall risk, raising the question whether these ubiquitous devices have inherent design flaws that are contributory (Stevens, Thomas, Teh, and Greenspan, 2009). Currently, falls in the elderly remain an intractable problem. Exercise programs have been evaluated extensively, with variably beneficial results in terms of fall rates and cost-effectiveness (Hektoen,

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Aas, and Luras, 2009; Tinetti and Kumar, 2010). Elderly patients with high fall risk and dementia may not benefit at all (Peek et al., 2018), and, unexpectedly, a tendency toward greater rates of hospitalization and death were reported with long-term (>1 year) exercise programs. However, a meta-analysis indicated modest benefits and safety of long-term, moderate-intensity exercise participation, not exceeding 3 sessions per week (de Souto Barreto, Rolland, Vellas, and Maltais, 2018). Biomedical engineers are developing devices that aim to diminish falls and their adverse consequences, including sensors on the body, in beds, or in flooring that detect and announce falling. Low-stiffness walking surfaces, and soft, protective shells for major joints may reduce the risk of serious injuries. Advances like these, along with screening of elderly persons for fall risk and preventive program enrollment, may eventually diminish the burden of this epidemic. The complete reference list is available online at https://expertconsult. inkling.com.

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4 Delirium Mario F. Mendez, Oleg Yerstein OUTLINE Clinical Characteristics, 23 Acute Onset with Fluctuating Course, 24 Cognitive and Related Abnormalities, 24 Behavioral and Emotional Abnormalities, 26 Pathophysiology, 26 Diagnosis, 27 Predisposing and Precipitating Factors, 27 Mental Status Examination, 28

Diagnostic Scales and Criteria, 28 Physical Examination, 28 Laboratory Tests, 29 Differential Diagnosis, 29 Common Causes of Delirium, 29 Special Problems in Differential Diagnosis, 31 Prevention and Management, 32 Prognosis, 33

Delirium is an acute mental status change characterized by abnormal and fluctuating attention. There is a disturbance in level of awareness and reduced ability to direct, focus, sustain, and shift attention (American Psychiatric Association [APA], 2013). These difficulties additionally impair other areas of cognition. The syndrome of delirium can be a physiological consequence of a medical condition or stem from a primary neurological cause. Delirium is by far the most common behavioral disorder in a medical-surgical setting. Most physicians across medical and surgical specialties are faced with delirious patients at some point in their careers. In general hospitals, the prevalence of delirium ranges from 15% to 24% on admission. The incidence ranges between 6% and 56% of hospitalized patients, 11%–51% postoperatively in elderly patients, and 80% or more of intensive care unit (ICU) patients (Alce et al., 2013; Inouye et al., 2014). The consequences of delirium are serious: they include prolonged hospitalizations, increased mortality, high rates of discharges to other institutions, severe impact on caregivers and spouses, and approximately $150 billion annually in direct healthcare costs in the United States (Kerr et al., 2013; Leslie and Inouye, 2011). The 30-day cumulative cost of ICU delirium per patient is more than $17,000 and would be even higher if not for the high mortality associated with ICU care (Vasilevskis et al., 2018). Knowledge of delirium dates to antiquity. Hippocrates referred to it as phrenitis, the origin of our word frenzy. In the first century ad, Celsus introduced the term delirium, from the Latin for “out of furrow,” meaning derailment of the mind, and Galen observed that delirium was often due to physical diseases that affected the mind “sympathetically.” In the nineteenth century, Gowers recognized that these patients could be either lethargic or hyperactive. Bonhoeffer, in his classification of organic behavioral disorders, established that delirium is associated with clouding of consciousness. Finally, Engel and Romano (1959) described alpha slowing with delta and theta intrusions on electroencephalograms (EEGs) and correlated these changes with clinical severity. They noted that treating the medical cause resulted in reversal of both the clinical and EEG changes of delirium.

In sharp contrast with this long history, physicians, nurses, and other clinicians often fail to diagnose delirium (Wong et al., 2010), and up to two-thirds of delirium cases go undetected or misdiagnosed (O’Hanlon et al., 2014). Healthcare providers miss this syndrome more from lack of recognition than from misdiagnosis. The elderly in particular may have a “quieter,” more subtle presentation of delirium that may evade detection. Adding to the confusion about delirium are the many terms used to describe this disorder: acute confusional state, altered mental status, acute organic syndrome, acute brain failure, acute brain syndrome, acute cerebral insufficiency, exogenous psychosis, metabolic encephalopathy, organic psychosis, ICU psychosis, toxic encephalopathy, toxic psychosis, and others. One of the most important clinical distinctions is that between delirium and dementia, the other common disorder impairing multiple cognitive domains. Delirium is acute in onset (usually hours to a few days), whereas dementia is chronic (usually insidious in onset and progressive). The definition of delirium must emphasize an acute behavioral decompensation with fluctuating attention, regardless of etiology or the presence of baseline cognitive deficits or preexisting dementia. Complicating this distinction is the fact that underlying dementia is a major risk factor for delirium. Clinicians must also take care to define the terms used with delirium. Attention is the ability to focus on specific stimuli to the exclusion of others. Awareness is the ability to perceive or be conscious of events or experiences. Arousal, a basic prerequisite for attention, indicates responsiveness or excitability into action. Coma, stupor, wakefulness, and alertness are states of arousal. Consciousness, a product of arousal, means clarity of awareness of the environment. Confusion is the inability for clear and coherent thought and speech.

CLINICAL CHARACTERISTICS The essential elements of delirium are summarized in Boxes 4.1 and 4.2. Proposed criteria for this disorder are a neurocognitive disturbance that develops over a short period of time; tends to

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PART I

Common Neurological Problems

Altered Level of Consciousness

Clinical Characteristics of Delirium

Consciousness, or clarity of awareness, may be disturbed. Most patients have lethargy and decreased arousal. Others, such as those with delirium tremens, are hyperalert and easily aroused. In hyperalert patients, the extreme arousal does not preclude attentional deficits because patients are indiscriminate in their alertness, are easily distracted by irrelevant stimuli, and cannot sustain attention. The two extremes of consciousness may overlap or alternate in the same patient or may occur from the same causative factor.

Acute onset of mental status change with fluctuating course Attentional deficits Confusion or disorganized thinking Altered level of consciousness Perceptual disturbances Disturbed sleep/wake cycle Altered psychomotor activity Disorientation and memory impairment Other cognitive deficits Behavioral and emotional abnormalities

Perceptual Disturbances

fluctuate; and impairs awareness, attention, and other areas of cognition (APA, 2013). In general, awareness, attention, and cognition fluctuate over the course of a day. Furthermore, delirious patients have disorganized thinking and an altered level of consciousness, perceptual disturbances, disturbance of the sleep/wake cycle, increased or decreased psychomotor activity, disorientation, and memory impairment. Other cognitive, behavioral, and emotional disturbances may also occur as part of the spectrum of delirium. Delirium can be summarized into the 10 clinical characteristics that follow.

The most common perceptual disturbance is decreased perceptions per unit of time; patients miss things that are going on around them. Patients may experience visual distortions, such as illusions, misperceptions, and even pareidolias, or the recognition of familiar objects or patterns superimposed on random stimuli. These perceptual abnormalities may be multiple, changing, or abnormal in size or location. Hallucinations are particularly common among younger patients with the hyperactive subtype. They usually occur in the visual sphere and are often vivid, three dimensional, and in full color. Patients may see lilliputian animals or people that appear to move about. Hallucinations are generally unpleasant, and some patients attempt to fight them or run away with fear. Some hallucinatory experiences may reflect intrusions of dreams or visual imagery into wakefulness. Psychotic auditory hallucinations with voices commenting on the patient’s behavior are unusual.

Acute Onset with Fluctuating Course

Disturbed Sleep/Wake Cycle

Delirium develops rapidly over hours or days but rarely over more than a week, and fluctuations in the course occur throughout the day. There are lucid intervals interspersed with the daily fluctuations. Gross swings in attention and awareness, arousal, or both occur unpredictably and irregularly and become worse at night. Because of potential lucid intervals, medical personnel may be misled by patients who exhibit improved attention and awareness unless these patients are evaluated over time.

Disruption of the day/night cycle causes excessive daytime drowsiness and reversal of the normal diurnal rhythm. “Sundowning”—with restlessness and confusion during the night—is common, and, in some patients, delirium may be manifest only at night. Nocturnal peregrinations can result in a serious problem when the delirious patient, partially clothed in a hospital gown, has to be retrieved from the hospital lobby or from the street in the middle of the night. This is one of the least specific symptoms and also occurs in dementia, depression, and other behavioral conditions. However, in delirium, disruption of circadian sleep cycles may result in rapid eye movement (REM) or dream-state overflow into waking.

Cognitive and Related Abnormalities Attentional Deficits

A disturbance of attention and consequent altered awareness is the cardinal symptom of delirium. Patients are distractible, and stimuli may gain attention indiscriminately, trivial ones often getting more attention than important ones. All components of attention are disturbed, including selectivity, sustainability, processing capacity, ease of mobilization, monitoring of the environment, and the ability to shift attention when necessary. Although many of the same illnesses result in a spectrum of disturbances from mild inattention to coma, delirium is not the same as a primary disorder of arousal.

Confusion or Disorganized Thinking Delirious patients are unable to maintain the stream of thought with accustomed clarity, coherence, and speed. There are multiple intrusions of competing thoughts and sensations, and patients are unable to order symbols, carry out sequenced activity, and organize goaldirected behavior. The patient’s speech reflects this jumbled thinking. Speech shifts from subject to subject and is rambling, tangential, and circumlocutory, with hesitations, repetitions, and perseverations. Decreased relevance of the speech content and decreased reading comprehension are characteristic of delirium. Confused speech is further characterized by an abnormal rate, frequent dysarthria, and nonaphasic misnaming, particularly of words related to stress or illness, such as those referable to hospitalization.

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Altered Psychomotor Activity There are three subtypes of delirium, based on changes in psychomotor activity. The hypoactive subtype is characterized by psychomotor retardation. These are the patients with lethargy and decreased arousal. The hyperactive subtype is usually hyperalert and agitated and has prominent overactivity of the autonomic nervous system. Moreover, the hyperactive type is more likely to have delusions and perceptual disorders such as hallucinations. Approximately half of patients with delirium manifest elements of both subtypes, called mixed subtype, alternating between hyperactive and hypoactive. Only approximately 15% are strictly hyperactive. In addition to the patients being younger, the hyperactive subtype has more drug-related causes, a shorter hospital stay, and a better prognosis. Many patients who present with an initial hyperactive phase evolve to a predominant hypoactive delirium.

Disorientation and Memory Impairment Disturbances in orientation and memory are related. Patients are disoriented first to time of day, followed by other aspects of time, and then to place. They may perceive abnormal juxtapositions of events or places. Disorientation to person—in the sense of loss of personal identity—is rare. Disorientation is one of the most common findings in delirium but is not specific for delirium; it occurs in dementia and amnesia as well. Among patients with delirium, recent memory is disrupted in large part by the decreased registration caused by attentional problems.

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BOX 4.2

DSM-5 Diagnostic Criteria: Delirium*

A. A disturbance in attention (i.e., reduced ability to direct, focus, sustain, and shift attention) and awareness (reduced orientation to the environment). B. The disturbance develops over a short period of time (usually hours to a few days), represents a change from baseline attention and awareness, and tends to fluctuate in severity during the course of a day. C. An additional disturbance in cognition (e.g., memory deficit, disorientation, language, visuospatial ability, or perception). D. The disturbances in Criteria A and C are not better explained by another preexisting, established, or evolving neurocognitive disorder and do not occur in the context of a severely reduced level of arousal, such as coma. E. There is evidence from the history, physical examination, or laboratory findings that the disturbance is a direct physiological consequence of another medical condition, substance intoxication or withdrawal (i.e., due to a drug of abuse or to a medication), or exposure to a toxin, or is due to multiple etiologies. Specify whether: Substance intoxication delirium: This diagnosis should be made instead of substance intoxication when the symptoms in Criteria A and C predominate in the clinical picture and when they are sufficiently severe to warrant clinical attention.

Coding note: The ICD-9-CM code for [specific medication]-induced delirium is 292.81. The ICD-10-CM code depends on the type of medication. If the medication is an opioid taken as prescribed, the code is F11.921. If the medication is a sedative, hypnotic, or anxiolytic taken as prescribed, the code is F13.921. If the medication is an amphetamine-type or other stimulant taken as prescribed, the code is F15.921. For medications that do not fit into any of the classes (e.g., dexamethasone) and in cases in which a substance is judged to be an etiological factor but the specific class of substance is unknown, the code is F19.921. 293.0 (F05) Delirium due to another medical condition: There is evidence from the history, physical examination, or laboratory findings that the disturbance is attributable to the physiological consequences of another medical condition. Coding note: Use multiple spate codes reflecting specific delirium etiologies (e.g., 572.2 [K72.90] hepatic encephalopathy, 293.0 [F05] delirium due to hepatic encephalopathy). The other medical condition should also be coded and listed separately immediately before the delirium due to another medical condition (e.g., 572.2 [K72.90] hepatic encephalopathy; 293.0 [F05] delirium due to hepatic encephalopathy). ICD-10-CM

With use disorder, mild F10.121 F12.121 F16.121 F16.121 F18.221 F11.121 F13.121 F15.121 F14.121 F19.221

ICD-9-CM 291.0 292.81 292.81 292.81 292.81 292.81 292.81 292.81 292.81 292.81

Alcohol Cannabis Phencyclidine Other hallucinogen Inhalent Opioid Sedative, hypnotic, or anxiolytic Amphetamine (or other stimulant) Cocaine Other (or unknown) substance

Coding note: The ICD-9-CM and ICD-10CM codes for the [specific substance] intoxication delirium are indicated in the table below. Note that the ICD-10-CM code depends on whether or not there is a comorbid substance use disorder present for the same class of substance. If a mild substance use disorder is comorbid with the substance intoxication delirium, the 4th position character is “1,” and the clinician should record “mild [substance] use disorder,” before the substance intoxication delirium (e.g., “mild cocaine use disorder is comorbid with the substance intoxication delirium”). If a moderate or severe substance use disorder is comorbid with the substance intoxication delirium, the 4th position character is “2,”and the clinician should record “moderate [substance] use disorder” or “severe [substance] use disorder,” depending on the severity of the comorbid substance use disorder. If there is no comorbid substance use disorder (e.g., after a one-time heavy use of the substance), then the 4th position character is “9,”and the clinician should record only the substance intoxication delirium. Substance withdrawal delirium: This diagnosis should be made instead of substance withdrawal when the symptoms in Criteria A and C predominate in the clinical picture and when they are sufficiently severe to warrant clinical attention. Code [specific substance] withdrawal delirium: 291.0 (F10.231) alcohol; 292.0 (F11.23) opioid; 292.0 (F13.231) sedative, hypnotic, or anxiolytic; 292.0 (F19.231) other (or unknown) substance/medication. Medication-induced delirium: This diagnosis applies when the symptoms in Criteria A and C arise as a side effect of a medication taken as prescribed.

With use disorder, moderate or severe F10.221 F12.221 F16.221 F16.221 F18.221 F11.221 F13.221 F15.221 F14.221 F19.221

Without use disorder F10.921 F12.921 F16.921 F16.921 F18.921 F11.921 F13.921 F15.921 F14.921 F19.921

293.0 (F05) Delirium due to multiple etiologies: There is evidence from the history physical examination, or laboratory findings that the delirium has more than one etiology (e.g., more than one etiological medical condition; another medical condition plus substance intoxication or medication side effect). Coding note: Use multiple separate codes reflecting specific delirium etiologies (e.g., 572.2 [K72.90] hepatic encephalopathy, 293.0 [F05] delirium due to hepatic failure; 291/0 [F10.231] alcohol withdrawal delirium). Note that the etiological medical condition both appears as a separate code that precedes the delirium code and is substituted into the delirium due to another medical condition rubric. Specify if: Acute: Lasting a few hours or days. Persistent: Lasting weeks or months. Specify if: Hyperactive: The individual has a hyperactive level of psychomotor activity that may be accompanied by mood lability, agitation, and/or refusal to cooperate with medical care. Hypoactive: The individual has a hypoactive level of psychomotor activity that may be accompanied by sluggishness and lethargy that approaches stupor. Mixed level of activity: The individual has a normal level of psychomotor activity even though attention and awareness are disturbed. Also includes individuals whose activity level rapidly fluctuates.

* Previously referred to in DSM IV as “dementia, delirium, amnestic, and other cognitive disorders.” Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (© 2013). American Psychiatric Association. Note: The following supportive features are commonly present in delirium but are not key diagnostic features: sleep/wake cycle disturbance, psychomotor disturbance, perceptual disturbances (e.g., hallucinations, illusions), emotional disturbances, delusions, labile affect, dysarthria, and EEG abnormalities (generalized slowing of background activity). @

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26

PART I

Common Neurological Problems like hallucinations, are generally fleeting, changing, and readily affected by sensory input. These delusions are most often persecutory. Some patients exhibit facetious humor and playful behavior, lack of concern about their illness, poor insight, impaired judgment, and confabulation. There can be marked emotional lability. Patients can be agitated and fearful or depressed and apathetic. Dysphoric (unpleasant) emotional states are the more common. Up to half of elderly delirious patients display symptoms of depression with low mood, loss of interests, fatigue, decreased appetite and sleep, and other feelings related to depression. There may be mood-congruent delusions and hallucinations. The mood changes of delirium are probably due to direct effects of the confusional state on the limbic system and its regulation of emotions. Finally, more elementary behavioral changes may be the principal symptoms of delirium. This is the case especially in the elderly, in whom decreased activities of daily living, urinary incontinence, and frequent falls are among the major manifestations of this disorder.

FINISHING

PRESIDENT (top is cursive, bottom is printing)

PATHOPHYSIOLOGY

IF HE IS NOT CAREFUL, THE STOOL WILL FALL. Fig. 4.1 Writing Disturbances in Delirium. Patients were asked to write indicated words to dictation. (Reprinted with permission from Chédru, J., Geschwind, N. (1972). Writing disturbances in acute confusional states. Neuropsychologia 10, 343–353.)

In delirium, reduplicative paramnesia, a specific memory-related disorder, results from decreased integration of recent observations with past memories. Persons or places are “replaced” in this condition. In general, delirious patients tend to mistake the unfamiliar for the familiar. For example, they tend to relocate the hospital closer to their homes. In a form of reduplicative paramnesia known as Capgras syndrome, a familiar person is mistakenly thought to be an unfamiliar impostor.

Other Cognitive Deficits Disturbances occur in visuospatial abilities and in writing. Higher visual-processing deficits include difficulties in visual object recognition, environmental orientation, and organization of drawings and other constructions. Writing is easily disrupted in these disorders, possibly because it depends on multiple components. The most salient characteristics are abnormalities in the mechanics of writing. The formation of letters and words is indistinct, and words and sentences sprawl in different directions (Fig. 4.1). There is a reluctance to write, and there are motor impairments (e.g., tremors, micrographia) and spatial disorders (e.g., misalignment, leaving insufficient space for the writing sample). Sometimes the writing shows perseverations of loops in aspects of the writing. Spelling and syntax are also disturbed, with spelling errors particularly involving consonants, small grammatical words (prepositions and conjunctions), and the last letters of words.

Behavioral and Emotional Abnormalities Behavioral changes include poorly systematized delusions, often with persecutory and other paranoid ideation, and personality alterations. Delusions,

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The pathophysiology of delirium is not entirely understood, but it depends on widely distributed neurological dysfunction. Delirium is the final common pathway of many pathophysiological disturbances that reduce or alter cerebral oxidative metabolism. These metabolic changes result in diffuse impairment in multiple neuronal pathways and systems. Several brain areas involved in attention are particularly disturbed in delirium. Dysfunction of the anterior cingulate cortex is involved in disturbances of the management of attention (Reischies et al., 2005). Other areas include the bilateral or right prefrontal cortex in attentional maintenance and executive control, the temporoparietal junction region in disengaging and shifting attention, the thalamus in engaging attention, and the upper brainstem structures in moving the focus of attention. The thalamic nuclei are uniquely positioned to screen incoming sensory information, and small lesions in the thalamus may cause delirium. In addition, there is evidence that the right hemisphere is dominant for attention. Cortical blood flow studies suggest that right hemisphere cortical areas and their limbic connections are the “attentional gate” for sensory input through feedback to the reticular nucleus of the thalamus. Another explanation for delirium is alterations in neurotransmitters, particularly a cholinergic-dopaminergic imbalance. There is extensive evidence for a cholinergic deficit in delirium (Alce et al., 2013). Anticholinergic agents can induce the clinical and EEG changes of delirium, which are reversible with the administration of cholinergic medications such as physostigmine. The beneficial effects of donepezil, rivastigmine, and galantamine—acetylcholinesterase-inhibitor medications used for Alzheimer disease—may be partly due to an activating or attention-enhancing role. Moreover, cholinergic neurons project from the pons and the basal forebrain to the cortex and make cortical neurons more responsive to other inputs. A decrease in acetylcholine results in decreased perfusion in the frontal cortex. Hypoglycemia, hypoxia, and other metabolic changes may differentially affect acetylcholine-mediated functions. Other neurotransmitters may be involved in delirium, including dopamine, serotonin, norepinephrine, γ-aminobutyric acid (GABA), glutamine, opiates, and histamine. Dopamine has an inhibitory effect on the release of acetylcholine, thereby contributing to the delirium-producing effects of l-dopa and other antiparkinsonism medications (Martins and Fernandes, 2012; Trzepacz and van der Mast, 2002). Opiates may induce the effects by increasing dopamine and glutamate activity. Polymorphisms in genes coding for a dopamine transporter and two dopamine receptors have been associated with the development of delirium (van Munster et al., 2010).

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CHAPTER 4 Delirium

Predisposing and Precipitating Factors for Delirium BOX 4.3

Elderly, especially 80 years or older Dementia, cognitive impairment, or other brain disorder Fluid and electrolyte disturbances and dehydration Other metabolic disturbance, especially elevated BUN level or hepatic insufficiency Number and severity of medical illnesses, including cancer Infections, especially urinary tract, pulmonary, and AIDS Malnutrition, low serum albumin level Cardiorespiratory failure or hypoxemia Prior stroke or other nondementia brain disorder Polypharmacy and use of analgesics, psychoactive drugs, or anticholinergics Drug abuse, alcohol or sedative dependency Sensory impairment, especially visual Sensory overstimulation and “ICU psychosis” Sensory deprivation Sleep disturbance Functional impairment Fever, hypothermia Physical trauma or severe burns Fractures Male gender Depression Specific surgeries: Cardiac, especially open heart surgery Orthopedic, especially femoral neck and hip fractures, bilateral knee replacements Ophthalmological, especially cataract surgery Noncardiac thoracic surgery and aortic aneurysmal repairs Transurethral resection of the prostate AIDS, Acquired immunodeficiency syndrome; BUN, blood urea nitrogen; ICU, intensive care unit.

Inflammatory cytokines such as interleukins, interferon, and tumor necrosis factor alpha (TNF-α) may contribute to delirium by altering blood-brain barrier permeability, by affecting neurotransmission (Cole, 2004; Fong et al., 2009; Inouye, 2006; Martins and Fernandes, 2012), and even by altering gut immune function (McCoy et al., 2018). The combination of inflammatory mediators and dysregulation of the limbic–hypothalamic–pituitary axis may lead to exacerbation or prolongation of delirium (MacLullich et al., 2008; Martins and Fernandes, 2012). Finally, secretion of melatonin, a hormone integral to circadian rhythm and the sleep/wake cycle, may be abnormal in delirious patients compared to those without delirium (Fitzgerald et al., 2013).

DIAGNOSIS Diagnosis is a two-step process. The first step is the recognition of delirium, which requires a thorough history, a bedside mental status examination focusing on attention, and a review of established diagnostic scales or criteria for delirium. The second step is to identify the cause from a large number of potential diagnoses. Because the clinical manifestations offer few clues to the cause, crucial to the differential diagnosis are the general history, physical examination, and laboratory assessments. The general history assesses several elements. An abrupt decline in mentation, particularly in the hospital, should be presumed to be delirium. Although patients may state that they cannot think straight

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or concentrate, family members or other good historians should also be available to describe the patient’s behavior and medical history. The observer may have noted early symptoms of delirium such as inability to perform at a usual level, decreased awareness of complex details, insomnia, and frightening or vivid dreams. It is crucial to obtain accurate information about systemic illnesses, drug use, recent trauma, occupational and environmental exposures, malnutrition, allergies, and any preceding symptoms leading to delirium. Furthermore, the clinician should thoroughly review the patient’s medication list.

Predisposing and Precipitating Factors The greater the number of predisposing factors, the milder in severity the precipitating factors need be in order to result in delirium (Anderson, 2005; Box 4.3). Four factors independently predispose to delirium: vision impairments (2

Off drugs

Okun et al. (2009)

22 unilateral STN

23 unilateral GPi

7

Off drugs

Ballanger et al. (2009)

7

NA

47 (range 19–94)

Off drugs

Herzog et al. (2009) 35

NA

6

Off drugs

Cavanagh et al. (2011)

19 included, 14 analyzed

HC: 15 senior participants and 50 college students

NA

NA

Coulthard et al. (2012)

11

11 PD 15 HC

26.5

Both on drugs and off drugs

Greenhouse et al. (2013)

11 included, 10 analyzed

10 age-matched sexmatched HC

NA

On drugs

Green et al. (2013)

10

9 HC

3–7 years

NA

Performance on picture word interference (lexical-semantic interference control) and Hayling task (response inhibition) on vs off DBS (counterbalanced and 6 weeks lapsed) Noun-verb generation task on DBS vs During off DBS: selective deficit in verb degeneration. off DBS (counterbalanced and 6 During on DBS: significantly more errors in the weeks lapsed) noun-noun and verb-verb tasks rCBF by PET during working memory STN-DBS-induced DLPFC rCBF changes were inversely correlated with changes in working (spatial delayed response) and memory, whereas STN-DBS-induced ACC rCBF response inhibition (go-no-go) changes were inversely correlated with changes in tasks on DBS vs off DBS (counresponse inhibition terbalanced order, double blind, in 2-day assessment) Verbal fluency No difference in verbal fluency between on and off DBS rCBF by PET during a go-no-go task On DBS: reduced reaction time, but also impaired on DBS vs off DBS (randomized response inhibition and increased rCBF in the order in the same day) subgenual ACC STN-DBS improved severe perseveration, whereas Vienna perseveration task during three conditions: off DBS, off L-dopa did not drug; on DBS, off drug; off DBS, on drug Reinforcing learning and conflict task Increased mPFC theta power (4–8 Hz) predicted with concurrent EEG: DBS on vs slower response times during high-conflict off (randomized counterbalanced decision in HC and PD with DBS off but not with order), HC tested once DBS on Probabilistic decision-making task: Reduced reaction time when DBS on off DBS, off drugs; on DBS, off drugs; off DBS, on drugs Switching task: double-blind Abnormal switching during off and dorsal DBS comassessment in three counterbalpared with HC; remediated in the ventral DBS anced conditions (time between sessions: 10–14 days): ventral vs dorsal vs off DBSHC tested once Reaction time on DBS vs. off DBS Reduced reaction time while on DBS

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With permission from Castrioto, A., Lhommée, E., Moro, E., et al., 2014. Mood and behavioural effects of subthalamic stimulation in Parkinson’s disease. Lancet Neurol. 13, 287–305. ACC, Anterior Cingulate Cortex; DBS, Deep Brain Stimulation; DLPFC, Dorsolateral Prefrontal Cortex; HC, Health Controls; PD, Parkinson’s disease; GPi, internal Globus Pallidus; mPFC, medial Prefrontal Cortex; NA, Not Available; PET, Positron Emission Tomography; rCBF, regional cerebral blood flow; STN, Subthalamic Nucleus; TMT A, Trail Making Test Part A; TMTB, Trail Making Test Part B.

Common Neurological Problems

Time from Surgery (months) Drug Status

PART I

Control Group

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eTABLE 9.8

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PART I

Common Neurological Problems

interpretations are difficult to make and further research is warranted to better characterize behavioral and personality changes following DBS. Authors provided prevention and management recommendations for clinicians to use to provide the best clinical care for PD patients undergoing DBS (eBox 9.3).

Dementia With Lewy Bodies DLB is increasingly being recognized as a common cause of dementia in older adults. DLB is associated with fluctuating cognitive difficulties, parkinsonism, and hallucinations. Clinical presentation overlap occurs between the presentation of DLB with AD and PD. Research has observed greater overall behavioral symptoms among individuals with DLB than in individuals with AD, particularly with regard to hallucinations and apathy (Ricci et al., 2009). Recent imaging research suggests that depressive symptoms in mild AD and DLB are associated with cortical thinning in prefrontal and temporal areas, suggesting a need to reevaluate antidepressants in these patients (Lebedev et al., 2014; Lebedeva et al., 2014).

Psychosis Psychotic symptoms, particularly hallucinations, are a hallmark feature of DLB. Insight is typically poor. Unlike patients with AD or PD, patients with DLB exhibit hallucinations early in the course of the illness. Delusions are also common in DLB. The neuropathological correlates of hallucinations in DLB are somewhat unclear. It has been suggested that hallucinations are likely due to decreased acetylcholine as well as to changes in the basal forebrain and the ventral temporal lobe (Ferman and Boeve, 2007). Hallucinations are correlated with poorer functioning with regard to instrumental activities of daily living (Ricci et al., 2009). Typical neuroleptics are avoided in DLB, because patients exhibit high sensitivity to these drugs and may experience severe parkinsonian symptoms and other side effects. In contrast, atypical neuroleptics such as clozapine and quetiapine, as well as cholinesterase inhibitors, are associated with improved cognition and decreased psychotic symptoms (McKeith, 2002).

Huntington Disease Up to 79% of individuals with HD report psychiatric and behavioral symptoms as the presenting manifestation of the disease. Symptom presentation varies across stage of illness in HD (Table 9.9). Behavioral symptoms are commonly observed among institutionalized patients with HD (Table 9.10). The behavioral difficulties can lead to placement difficulties in these patients.

Depression Depression is one of the most common concerns for individuals and families with HD, occurring in up to 69% of patients (van Duijn et al., 2008). Depression in HD is associated with worse cognitive performance (Smith et al., 2012) and contributes to significant morbidity (Beglinger et al., 2010) as well as early mortality due to suicide (Fiedorowicz et al., 2011). Depression may precede the onset of neurological symptoms in HD by 2–20 years, although large-scale empirical research has been minimal. Depression is common immediately before diagnosis, when neurological soft signs and other subtle abnormalities become evident (Epping et al., 2013). However, following a definite diagnosis of HD, depression is most prevalent in the middle stages of the disease (i.e., Shoulson-Fahn stages 2 and 3) and may diminish in the later stages (Paulsen et al., 2005b). Positron emission tomography (PET) studies indicate that patients with HD with depression have hypermetabolism in the inferior frontal cortex and thalamus relative to nondepressed patients with HD or normal age-matched controls.

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Efforts to understand the cellular and molecular mechanisms underlying behavioral disorders in patients with HD have suggested that dysfunctional huntingtin (HTT) affects cellular pathways that are involved in mood disorders or in the response to antidepressants, including BDNF/TrkB and serotonergic signaling. Thus the pathogenic polyQ expansion in HTT could lead to mood disorders not only by the gain of a new toxic function but also by the perturbation of its normal function (Pla et al., 2014).

Suicide Suicide is more common in HD than in other neurological disorders with high rates of depression such as stroke and PD. Most studies have found a fourfold to sixfold increase of suicide in HD, with reports as high as 8–20 times greater than the general population. Two “critical periods” during which suicidal ideation in HD increases dramatically have been identified. First, frequency of suicidal ideation doubles from 10.4% in at-risk persons with a normal neurological examination to 20.5% in at-risk persons with soft neurological signs. Second, in persons with a diagnosis of HD, 16% had suicidal ideation in stage 1, whereas nearly 21% had suicidal ideation in stage 2. Although the underlying mechanisms for suicidal risk in HD are poorly understood, it may be beneficial for healthcare providers to be aware of periods during which patients may be at an increased risk of suicide (Paulsen et al., 2005a). A history of suicide attempts and the presence of depression were strongly predictive of suicidal behavior in a large sample of prodromal HD (n = 735; Fiedorowicz et al., 2011).

Psychosis Psychosis occurs with increased frequency in HD, with estimates ranging from 3% to 12%. Psychosis is more common among early adulthood-onset cases than among those whose disease begins in middle or late adulthood. Psychosis in HD is more resistant to treatment than psychosis in schizophrenia. Huntington Study Group data suggest that psychosis may increase as the disease progresses (see Table 9.9), although psychosis can become difficult to measure in the later stages of disease.

Obsessive-Compulsive Traits Although true obsessive-compulsive disorder (OCD) is rare in HD, obsessive and compulsive behaviors are prevalent (13%–30%). Obsessive thinking often increases with proximity to disease onset and then remains stable throughout the illness. Obsessive thinking associated with HD is reminiscent of perseveration, such that individuals get “stuck” on a previous occurrence or need and are unable to shift.

Aggression Aggressive behaviors ranging from irritability to intermittent explosive disorders (IEDs) occur in 19%–59% of patients with HD. Although aggressive outbursts are often the principal reason for admission to a psychiatric facility, research on the prevalence and incidence of irritability and aggressive outbursts in HD is sparse. The primary limitation in summarizing these symptoms in HD is the varied terminology used to describe this continuum of behaviors. Clinicians and HD family members report that difficulty with placement attributable to the patient’s aggression was among the principal obstacles to providing placement, although recent research demonstrates that problematic behaviors are evident in a minority of HD patients in nursing homes (Zarowitz et al., 2014).

Apathy Early signs of HD may include withdrawal from activities and friends, decline in personal appearance, lack of behavioral initiation, decreased spontaneous speech, and constriction of emotional expression. Frequently, these symptoms are considered reflective of depression.

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CHAPTER 9 Behavior and Personality Disturbances

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Prevention and Management of Postoperative Neuropsychiatric Issues

eBOX 9.3

Preventive Management Education Inform patient and caregiver of: Potential behavioral side effects of dopaminergic treatment to enable early detection and management both before and after surgery. Possible occurrence of apathy and hypodopaminergic syndrome following dopaminergic drug reduction. Possible changes in social and familial equilibrium after motor improvement. Clarify patient’s expectations and awareness of potential DBS side effects. Assessment of Mood and Behavior Focus on past and present neuropsychiatric history, especially for hypomania, anxiety, and major depressive disorder. In case of severe depression with suicidal ideation, psychiatric management is mandatory and DBS surgery should be delayed. If hypodopaminergic syndrome is present, postoperative tapering of L-dopa, rather than dopaminergic agonists, is necessary, with careful postoperative follow-up to rule out severe depression. If hyperdopaminergic syndrome is present, slow and progressive reduction of dopaminergic treatment is necessary to avoid dopaminergic withdrawal syndrome. Cognitive Assessment Careful assessment for cognitive decline (in case of significant deficit DBS should be avoided). Postoperative Management Hyperdopaminergic Behaviors Hypomania/Mania Reduce dopaminergic drug, especially dopamine agonists. Reduce stimulation amplitude and/or switch to a more dorsal contact. Stop antidepressant treatment.

If mania or hypomania occurs, consider hospital admission and psychiatric advice, and introduce quetiapine or clozapine. Psychiatric follow-up. Impulse Control Disorders, Punding, Dopamine Dysregulation Syndrome Progressive withdrawal of dopamine agonists (if motor worsening or nonmotor off, increase fractionated L-dopa and/or stimulation). If occurs abruptly after adjustment of stimulation parameters, consider returning to previous parameters. Consider clozapine or quetiapine. Multidisciplinary approach, involving neuropsychologist, psychiatrist, and cognitive behavioral therapist. Psychosis Reduce dopaminergic treatment (dopamine agonists first), stimulation, or both. Introduce clozapine or quetiapine. If cognitive decline occurs, add cholinesterase inhibitors. Hypodopaminergic Behaviors Apathy Increase dopaminergic drugs (dopamine agonists as first line). Try methylphenidate. Depression Careful screening for suicidal ideation. Increase dopaminergic treatment (dopamine agonists as first line). Antidepressant treatment. Psychiatric follow-up. Multidisciplinary approach, involving neuropsychologist. Anxiety Increase dopaminergic treatment (dopamine agonists as first line). Add on antidepressant treatment.

DBS, Deep brain stimulation. Modified with permission from Castrioto, A., Lhommée, E., Moro, E., et al., 2014. Mood and behavioural effects of subthalamic stimulation in Parkinson’s disease. Lancet Neurol. 13, 287–305.

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CHAPTER 9 Behavior and Personality Disturbances

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Percentage of Patients With Huntington Disease Endorsing Psychiatric Symptoms by Total Functional Capacity (TFC) Stage

TABLE 9.9 Symptom

Stage 1 (n = 432)

Stage 2 (n = 660)

Stage 3 (n = 520)

Stage 4 (n = 221)

Stage 5 (n = 84)

Depression Suicide Aggression Obsessions Delusions Hallucinations

57.5% 6.0% 39.5% 13.3% 2.4% 2.3%

62.9% 9.7% 47.7% 16.9% 3.5% 4.2%

59.3% 10.3% 51.8% 25.5% 6.1% 6.3%

52.1% 9.9% 54.1% 28.9% 9.9% 11.2%

42.2% 5.5% 54.4% 13.3% 2.2% 3.3%

Data provided by the Huntington Study Group.

and anxiety symptoms are common in TS. The relationship between severity of depression and presence/prevalence of tics is unclear. The comorbid presence of obsessive-compulsive symptoms is associated with increased risk for depressive symptoms (Zinner and Coffey, 2009).

Ratings by Nursing Home Staff of Problematic Behaviors in Patients With Huntington Disease TABLE 9.10

Behavior Problem

Percentage

Rank

Agitation Irritability Disinhibition Depression Anxiety Appetite Delusions Sleep disorders Apathy Euphoria

76 72 59 51 50 54 43 50 32 40

2.0 2.9 3.3 4.2 4.4 5.1 5.5 5.5 6.8 6.9

Multiple Sclerosis The assessment of behavioral symptoms in MS is complicated because one of the hallmark symptoms of MS is variability of symptoms across time. In addition, there is significant heterogeneity within patients with MS. Finally, a disconnection between the experience of emotion and the expression of emotion has historically been observed in individuals with MS.

Depression

From Paulsen and Hamilton, unpublished data.

Although difficult to distinguish, apathy is defined as diminished motivation not attributable to cognitive impairment, emotional distress, or decreased level of consciousness. Depression involves considerable emotional distress evidenced by tearfulness, sadness, anxiety, agitation, insomnia, anorexia, feelings of worthlessness and hopelessness, and recurrent thoughts of death. Both apathy (59%) and depression (70%) are common in HD. However, 53% of individuals experienced only one of these symptoms rather than the two combined. Furthermore, depression and apathy were not correlated. Recent reports suggest that apathy is one of the most common symptoms reported in HD (van Duijn et al., 2014) and severity of apathy may progress with disease duration.

Tourette Syndrome TS is associated with disinhibition of frontosubcortical circuitry; as a result, it is not surprising that increased rates of psychiatric and behavioral symptoms are observed. These behavioral difficulties are more strongly associated with psychosocial functioning than the presence of tics (Zinner and Coffey, 2009). Rates of psychiatric disorders vary widely; significantly higher rates of psychiatric disorders are reported when samples are drawn from psychiatric clinics than from movement disorder clinics. Given the correlation between psychiatric symptoms and changes in psychosocial functioning, treatments in TS that consider psychiatric and behavioral symptoms are encouraged (Shprecher et al., 2014). Approximately 20%–40% of individuals with TS meet criteria for OCD, whereas up to 90% of individuals in a clinic-referred sample may exhibit subthreshold levels of obsessive-compulsive symptoms (Zinner and Coffey, 2009). The frequency and severity of tics often decrease as individuals enter adulthood, but the comorbid obsessive-compulsive symptoms are more likely to continue into adulthood and are associated with difficulties in psychosocial functioning (Cheung et al., 2007). Mood

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Depression is the most common behavioral symptom in MS, occurring at rates of 37%–54%. Patients with MS may report symptoms of depression even with outward signs of euphoria. Although depression is frequently associated with reduced quality of life, the correlation between depressive symptoms and disability in MS is equivocal. Depression in MS is not consistently associated with increased rates of stressful events, disease duration, sex, age, or socioeconomic status. Among the subtypes of MS, depression may be most common in those with relapsing-remitting MS (Beiske et al., 2008). Fatigue is a strong predictor of depression among individuals with MS (Beiske et al., 2008). Depression in MS is largely chronic and may require intervention at various times throughout the course of disease (Koch et al., 2014). Increased rates of suicidal ideation, suicide attempts, and completed suicides have been observed in individuals with MS. Suicide rates in MS are between two and seven times higher than in the general population (Bronnum-Hansen et al., 2005). Risk factors for suicidal ideation in MS include social isolation, current depression, and lifetime diagnosis of alcohol abuse disorder. Although suicide attempts occur throughout the progression of the disease, some have suggested that increased risk may be particularly high in the year following diagnosis (Bronnum-Hansen et al., 2005). Biological factors likely contribute to depressive symptoms in MS. It has been hypothesized that the inflammatory process associated with MS may directly lead to depressive symptoms. Similarly, demyelination lesions in MS may directly contribute to the etiology of depression. However, imaging studies in MS have failed to show clear neuropathological correlates of depression. Disruptions have been observed in right parietal, right temporal, and right frontal areas (Zorzon et al., 2001) as well as the limbic cortex, implying disruption of frontosubcortical circuitry. It is likely that depression in MS results from a combination of psychosocial and biological factors. Although controversial, depression may be a side effect for some individuals treated with interferon beta-1b (IFN-β-1b) (Feinstein, 2000). Patients with severe depression should be closely monitored while receiving IFN-β-1b. The relationship between depression and

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TABLE 9.11 Neuroanatomical Structures and Pseudobulbar Affect

BOX 9.2 Strategies to Minimize Anxiety in Patients With Multiple Sclerosis Respect adaptive denial as a useful coping mechanism. Provide referrals to the National Multiple Sclerosis Society (1-800-Fight-MS) early in disease. Help patients to live “one day at a time,” and restrict predictions regarding the future. Help patients to manage stress with relaxation techniques. Involve occupational therapists for energy conservation techniques. Focus on the patient’s abilities, not disabilities. Consider patient’s educational and financial background when giving explanations and referrals. Realize that patients have access to the Internet, self-help groups, and medical journals and may ask “difficult” questions. Expect grief reactions to losses. Deal with losses one at a time. Attend to the mental health needs of patients’ families and caregivers. Respect the patient’s symptoms as real. Avoid overmedicating. Focus supportive psychotherapy on concrete, reality-based cognitive and educational issues related to multiple sclerosis. Provide targeted pharmacotherapy. Refer appropriate patients for cognitive remediation training. Ask about sexual problems, as well as bowel and bladder dysfunction. Keep an open dialogue with the patient about suicidal thoughts.

Although common, anxiety is often overlooked because anxiety symptoms may be viewed as a result of poor coping skills. Some strategies to minimize anxiety in individuals with MS are described in Box 9.2. Comorbid anxiety and depression are associated with greater somatic complaints, social difficulties, and suicidal ideation than either anxiety or depression alone. Predictors of anxiety in individuals with MS include fatigue, pain, and younger age of onset (Beiske et al., 2008).

Euphoria Increased rates of cheerfulness, optimism, and denial of disability may occur in MS. Early studies suggested that more than 70% of individuals with MS experienced periods of euphoria. However, more recent studies suggest that prevalence rates of euphoria are between 10% and 25%. Euphoria frequently co-occurs with disinhibition, impulsivity,

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A major component of the limbic lobe, with motor efferents to the brainstem structures involved in emotional expression A white matter structure consisting of pathways descending from the brain to the brainstem and spinal cord. Some of these pathways are related to the brainstem nuclei, some to the cerebellum (via basis pontis), and some reach the spinal cord A node in the pathways to the cortex originated from the brainstem, cerebellum, and basal ganglia A crucial node in the indirect pathways that carry signals from the striatum to the frontal lobe via the thalamus Relay center for pathways entering the cerebellum Receives inputs from many parts of the nervous system and sends its signals to the spinal cord, brainstem, and cerebral cortex (mostly frontal lobe and some to somatomotor parietal cortical areas) through the thalamus

Basis pontis Cerebellar white and gray matter

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Subthalamic nucleus

IFN-β-1a and interferon alpha (IFN-α) is equivocal, because conflicting results have been reported. In contrast, glatiramer acetate has not been associated with increased depressive symptoms (Feinstein, 2000). Because of the potential relationship between depression and treatment for MS, as well as the high rates of depression in MS, it is critical that physicians take care to thoroughly assess a patient’s current and past history of depression. This may be particularly important prior to beginning IFN interventions, as patients with histories of depression may be more likely to experience symptoms of depression following IFN treatment. Few randomly assigned clinical trials have been conducted for the treatment of depression in MS. Several open-label trials of SSRIs have been conducted, which suggest that SSRIs may be effective in the treatment of depression in MS (Siegert and Abernethy, 2005). In addition, psychotherapy, particularly that focusing on coping skills, is efficacious in the reduction of depressive symptoms.

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Modified with permission from Riether, A.M., 1999. Anxiety in patients with multiple sclerosis. Semin, Neuropsychiatry 4, 103–113.

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Modified with permission from Parvizi, J., Coburn, K.L., Shillcutt, S.D., et al., 2009. Neuroanatomy of pathological laughing and crying: a report of the American Neuropsychiatric Association Committee on Research. J. Neuropsychiatry Clin. Neurosci. 21, 75–87. Copyright 2009, American Psychiatric Association.

and emotional lability. Individuals with euphoria are more likely to have cerebral involvement, enlarged ventricles, poorer cognitive and neurological function, and increased social disability.

Pseudobulbar Affect Pseudobulbar affect (PBA) occurs when there is disparity between an individual’s emotional experience and his or her emotional expression; affected individuals are unable to control laughter or crying. Approximately 10% of individuals with MS exhibit periods of PBA (Parvizi et al., 2009). PBA is more common in MS patients who have entered the chronic-progressive disease course, have high levels of disability, and have cognitive dysfunction. The neuropathological substrate for PBA is believed to involve several aspects of the frontosubcortical circuits as well as the cerebellum (Parvizi et al., 2009). Table 9.11 gives more detailed information. Dextromethorphan/quinidine may be effective in treating such symptoms (Panitch et al., 2006; Pioro et al., 2010) and is FDA approved. In addition, tricyclic and SSRI antidepressant medications may be helpful in reducing PBA symptoms (Parvizi et al., 2009).

Amyotrophic Lateral Sclerosis Historically, amyotrophic lateral sclerosis (ALS) has been largely viewed as a pure motor neuron disease. Increased awareness of cognitive and behavioral changes in individuals with ALS has burgeoned over the past few years. Mutations in the gene C9orf72, which causes TDP-43 positive inclusions, have been implicated in a large number of cases of both conditions. In fact, the two can coexist in the same family or in the same individual with a single mutation (Bennion Callister and Pickering-Brown, 2014; Seelaar et al., 2007). Patients with ALS and the C9orf72 repeat expansion seem to present a recognizable phenotype characterized by earlier disease onset, the presence of cognitive and behavioral impairment, specific neuroimaging changes, a family

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CHAPTER 9 Behavior and Personality Disturbances history of autosomal dominant neurodegeneration, and reduced survival (Byrne et al., 2012). It is currently well understood that behavioral and cognitive disturbances occur in a substantial proportion of patients, a subgroup of whom present with frontotemporal dementia. Deficits are characterized by executive and working memory impairments extending to changes in language and social cognition. Behavior and social cognition deficits closely resemble those reported in the behavioral variant of frontotemporal dementia, and consensus criteria for diagnosis of cognitive and behavioral syndromes related to ALS are reprinted in Table 9.12.

Depression Depressive symptoms occur in 40%–50% of individuals with ALS (Kubler et al., 2005), although most individuals exhibit subsyndromal depression. Depression in ALS has historically been thought to be associated with increased physical impairment, although these results are increasingly overturned (Kubler et al., 2005; Lule et al., 2008). Individuals with low psychological well-being were at increased risk of mortality (Fig. 9.7). Mortality risk was more strongly associated with psychological distress than age and was similar to the association of risk associated with severity of illness. Depression is correlated with duration of illness; however, depression is not associated with ventilator use or tube feeding (Kubler et al., 2005). Quality of life is highly impacted by presence of depressive symptoms, more so than the presence of physical limitations, indicating that physicians should be aware of available treatments for depressive symptoms (Lule et al., 2008).

Pseudobulbar Affect Up to 50% of individuals with ALS, most often those with pseudobulbar syndrome, report PBA (Parvizi et al., 2009). Individuals with PBA may be more likely to exhibit behavioral changes similar to those observed among individuals with FTD (Gibbons et al., 2008). Little research has assessed treatment of PBA. Potential pharmacological interventions include use of tricyclic and SSRI antidepressant medications (Parvizi et al., 2009). Dextromethorphan/quinidine may also be an effective treatment for PBA (Parvizi et al., 2009) and is currently FDA approved. Reduction in PBA symptoms was associated with improved quality of life and quality of relationships.

Personality Change With recognition of the correlation between ALS and FTD, increased interest has been placed on assessing for potential behavioral changes in ALS. Minimal research has fully explored this question. Gibbons and colleagues (2008) assessed behavioral changes among a small group of individuals with ALS by using a structured interview of close family members of those with ALS. In this small study, 14 of 16 individuals with ALS exhibited behavioral changes. Of those with behavioral changes, 69% exhibited reduced concern for others, 63% exhibited increased irritability, and 38% exhibited increased apathy. A questionnaire to assess behavioral change has been developed specifically for ALS to minimize exaggerations of behavior related to motor dysfunction (Raaphorst et al., 2012). Additional screening instruments for the detection and tracking of these syndromes in ALS are provided in Table 9.13.

Epilepsy Behavioral and personality disturbances occur in up to 50% of individuals with epilepsy. Identification and treatment of these behavioral disturbances remain inadequate, with less than half of individuals with epilepsy and major depressive disorder (MDD) being treated for depression. Presence of a psychiatric disorder is an independent predictor of quality of life in individuals with epilepsy (Kanner et al.,

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2010). In epilepsy, psychiatric disturbances are classified based on their chronological relationship to seizures. Ictal disturbances occur during the seizure. Periictal disturbances occur immediately before (preictal) or after (postictal) a seizure. Finally, interictal disturbances are those that occur independently of seizure states (Table 9.14). To facilitate patient understanding and provide accurate treatment of psychiatric symptoms, it is important to recognize that behavioral and personality disturbances can occur during the ictal state. Individuals in the ictal period may experience episodes of anxiety, depression, psychosis, and aggression. In addition, some seizures can cause uncontrollable but mirthless laughter, so-called gelastic epilepsy, which is classically seen with hypothalamic hamartomas (Parvizi et al., 2011). However, because much of the research regarding psychiatric disturbances in epilepsy has focused on interictal behavioral and personality disturbances, these disturbances will be the focus of this section.

Depression Depression is the most common psychiatric disorder in epilepsy. Rates of depression vary as a function of the sample assessed (clinical samples report higher rates of depression than population samples) and the measures used to diagnose depression. Depression often goes undiagnosed in patients with epilepsy, because symptoms of depression may be viewed as a normal reaction to illness. However, accurate diagnosis of depression is critical because depression is associated with poorer quality of life, underemployment, and family dysfunction (Ettinger et al., 2004). Interestingly, presurgical depression is associated with poorer postsurgical seizure outcomes (Metternich et al., 2009). Attempted and completed suicides are common in epilepsy. The suicide rate in epilepsy is two or more times greater than in the general population (Stefanello et al., 2010). Rates of suicide are even higher in temporal lobe epilepsy. Risk factors for suicide include history of self-harm, family history of suicide, stressful life situations, poor morale, stigma, and psychiatric disorders. Individuals with comorbid anxiety and depression are at greater risk for suicidal ideation than individuals with only one syndrome (Stefanello et al., 2010). People with drug-resistant epilepsy have a particularly high rate of suicide, and efforts to better predict risk factors in this cohort are underway (Kwon and Park, 2019). The cause of depression in epilepsy is unclear. Psychosocial stressors, genetic disposition, and neuropathology may play contributing roles. Although psychosocial stressors have been suggested as important in the cause of depression in epilepsy, observed rates of depression in epilepsy are higher than those in other chronically ill patient populations, lending support to theories of biological causes. Perception of seizure control is an important psychosocial variable to consider because a lower perception of seizure control is associated with increased depressive symptoms. Although results are somewhat mixed, there appears to be no relationship between age of onset or duration of epilepsy and depression. Depression appears to be more common in individuals with focal epilepsy than in those with primarily generalized epilepsy. Lateralization of seizure foci may be related to depression, with left-sided foci being more commonly associated with depression. Pharmacological treatment of epilepsy may contribute to depression and psychiatric symptoms in general. Table 9.15 notes commonly used antiepileptic drugs (AEDs) and their psychotropic effects. Medications associated with sedation (e.g., barbiturates, benzodiazepines) may lead to depression, fatigue, and mental sluggishness. Although the phenomenology of depression in epilepsy may prove dissimilar from that in patients with general depression, similar treatments are efficacious in the treatment of depression. Supportive psychotherapy may prove beneficial, particularly after initial diagnosis as

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TABLE 9.12 Consensus Criteria (Strong et al., 2009) for Diagnosis of Cognitive and Behavioral Syndromes Related to Amyotrophic Lateral Sclerosis and Their Potential Limitations Features Listed by Strong et al. (2009)

Comments

A comprehensive list of potential confounds that Premorbid intellectual ability; bulbar dysfunction; motor might underlie or affect the presentation of cogweakness; neurological comorbidities; systemic disorders nitive impairment and behavioral change and that (e.g., diabetes, hypothyroidism); drug effects (e.g., substance should be considered on a case-by-case basis use, narcotic analgesics, psychotropics); psychiatric disorders (e.g., severe anxiety or depression, psychosis); respiratory dysfunction (measured by forced vital capacity, maximum inspiratory force, nocturnal oximetry or carbon dioxide readings); disrupted sleep; delirium; pain; fatigue; low motivation to undertake tests Psychiatric disorders; psychological reaction to diagnosis A comprehensive list of potential confounds that of amyotrophic lateral sclerosis; premorbid diagnosis of might underlie or affect the presentation of cogpersonality disorder; pseudobulbar affect/emotional lability/ nitive impairment and behavioral change and that pathological laughing and crying should be differentiated should be considered on a case-by-case basis from depression Full assessments should control adequately for Patient should have impaired scores (i.e., ≤5th percentile) motor dysfunction and speech difficulties or use of on standardized neuropsychological tests compared with assistive communication; examination of executive age-matched and education-matched norms, on two or more dysfunction only might underestimate prevalence of separate neuropsychological tests that are sensitive to execcognitive impairment; (Taylor et al., 2012) no data utive dysfunction; domains other than executive functions yet as to whether inclusion of measures of social should be assessed cognition or theory of mind would affect detection; should ensure that impairments cannot be better explained by the potential confounds Tests of social cognition or the theory of mind might Patient should meet two or more nonoverlapping supportive corroborate informants’ reports; questionnaires spediagnostic features from established criteria for behavcific to amyotrophic lateral sclerosis might improve ioral variant frontotemporal dementia (Neary et al., 1998; correct identification of behavioral change (most Rascovsky et al., 2007) (presence of only one feature might available tests do not take into account the physical lead to overdiagnosis); presence of two behavioral abnorand resulting functional restrictions imposed by the malities necessitates support obtained from two or more disease); should ensure that impairments cannot be sources selected from interview or observation of the patient, better explained by the potential confounds report from a carer, or structured interview or questionnaire; reports from family or friends are essential; need to clarify that changes in behavior should be new, disabling, and not better accounted for by physical limitations that result from the disease Three categories are commonly recognized—behavioral variant Criteria for frontotemporal lobar degeneration syndromes (of which behavioral variant frontotemfrontotemporal dementia (progressive behavioral change poral dementia, progressive nonfluent aphasia, and characterized by insidious onset, changed social behavior, semantic dementia are subtypes) were not originally impaired self-control of interpersonal behavior, emotional defined for amyotrophic lateral sclerosis; should blunting, and loss of insight); progressive nonfluent aphasia ensure that impairments cannot be better explained (progressively nonfluent speech accompanied by agrammaby the potential confounds tism, paraphasias, or anomia); and semantic dementia (fluent For behavioral variant frontotemporal dementia, speech but impaired comprehension of word meaning or diagnosis is mainly based on behavioral sympobject identity, or both) toms—thus the illness will not be diagnosed in patients without behavioral change but with primary executive dysfunction; diagnosis does not place main emphasis on evidence of executive dysfunction as measured with cognitive tests (although such evidences does contribute) Association with a dementia not typical of frontotemporal Alzheimer pathological changes might be noted in dementia (e.g., Alzheimer disease, vascular dementia, mixed patients presenting with behavioral variant frontodementias) temporal dementia (Snowden et al., 2011), so this possible classification should not be discounted in amyotrophic lateral sclerosis

Relevant background characteristics for assessment of cognitive impairment

Background characteristics to be taken into account in diagnosis of behavioral impairment

Amyotrophic lateral sclerosis–cognitive impairment

Amyotrophic lateral sclerosis–behavioral impairment

Amyotrophic lateral sclerosis–frontotemporal dementia

Amyotrophic lateral sclerosis–comorbid dementia

With permission from Goldstein, L.H., Abrahams, S., 2013. Changes in cognition and behaviour in amyotrophic lateral sclerosis: nature of impairment and implications for assessment. Lancet Neurol. 12, 368–380.

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All patients n = 257 No depression or executive dysfunction n = 91 10.3 years (Cl 8.6–12.1)

Depression without executive dysfunction n = 52 11.1 years (Cl 9.4–12.7)

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patients begin to adapt to their illness. Few clinical trials have assessed the efficacy of antidepressant medications in patients with epilepsy. Older antidepressants and the antidepressant bupropion have been associated with increased seizures and should be avoided. Prueter and Norra (2005) suggest that citalopram and sertraline be considered first-line antidepressant medications in epilepsy because of their limited interactions with antiepileptic medication.

Anxiety

Executive dysfunction without depression n = 67 5.8 years (Cl 3.9–7.8)

Depression-executive function syndrome (DES) n = 47 6.6 years (Cl 5.1–8.1)

Fig. 9.7 Poststroke survival by presence or absence of depression and executive dysfunction (endpoint, all causes of death). NOTE: determined by Kaplan-Meier Logistic-Rank Analysis. (Reprinted with permission from Melkas, S., Vataja R., Oksala, N.K., et al., 2010. Depression-executive dysfunction syndrome relates to poor poststroke survival. Am. J. Geriatr. Psychiatry 18, 1007–1016.)

Increased rates of anxiety disorders occur in patients with epilepsy. Between 19% and 50% of individuals with epilepsy meet criteria for one or more Diagnostic and Statistical Manual of Mental Disorders Fifth Editions (DSM-V) anxiety disorders (Beyenburg et al., 2005). Individuals with comorbid anxiety and depressive disorders report lower quality of life than individuals with either disorder alone (Kanner et al., 2010). Common anxiety disorders include agoraphobia, generalized anxiety disorder, and social phobia. Fear of having a seizure and anticipatory anxiety are quite common. Care must be taken to distinguish between panic attacks and fear occurring in the context of a seizure (“ictal fear”). Fear is the most common psychiatric symptom to manifest during a seizure. The relationship between AEDs and anxiety is complex. Some AEDs appear to exacerbate anxiety symptoms, whereas others are associated with reductions in anxiety symptoms. Antidepressant

TABLE 9.13 Screening Instruments for Cognitive Impairment and Behavioral Change in Amyotrophic Lateral Sclerosis Description

Strengths

Penn State screen exam Neurobehavioral cognitive status (Flaherty-Craig et al., 2006, 2009) examination, letter and category fluency, and the American National Adult Reading Test Screening assessment for cognitive Verbal fluency and frontal behavior impairment in amyotrophic lateral inventory sclerosis (Gordon et al., 2007) Amyotrophic Lateral Sclerosis Cog- Eight short cognitive tasks (execunitive Behaviour Screen (Woolley tive functions) and carer behavior et al., 2010) questionnaire Written verbal fluency (Abrahams Verbal fluency with motor control et al., 2000) condition producing verbal fluency index Frontal Assessment Battery (Dubois Brief six-item screen et al., 2000)

Weaknesses

Multidomain assessment; includes premor- Developed for other neurological disorders; not bid functions designed or modified for physical disability (Wicks et al., 2007); not formally validated

Brief; verbal fluency is particularly sensitive Only one cognitive subtest (fluency); not to cognitive impairment adapted for physical disability; not formally validated Brief; validated against neuropsychological Assesses executive functions only; no lanbattery in patients with amyotrophic guage or memory assessment lateral sclerosis Designed to accommodate motor slowing; Only one cognitive test; needs further validasensitive to frontal lobe dysfunction; tion and normative data validated with brain imaging Brief; sensitive in patients with severe Investigated in a small sample of patients; not cognitive impairment designed for patients with physical disability; assesses only one cognitive domain Amyotrophic lateral sclerosis–fron- Behavioral screen, informant based Developed for amyotrophic lateral sclero- Further validation data not yet available totemporal dementia questionsis; good construct and clinical validity naire (Raaphorst et al., 2012) Frontal Systems Behavior Scale Behavioral screen (patient and Determines change in behavior from before Not designed for amyotrophic lateral sclerosis; (Grace and Malloy, 2002; Grosscarer); three subscales (apathy, illness to after onset overlapping with physical symptoms particuman et al., 2007) disinhibition, executive dysfunclarly for apathy scale; potentially exaggertion) ates behavioral change Not designed for amyotrophic lateral sclerosis Frontal Behavior Inventory (Kertesz Carer interviewed about patients’ Sensitive to subtypes of frontotemporal dementia and amyotrophic lateral sclero- (items overlap with physical symptoms) et al., 1997) behavior and personality change; sis–frontotemporal dementia two subscales—negative behavior and disinhibition; modified version (Heidler-Gary and Hillis, 2007) is a self-complete measure* Neuropsychiatric Inventory (CumCarer-completed questionnaire with Used widely in other neurological groups; Not designed for amyotrophic lateral sclerosis mings et al., 1994) 12 neuropsychiatric domains sensitive to moderate and severe dementia (items overlap with physical symptoms)

*Frontal Behaviour Inventory—modified as described by Heidler-Gary and Hillis (2007). For a comprehensive list, including further recommendations on depression and pseudobulbar affect, see NINDS Common Data Elements. With permission from Goldstein, L.H., Abrahams, S., 2013, Changes in cognition and behaviour in amyotrophic lateral sclerosis: nature of impairment and implications for assessment. Lancet Neurol. 12, 368–380. @

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Common Neurological Problems 20 years, duration of illness greater than 10 years, history of complex partial seizures, and temporal lobe epilepsy are at increased risk of psychotic disturbances. Postictal and interictal psychosis are most commonly reported. Postictal psychosis most commonly develops after many years of epilepsy (Devinsky, 2003). Episodes of postictal psychosis are short in duration, lasting from a few hours to a few months. Postictal psychosis is more common with limbic lesions (Devinsky, 2003). In interictal psychosis, episodes of psychosis are not temporally tied to seizure onset and typically last for more than 6 months.

medication, particularly the SSRIs, is the most common pharmacological treatment for anxiety in epilepsy. See the review by Beyenburg and colleagues (2005) for a more detailed discussion of treatment of anxiety in epilepsy.

Psychosis The association between epilepsy and psychosis has been debated throughout the past century. Individuals with epilepsy onset before age

TABLE 9.14 Psychiatric Disturbances in Ictal, Postictal, and Interictal States Ictal

Postictal

The relationship between epilepsy and aggression remains controversial. Early research suggested that the prevalence of aggression in epilepsy ranged from 4.8% to 50.0%. Aggression occurring in the context of a seizure is quite rare (Devinsky, 2003). Rates of aggression are believed to be higher in individuals with temporal lobe epilepsy. Results vary owing to the definition of aggression used and the method of group selection. Interictal aggression may be described as episodic dyscontrol or, as in the DSM nosology, IED, which is characterized by periods of largely unprovoked anger, rage, severe aggression, and violent behavior. Hippocampal sclerosis is less common in individuals with epilepsy and aggression (Tebartz van Elst et al., 2000). A subgroup of individuals with epilepsy and aggression has significant amygdala atrophy (Tebartz van Elst, 2002).

Interictal

Anxiety Agitation Intense feelings of horror Panic attacks Depressed mood Depression Tearfulness

Paranoia Hallucinations Illusions Forced thoughts resembling obsessions Obsessions Aggression/violence

Aggression

Panic disorder Generalized anxiety disorder Phobias Major depressive disorder Dysthymic disorder Atypical depressive syndromes Medication-induced mood changes Adjustment disorder Psychotic syndromes

Paranoia Hallucinations

Stroke

Obsessive-compulsive disorder

Aggression/ violence Confusion

Confusion Sexual excitement Laughter Déjà vu and other memory experiences

Neuropsychiatric disorders after stroke are common and distressing to patients and their families but often go undertreated. The most common neuropsychiatric outcomes of stroke are depression, anxiety, fatigue, and apathy, which each occur in at least 30% of patients and have substantial overlap. Emotional lability, personality changes, psychosis, and mania are less common. Neuropsychiatric complications of stroke are challenging to manage and require more research (Hackett et al., 2014).

Aggression/violence

Mania

Depression

Conversion disorder Medication-induced conditions

Within the first year following a stroke, 30%–40% of patients experience depression, with most developing depression within the first month (Ballard and O’Brien, 2002). Interestingly, rates appear to be similar for individuals in early, middle, and late stages following stroke.

Reprinted with permission from Marsh, L., Rao, V., 2002. Psychiatric complications in patients with epilepsy: a review. Epilepsy Res. 49, 11–33.

TABLE 9.15

Psychotropic Effects of Antiepileptic Drugs

Drug

Positive Effects

Negative Effects

Complications

Barbiturates Benzodiazepines Ethosuximide Phenytoin Carbamazepine Valproate Vigabatrin

— Anxiolytic, sedative — — Mood stabilizing/impulse control Mood stabilizing, antimanic —

ADHD in children Disinhibition Alternative psychoses Toxic schizophreniform psychoses, encephalopathy — Acute and chronic encephalopathy ADHD, encephalopathy, alternative psychoses

Lamotrigine Felbamate Gabapentin Tiagabine Topiramate Levetiracetam

Mood stabilizing, antidepressive Stimulating? Anxiolytic, antidepressive? — Mood stabilizing? —

Aggression, depression, withdrawal syndromes Withdrawal syndromes Insomnia — Rarely, mania and depression — Aggression, depression, psychosis, withdrawal syndromes Insomnia Agitation Rarely aggression in children Depression Depression —

Rarely psychoses Psychoses possible — Nonconvulsive status epilepticus Psychoses —

ADHD, Attention-deficit/hyperactivity disorder; ?, Minimal data; —, not applicable. Reprinted with permission from Schmitz, B., 2002. Effects of antiepileptic drugs on behavior, in: Trimble, M., Schmitz, B. (Eds.), The Neuropsychiatry of Epilepsy. Cambridge University Press, Cambridge, UK.

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CHAPTER 9 Behavior and Personality Disturbances Depression after a stroke is associated with age, time since stroke, cognitive impairment, and social support. Significantly higher rates (five to six times more likely) of poststroke depression have been reported among individuals with a premorbid diagnosis of depression (Ried et al., 2010). Depression is associated with longer hospital stays, suggesting that it affects rehabilitation efforts. Depression is associated with poorer recovery of activities of daily living and increased morbidity. Depression and executive dysfunction commonly co-occur following a stroke. The presence of executive dysfunction with or without co-occurring depressive symptoms may be the strongest predictor of morbidity following stroke (Melkas et al., 2010) (see Fig. 9.7). Studies assessing the relationship between disability and depression in stroke patients have been equivocal. Depression is associated with poorer quality of life in individuals who have had a stroke, even when neurological symptoms and disability are held constant. The relationship between depression and lesion location has been the focus of significant research and controversy. Early research by Robinson and Price showed that left anterior lesions were associated with increased rates and severity of depression. Lesions nearer the left frontal pole or left caudate nucleus were associated with increased rates of depression. Some researchers have replicated these findings, but others have failed to do so. More recent review articles have not supported a relationship between lesion location and depression in poststroke patients (Bhogal et al., 2004). Of note, there is significant heterogeneity in previous studies, particularly between different sample sources. If more homogeneous groups of patients are considered, some relationships emerge. Depression is associated with left-sided lesions in studies using hospital samples, whereas depression is associated with right-sided lesions in community samples (Bhogal et al., 2004). Time since stroke is an additional important variable to consider. Poststroke depression is associated with left-sided lesions in individuals in the first month following stroke (Bhogal et al., 2004). However, poststroke depression is associated with right-sided lesions in individuals more than 6 months after the stroke (Bhogal et al., 2004). Other differences in previous research, such as method of depression diagnosis, may contribute to the mixed results. Few studies have assessed the effectiveness of various treatments for depression in these patients. A recent review suggests that there is no clear evidence that standard antidepressant medications are effective in the treatment of poststroke depression (Hackett et al., 2005). Although such interventions may not lead to effective cessation of depressive disorders, they may result in overall reductions in depressive severity. One study suggests that nortriptyline was more effective in the treatment of depression than either placebo or fluoxetine (Robinson et al., 2000). In this study, response to treatment with nortriptyline was associated with improvement in cognitive and functional abilities. This improvement in cognition and functional abilities following reduction in depressive symptoms has not always been replicated (Hackett et al., 2005).

Pseudobulbar Affect A portion of individuals experience PBA after a stroke. Between 11% and 35% of individuals experience emotional incontinence after stroke (Parvizi et al., 2009). Emotional incontinence is associated with lesions of the brainstem and cerebellar region (see Parvizi et al., 2009 for a review). Dextromethorphan with quinidine is currently FDA approved for PBA. Preliminary evidence suggests that tricyclic and SSRI antidepressants may be helpful in alleviating symptoms of PBA (Parvizi et al., 2009).

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TABLE 9.16 Lifetime Prevalence of Major Psychiatric Disorders by Head Injury Status From the New Haven Epidemiologic Catchment Area Study (n = 5034) Head Injury (%) No Head Injury (%) Major depression (n = 242) Dysthymia (n = 172) Bipolar disorder (n = 45) Panic disorder (n = 60) Obsessive-compulsive disorder (n = 102) Phobic disorder (n = 361) Alcohol abuse/dependence (n = 412) Drug abuse/dependence (n = 175) Schizophrenia (n = 73)

11.1 5.5 1.6 3.2 4.7

5.2 2.9 1.1 1.3 2.3

11.2 24.5

7.4 10.1

10.9

5.2

3.4

1.9

Note: Adjusted for age, sex, marital status, socioeconomic status, alcohol abuse, and quality of life. Reprinted with permission from Silver, J.M., Kramer, R., Greenwald, S., et al., 2001. The association between head injuries and psychiatric disorders: findings from the New Haven NIMH epidemiologic catchment area study. Brain Inj. 15, 935–945.

Aggression Reports have suggested that individuals have difficulty controlling aggression and anger following a stroke. Inability to control anger or aggression was associated with increased motor dysfunction and dysarthria. Aggression following stroke is associated with increased rates of MDD and generalized anxiety disorder. There is some evidence that lesions in the area supplied by the subcortical middle cerebral artery are associated with inability to control anger. Poststroke irritability and aggression are associated with lesions nearer to the frontal pole. Fluoxetine has been shown to successfully reduce levels of poststroke anger (Choi-Kwon et al., 2006). Similarly, reductions in irritability and aggression have been associated with reductions in depression following pharmacological intervention (Chan et al., 2006).

Psychosis Psychosis appears to be a rare sequela of stroke but has been reported to happen in the setting of large strokes in the right hemisphere. Preexisting atrophy (Rabins et al., 1991), preexisting untreated psychiatric disorders, and right inferior frontal gyrus involvement appear to be risk factors (Devine et al., 2014) for poststroke psychosis.

Traumatic Brain Injury TBI is a significant public health concern, affecting approximately 1.7 million individuals annually, with 275,000 individuals hospitalized each year in the United States. Public interest in TBI has increased secondary to recent military conflicts resulting in frequent blast injuries, as well as growing recognition of sports-related head injury. Significant behavioral and psychiatric disturbances are common following TBI, are typically chronic and a major cause of disability, and remain one of the most consistent risk factors for dementia in later life (Table 9.16) (Kim et al., 2007; Mortimer et al., 1991). Behavioral or mood disturbances are associated with decreased quality of life, increased caregiver burden, and more challenges to the treating physician and can significantly affect daily functioning, including management of close relationships and employment. Psychiatric diagnoses following TBI

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Dorsolateral prefrontal cortex executiv

ev t

Orbitofrontal cortex

A

B

Temporal polar cortex ev

Ventral brainstem

Entorhinalhippocampal complex e

Amygdala

Cerebellum

Fig. 9.8 (A) Brain regions vulnerable to damage in a typical traumatic brain injury (TBI); (B) Relationship of vulnerable brain regions to common neurobehavioral sequelae associated with TBI. (A, Adapted from Bigler, E., 2005. Structural imaging. In: Silver, J., McAllister, T., Yudofsky, S. (Eds.), Textbook of Traumatic Brain Injury. American Psychiatric Press, Washington, DC, p. 87. Copyright © American Psychiatric Press, 2005. B, Adapted from Arciniegas, D.B., Beresford, T.P., 2001. Neuropsychiatry: An Introductory Approach. Cambridge University Press, Cambridge, UK, p. 58. Copyright © Cambridge University Press, 2001.)

are more common in individuals with a history of psychiatric illness, poor social functioning, alcoholism, arteriosclerosis, lower MMSE score, and fewer years of education. Many behavioral changes such as increased disinhibition are associated with dysfunction within the frontal cortex. Fig. 9.8 (McAllister, 2011) depicts brain regions vulnerable to TBI and the associated relationships to neurobehavioral sequelae.

family members. Overreporting may be associated with depressive symptoms or litigation. Although symptoms of TBI frequently lead to difficulties in independent living and in the workplace, accurate assessment of these difficulties serves to mitigate this relationship. Thus it is possible that improved levels of awareness may lead to reductions in disability.

Anosognosia

Depression following TBI is common. Diagnosis of depression in TBI is complicated because symptoms of depression (e.g., fatigue, concentration difficulties, sleep disturbances) are common following TBI. For further discussion regarding the diagnosis of depression in TBI, see Seel et al. (2010). MDD occurs in up to 60% of individuals who have suffered TBI (Kim et al., 2007). Rates of depression in TBI vary as a function of severity of TBI assessed, method of depression diagnosis, and sample source. The best predictor of depression after TBI is the presence of premorbid depression; however, some have failed to replicate this finding. Other factors associated with post-TBI depression

Although TBI is often associated with changes in motor, cognitive, and behavioral functioning, individuals with TBI frequently do not accurately assess these changes. Impairments in awareness have been associated with functional outcomes. Although it is most commonly reported that individuals with TBI underreport their difficulties, a subgroup of individuals appears to overreport their difficulties. It has been reported that individuals with mild to moderate TBI report greater impairments than their family members do of them, whereas those with more severe TBI report fewer impairments than their

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TABLE 9.17 Core Features

Depression

Apathy

Anxiety

Dysregulation

Mood (Intensity, scope)

Flat, unexcited (constant, global) Lack of initiative, behavior

Worried, distressed (frequent, situational) Restless, “keyed up”

Angry, tense (frequent, global)

Activity level

Sad, irritable, frustrated (constant, global) Low activity

Attitude Awareness Cognitions Physiological Coping style

Loss of interest, pleasure Overestimates problems Rumination on loss, failures Underaroused or hyperaroused Avoidance, social withdrawal

Lack of concern Does not notice problems Unresponsive to events Underaroused Compliant, dependent

Overconcern Overestimates problems Rumination on harm, danger Hyperaroused Avoidance, checking behaviors

Impulsive, physically aggressive, argumentative Argumentative Underestimates problems Rumination on tension, arousal Underaroused or agitated Uncontrolled outbursts

Modified from Seel, R.T., Macciocchi, S., Kreutzer, J.S., 2010. Clinical considerations for the diagnosis of major depression after moderate to severe TBI. J. Head Trauma Rehabil. 25, 99–112.

include poor coping styles, social isolation, and increased stress (Kim et al., 2007). Depression in TBI is associated with increased suicidality, increased cognitive problems, greater disability, and aggression. See Table 9.17 for additional information regarding differentiating features associated with depression in TBI. Suicidal ideation (65%) and attempts (8.1%) are common following TBI (Silver et al., 2001). In contrast to sex differences reported in the general population, women with TBI are more likely to commit suicide than men with TBI. Furthermore, suicide was more common in individuals with more severe injury and those younger than 21 years or older than 60 years at the time of injury. No large class I studies of use of antidepressant medications, particularly SSRIs, in TBI have been completed, but small studies provide preliminary support for their use to treat depressive symptoms following TBI. Care must be taken in certain situations, because some antidepressants (i.e., bupropion) are associated with increased risk of seizures. Close monitoring following the beginning of a trial of antidepressant medication is encouraged; in some settings, such medications can increase agitation or anxiety in individuals with TBI. Please see Alderfer and colleagues (2005) for more details regarding recommendations for treatment of depression following TBI.

Anxiety Less research has assessed the prevalence of anxiety disorders in TBI; however, studies suggest that 11%–70% of individuals meet criteria for an anxiety disorder. A meta-analysis suggested that the mean prevalence of anxiety disorders following TBI is 29%. Panic disorder occurs in 3.2%–9.0% of individuals with a TBI (Silver et al., 2001).

Apathy Symptoms of apathy are reported in 10%–60% of individuals with a TBI. Among individuals with TBI referred to a behavioral management program, lack of initiation was among the most commonly reported problems, occurring in approximately 60% of the sample (Kelly et al., 2008). Apathy in TBI is often associated with depressive symptoms, although a significant number of individuals (28%) report experiencing apathy but not depression. Lesions affecting the right hemisphere and subcortical regions are more strongly associated with apathy than lesions affecting the left hemisphere.

Personality Change Personality change following TBI is common secondary to frequent injury to the frontal lobe and disruption of the frontosubcortical circuitry. Common changes include increased irritability, aggression, disinhibition, and inappropriate behavior. Although these difficulties can

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be among the most disabling for individuals with TBI, research in these areas is limited, and no uniform, agreed-upon diagnostic criteria for these behavioral changes exist. Aggression within 6 months of TBI has been reported in up to 60% of individuals with TBI (Baguley et al., 2006). Among individuals referred to a TBI behavior management service, verbal aggression and inappropriate social behavior were among the most commonly reported behavioral difficulties and occurred in more than 80% of individuals (Kelly et al., 2008). Aggression following TBI is associated with depression, poorer psychosocial functioning, and greater disability (Rao et al., 2009). A number of pharmacological interventions have been used to reduce and remediate behavioral changes following brain injury. See Nicholl and LaFrance (2009) for a review. One class of medication used in these settings is AEDs, currently routinely used to treat aggression, disinhibition, and mania following TBI. Again, few large-scale studies have assessed the effectiveness of AEDs in the treatment of behavioral change following TBI. Historically, neuroleptic drugs were used in high doses to treat behavioral dyscontrol in individuals with cognitive impairment. More recently, there has been increased interest in the use of atypical neuroleptics to treat both psychosis and behavioral changes following TBI. In addition to pharmacological interventions, behavioral and environmental interventions have been shown to be effective at remediating behavioral dyscontrol following TBI. The discussion of behavioral and environmental techniques aimed at decreasing behavioral dyscontrol, including aggression and irritability, is beyond the scope of this chapter (see Sohlberg and Mateer, 2001, for more information). Providers may find referrals for such interventions within rehabilitation programs. Briefly, interventions may seek to reduce stimulation in the environment, increase structure and predictability, reinforce good behavior with limited response to undesired behavior, and use structured problem-solving strategies.

Nonpharmacological Management of Behavior and Personality Change Although there have been increasing improvements to pharmacological strategies used to treat behavior and personality change in those with neurological illness and injury, often some degree of these symptoms persists following pharmacological intervention. In addition, side effects of pharmacological interventions may make pharmacological interventions nontenable. In these situations, nonpharmacological interventions can be of benefit. Consideration of referral to geriatric psychiatry, neuropsychology, psychology, or other specialized providers is encouraged.

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Nonpharmacological Intervention for Behavior and Personality Change TABLE 9.18

Modification of Patient Variables Psychotherapy for individuals with less severe cognitive impairment Reinforce desired behaviors Distraction Provide with two appropriate choices (i.e., walk with walker or my arm) Acknowledge emotions even if rationale for emotions is faulty/unclear Assess for unmet or acute needs (i.e., pain, urinary tract infection (UTI), constipation) Modification of Caregiver Variables Psychoeducation Psychotherapy for caregiver Support groups Working to change their expectations of patient Respite Modification of Environmental Variables Limit access to safety concerns (i.e., car keys, guns) Increase supervision in the home setting Reduce degree of stimulation (i.e., noise, number of people, number of requests) Bed or door alarms UTI, Urinary tract infection.

The complete reference list is available online at https://expertconsult. inkling.com/.

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10 Depression and Psychosis in Neurological Practice David L. Perez, Evan D. Murray, Brent P. Forester, Bruce H. Price

OUTLINE Principles of Differential Diagnosis, 97 Principles of Neuropsychiatric Evaluation, 98 Cognitive-Affective-Behavioral Brain–Behavior Relationships, 99 Cortical Networks, 99 Biology of Psychosis, 102 Biology of Depression, 103 Clinical Symptoms and Signs Suggesting Neurological Disease, 104 Psychiatric Manifestations of Neurological Disease, 104 Stroke and Cerebral Vascular Disease, 104 Infectious, 106 Metabolic and Toxic, 107

Neoplastic, 110 Degenerative, 110 Traumatic Brain Injury, 114 Depression-Related Cognitive Impairment, 115 Delirium, 115 Catatonia, 115 Treatment Modalities, 116 Electroconvulsive Therapy, 117 Vagus Nerve Stimulation, 118 Repetitive Transcranial Magnetic Stimulation, 118 Psychiatric Neurosurgery or Psychosurgery, 118 Treatment Principles, 119

The disciplines of behavioral neurology, neuropsychiatry, and geriatric psychiatry are undergoing a scientific renaissance on a global scale (Perez et al., 2018; Price et al., 2000). The distinctions between traditional neurological and idiopathic psychiatric conditions are eroding, and the time is ripe to deconstruct the implicit Cartesian dualism that divides the clinical neurosciences—neurology, psychiatry, and neurosurgery. Brain–behavior relationships are bidirectional and should be considered within social and environmental contexts. Patients with neurological disorders presenting with prominent mood, perceptual, or thought disturbances, the focus of this chapter, exemplify the need to integrate neurological and psychiatric perspectives to assess and manage neuropsychiatrically complex patient populations in a comprehensive manner. The most widely recognized nomenclature used for discussion of mental disorders derives from the classification system developed for the Diagnostic and Statistical Manual of Mental Disorders (DSM). The American Psychiatric Association introduced the DSM in 1952 to facilitate psychiatric diagnosis through improved standardization of nomenclature. There have been consecutive revisions of this highly useful and relied-upon document since its inception, with the last revision being in 2013. Discussion about the potential secondary causes of depression and psychosis requires a familiarity with the most salient features of the primary (idiopathic) psychiatric conditions. A brief outline of selected conditions is included in eBoxes 10.1 and 10.2, along with other content in this chapter marked “online only.”

obsessive compulsive behaviors, and anxiety all can occur as a result of neurological disease and can be virtually indistinguishable from the idiopathic forms (Rickards, 2005; Robinson and Travella, 1996). Neurological conditions should be considered in the differential diagnosis of any disorder with psychiatric symptoms. Neuropsychiatric abnormalities can be associated with altered functioning in anatomical regions. Any disease, toxin, drug, or process that affects a particular region can be expected to show changes in behavior mediated by the distributed network encompassing that region. The limbic system and the frontosubcortical circuits are most commonly implicated in neuropsychiatric symptoms. This neuroanatomical conceptual framework can provide useful information for localization and thus differential diagnosis. For example, the Klüver-Bucy syndrome—which consists of placidity, apathy, visual and auditory agnosia, hyperorality, and hypersexuality—occurs in processes that cause injury to the bilateral medial temporoamygdalar regions. A few of the most common causes of this syndrome include herpes encephalitis, traumatic brain injury (TBI), frontotemporal dementias (FTDs), and late-onset or severe Alzheimer disease (AD). Disinhibition, a particularly common neuropsychiatric symptom, may be observed in patients with brain trauma, cerebrovascular ischemia, demyelination, abscesses, or tumors as well as neurodegenerative disorders. Damage to any portion of the cortical and subcortical portions of the orbitofrontal-striatal-pallidal-thalamic circuit can result in disinhibition (Bonelli and Cummings, 2007). Mood disorders, paranoia, disinhibition, and apathy derive in part from dysfunction in the limbic system and basal ganglia, which are phylogenetically more primitive (Mesulam, 2000). In some cases, the behavioral changes represent a psychological response to the underlying disability; in others, neuropsychiatric abnormalities manifest as a result of intrinsic alterations of the neural network caused by the disease itself. For example, studies have shown that apathy in Parkinson

PRINCIPLES OF DIFFERENTIAL DIAGNOSIS Emotional and cognitive processes are based on brain structure and physiology. Abnormal behavior can be attributable to the complex interplay of neural physiology, social influences, and physical environment (Andreasen, 1997). Psychosis, mania, depression, disinhibition,

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eBOX 10.1

Depression and Psychosis in Neurological Practice

Diagnostic Features of Primary Psychiatric Disorders

The following conditions require clinically significant distress or impairment in social or occupational functioning: Schizophrenia is a condition that lasts for at least 6 months and includes at least 1 month of active symptoms (two or more of the following: delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, or negative symptoms). Schizoaffective disorder is a condition in which a mood episode and the active symptoms of schizophrenia occur together and are preceded or followed by at least 2 weeks of delusions or hallucinations without prominent mood symptoms. Major depressive disorder is characterized by one or more major depressive episodes (at least 2 weeks of depressed mood or loss of interest accompanied by at least four additional symptoms of depression). Additional symptoms of depression may include significant weight changes, sleep dysfunction, psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness or guilt, diminished concentration, and suicidal ideational or thoughts of death.

eBOX 10.2

A manic episode is defined by an abnormally and persistently elevated, expansive, or irritable mood persisting for at least 1 week (or less if hospitalization is required). At least three of the following symptoms must be present if the mood is elevated or expansive (four symptoms are required if the mood is irritable): inflated self-esteem or grandiosity, decreased need for sleep, pressured speech, flight of ideas, distractibility, increased goal-directed activities or psychomotor agitation, and excessive involvement in pleasurable activities with a high potential for painful consequences. Psychotic features may be present. Bipolar I disorder is characterized by the presence of both manic and major depressive episodes or manic episodes alone. Bipolar II is characterized by the presence of major depressive episodes alternating with episodes of hypomania. Hypomania is characterized by an abnormally and persistently elevated, expansive, or irritable mood persisting for at least 4 days. Other criteria required for diagnosis are identical to those of a manic episode except that the symptoms are not so severe as to cause marked impairment in social or occupational functioning, hospitalization is not required, and no psychotic symptoms are present.

Psychiatric Terms of Relevance to Neurologists

Abulia is the state of reduced impulse to act and think associated with indifference about consequences of action. Affect is the examiner’s observation of the patient’s emotional state. Frequently used descriptive terms include the following: Constricted affect is reduced range and intensity of expression. Blunted affect is further reduced. Usually there is little facial expression and a voice that is monotone and lacking normal prosody. Flat describes severely blunted affect in which there is no affective expression. Inappropriate affect is an incongruous expression of emotion or behavior relative to the content of a conversation or social norms. Labile affect exhibits abrupt and sudden changes in both type and intensity of emotion. Anxiety is the feeling of apprehension or worry caused by the anticipation of internal or external danger. Apathy is a dulled emotional tone associated with detachment or indifference. Comportment refers to self-regulation of behavior through complex mental processes that include insight, judgment, self-awareness, empathy, and social adaptation. Compulsion is the uncontrollable impulse to perform an act repetitively. Confusion is the inability to maintain a coherent stream of thought owing to impaired attention and vigilance. Secondary deficits in language, memory, and visuospatial skills are common. Delusion is a false, unshakable conviction or judgment that is out of keeping with reality and with socially shared beliefs of the individual’s background and culture. It cannot be corrected with reasoning. Depression is a sustained psychopathological feeling of sadness often accompanied by a variety of associated symptoms, particularly anxiety, agitation, feelings of worthlessness, suicidal ideation, abulia, psychomotor retardation, and various somatic symptoms and physiological dysfunctions and complaints that cause significant distress and impairment in social functioning. Hallucination is a false sensory perception not associated with real external stimuli.

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Mood is the emotional state experienced and described by the patient and observed by others. Obsession is the pathological persistence of an irresistible thought or feeling that cannot be eliminated from consciousness by logical effort. It is associated with anxiety and rumination. Paranoia is a descriptive term designating either morbid dominant ideas or delusions of self-reference concerning one or more of several themes, most commonly persecution, love, hate, envy, jealousy, honor, litigation, grandeur, and the supernatural. Prosody is the melodic patterns of intonation in language that convey shades of meaning. Psychosis is the inability or impaired ability to distinguish reality from hallucinations and/or delusions. Thought process and content. Common descriptive terms include the following: Circumstantial thought follows a circuitous route to the answer. There may be many superfluous details, but the patient eventually reaches the answer. Linear thought demonstrates goal-directed associations and is easy to follow. Loose associations are thoughts that have no logical or meaningful connection with ensuing thoughts. Tangential thoughts are initially clearly linked to a current thought but fail to maintain goal-directed associations; the patient never arrives at the desired point or goal. Clang associations describes speech in which the sounds of words are similar but not the meanings. The words have no logical connection to each other. Flight of ideas describes a rapid stream of thoughts that tend to be related to each other. Magical thinking describes the belief that thoughts, words, or actions have power to influence events in ways other than through reality-based mechanisms. Thought blocking is characterized by abrupt interruptions in speech during conversation before an idea or thought is finished. After a pause, the individual indicates no recall of what was being said or what was going to be said.

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disease (PD) is probably related to the underlying disease process rather than being a psychological reaction to disability or to depression and is closely associated with cognitive impairment (Kirsch-Darrow et al., 2006). Positron emission tomography (PET), single-photon emission computed tomography (SPECT), and functional magnetic resonance imaging (fMRI) studies suggest the involvement of similar regions of abnormality in acquired (secondary) forms of depression, mania, obsessive-compulsive disorder (OCD), and psychosis as in their primary psychiatric presentations (Lee et al., 2019; Milad and Rauch, 2012; Rubinsztein et al., 2001). Table 10.1 summarizes neuropsychiatric symptoms and their anatomical correlates. Additionally, the developmental phase during which a neurological illness occurs influences the frequency with which some neuropsychiatric syndromes are manifested. Adults with post-TBI sequelae tend to exhibit a higher rate of depression and anxiety. In contrast, post-TBI sequelae in children often involve attention deficits, hyperactivity, irritability, aggressiveness, and oppositional behavior (Max, 2014). When temporal lobe epilepsy or Huntington disease (HD) begins in adolescence, a higher incidence of psychosis is noted than when their onset occurs later in life. Earlier onset of multiple sclerosis (MS) and stroke are associated with a higher incidence of depression (Rickards, 2005). Patients with AD, PD, HD, and FTDs can develop multiple coexisting symptoms such as irritability, agitation, impulse-control disorders, apathy, depression, delusions, and psychosis, many of which may be exacerbated by medications used to treat the underlying disorder (Table 10.2). For example, in patients with PD, dopamine (DA) agonists such as pramipexole and ropinirole have been found to increase the risk of pathological gambling, compulsive shopping, hypersexuality, and other impulse-control disorders, sometimes referred to as dopamine dysregulation (Voon et al., 2006; Weintraub et al., 2006). Management outcome can be influenced by multiple factors. For instance, the complex relationship between behavioral changes and the caregiver’s ability to cope play a role in illness management and nursing home placement (de Vugt et al., 2005). For example, behavioral disturbances in patients with neurological illnesses are well described to be associated with caregiver distress and fatigue (Adams and Dahdah, 2016).

A number of important principles must be considered when patients are being evaluated and treated for behavioral disturbances. 1. The clinical history may offer clues to the index of suspicion for a secondary (neuropsychiatric) etiology versus an idiopathic presentation. For example, late-life initial onset of mania or depression is more commonly associated with central nervous system (CNS) pathology (van Agtmaal et al., 2017). 2. A normal neurological examination does not exclude neurological conditions. Lesions in the limbic, paralimbic, and prefrontal regions may manifest with cognitive-affective-behavioral changes in the absence of elemental neurological abnormalities. 3. Normal routine laboratory testing, brain imaging, electroencephalography, and cerebrospinal fluid (CSF) analysis do not necessarily exclude diseases of neurological origin. 4. New neurological complaints or behavioral changes that are atypical for a coexisting primary psychiatric disorder should not be dismissed as being of psychiatric origin in a person with a preexisting psychiatric history. 5. The possibility of iatrogenically induced symptoms—such as lethargy with benzodiazepines, parkinsonism with neuroleptics, or hallucinations with dopaminergic medications—must be taken into account. Medication side effects can significantly complicate

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Neuroanatomical Region

Depression

Prefrontal cortex (particularly left anterior regions, anterior cingulate gyrus, subgenu of the corpus callosum, orbitofrontal cortex), basal ganglia, left caudate Inferomedial and ventromedial frontal cortex, right inferomedial frontal cortex, anterior cingulate, caudate nucleus, thalamus, and temporothalamic projections Anterior cingulate cortex, nucleus accumbens, globus pallidus, thalamus Orbital or medial frontal cortex, caudate nucleus, globus pallidus Orbitofrontal cortex, hypothalamus, septum Mediotemporal cortex, hypothalamus, septum, rostral brainstem Unimodal association cortex, orbitofrontal cortex, paralimbic cortex, limbic cortex, striatum, thalamus, midbrain Orbitofrontal cortex, amygdala, striatum, thalamus

Mania

Apathy OCD Disinhibition Paraphilia Hallucinations Delusions

OCD, Obsessive-compulsive disorder.

TABLE 10.2 Neurological Disorders and Associated Prominent Behavioral Features Neurological Disorder Alzheimer disease Lewy body dementia Vascular dementia Parkinson disease FTD PSP TBI

PRINCIPLES OF NEUROPSYCHIATRIC EVALUATION

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Associated Behavioral Disturbances Depression, irritability, anxiety, apathy, delusions, paranoia, psychosis Fluctuating confusion, hallucinations, delusions, depression, RBD Depression, apathy, psychosis Depression, anxiety, drug-associated hallucinations and psychosis, RBD Early impaired judgment, disinhibition, apathy, loss of empathy, depression, delusions, psychosis Disinhibition, apathy Depression, disinhibition, apathy, irritability, psychosis (uncommon) Depression, irritability, delusions, mania, apathy, obsessive-compulsive tendencies, psychosis Depression, irritability, RBD, alien hand syndrome Depression, psychosis Apathy, depression, mania, psychosis Depression, irritability, anxiety, euphoria, psychosis, pseudobulbar affect Depression, disinhibition, apathy, impaired judgment; can coexist with FTD

ALS, Amyotrophic lateral sclerosis; FTD, frontotemporal dementia; HD, Huntington disease; HIV, human immunodeficiency virus; MS, multiple sclerosis; PSP, progressive supranuclear palsy; RBD, rapid-eyemovement behavior disorder; TBI, traumatic brain injury.

the clinical history and physical examination in both the acute and long-term setting. Medication side effects can also potentially be harbingers of underlying pathology or progression of illness. For example, marked parkinsonism occurring after neuroleptic exposure can be a feature of PD and dementia with Lewy bodies (DLB)

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CHAPTER 10 Depression and Psychosis in Neurological Practice (Aarsland et al., 2005) before the underlying neurodegenerative condition becomes clinically apparent. PD patients may develop hallucinations as a side effect of dopaminergic medications (Starkstein et al., 2012). 6. Treatments of primary psychiatric and neurological behavioral disturbances share common principles. A response to therapy does not constitute evidence for a primary psychiatric condition. The medical evaluation of affective and psychotic symptoms must be individualized based on the patient’s family history, social environment (including social network), habits, risk factors, age, gender, clinical history, and examination findings. A careful review of the patient’s medical history and a general physical examination as well as a neurological examination (Murray and Price, 2008; Ovsiew et al, 2008) should be performed to assess for possible neurological and medical causes. The most basic evaluation should include vital signs (blood pressure, pulse, respirations, and temperature) and a laboratory evaluation that minimally includes a complete blood cell count (CBC), electrolyte panel, serum glucose, blood urea nitrogen (BUN), creatinine, calcium, total protein and albumin as well as assessments of liver and thyroid function. Additional laboratory testing may be considered according to the clinical history and risk factors. These studies might include a toxicology screen, cobalamin (vitamin B12), homocysteine, methylmalonic acid, folate, vitamin D, human immunodeficiency virus (HIV) serology, rapid plasma reagin (RPR), antinuclear antibodies (ANAs), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), ceruloplasmin, heavy metal screen, ammonia, serum and CSF paraneoplastic panel, urine porphobilinogen, number of cytosine-adenine-guanine (CAG) repeats for HD, and other specialized rheumatologic, metabolic, and genetic tests. Consideration should also be given to checking (especially in the elderly) the patient’s oxygen saturation on room air. Neurological abnormalities suggested by the clinical history or identified on examination, especially those attributable to the CNS, should prompt further evaluation for neurological and medical causes of psychiatric illness. A clear consensus has not been reached as to when neuroimaging is indicated as part of the evaluation of new-onset depression in patients without focal neurological complaints and a normal neurological examination. This must be individualized based on clinical judgment. Treatment-resistant depression should prompt reassessment of the diagnosis and evaluation to rule out secondary causes of depressive illness, including cerebrovascular (small vessel) disease. A careful history to rule out a primary sleep disorder such as obstructive sleep apnea should be considered in the evaluation of refractory depressive symptoms (Haba-Rubio, 2005) or cognitive complaints. When new-onset atypical psychosis presents in the absence of identifiable infectious/inflammatory, metabolic, toxic, or other causes, we recommend that magnetic resonance imaging (MRI) of the brain be incorporated into the evaluation. In our experience, 5%–10% of such patients have MRI abnormalities that identify potential neurological contributions (particularly in those 65 years of age and older). The MRI will help to exclude lesions (e.g., demyelination, ischemic disease, neoplasm, congenital structural abnormalities, evidence of metabolic storage diseases) in limbic, paralimbic, and frontal regions that may not be clearly associated with neurological abnormalities on elemental examination (Walterfang et al., 2005). An electroencephalogram (EEG) should be considered to evaluate for complex partial seizures if there is a history of intermittent, discrete, or abrupt episodes of psychiatric dysfunction (e.g., confusion, spells of lost time, psychotic symptoms), stereotypy of hallucinations, automatisms (e.g., lip smacking, repetitive movements) associated with episodes of psychiatric

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dysfunction (or confusion), or a suspicion of encephalopathy (or delirium). Sensitivity of the EEG for detecting seizure activity is highest when the patient has experienced the specific symptoms while undergoing the study. Selected cases may require 24-hour or prolonged EEG monitoring to capture a clinical event and thus to clarify whether a seizure disorder is present.

COGNITIVE-AFFECTIVE-BEHAVIORAL BRAIN–BEHAVIOR RELATIONSHIPS We begin with a brief overview of cortical functional anatomy related to perceptual, cognitive, affective, and behavioral processing. Thereafter a synopsis of frontal network functional anatomy will follow, describing the distinct prefrontosubcortical circuits subserving important cognitive-affective-behavioral domains. The cerebral cortex can be subdivided into five major functional subtypes: primary sensorimotor, unimodal association, heteromodal association, paralimbic, and limbic (Fig. 10.1). The primary sensory areas are the points of entry for sensory information into the cortical circuitry. The primary motor cortex conveys complex motor programs to motor neurons in the brainstem and spinal cord. Processing of sensory information occurs as information moves from primary sensory areas to adjacent unimodal association areas. The unimodal and heteromodal cortices are involved in perceptual processing and motor planning. The complexity of processing increases as information is then transmitted to heteromodal association areas, which receive input from more than one sensory modality. Examples of heteromodal association cortices include the prefrontal cortex, posterior parietal cortex, parts of the lateral temporal cortex, and portions of the parahippocampal gyrus. These cortical regions have a six-layered cytoarchitecture. Further cortical processing occurs in areas designated as paralimbic. These regions demonstrate a gradual transition of cortical architecture from the six-layered areas to the more primitive and simplified allocortex of limbic structures. The paralimbic regions, implicated in idiopathic and secondary neuropsychiatric symptoms, consist of the orbitofrontal cortex (OFC), cingulate gyrus, insula, temporal pole, and parahippocampal cortex. Cognitive, emotional, and visceral inputs merge in these regions. The limbic subdivision is composed of the hippocampus, amygdala, substantia innominata, prepiriform olfactory cortex, and septal area (Fig. 10.2). Limbic structures are to a great extent reciprocally interconnected with the hypothalamus. Limbic regions are intimately involved with processing and regulation of emotion, memory, motivation, and autonomic and endocrine function. The highest level of cognitive processing occurs in regions referred to as transmodal areas. These are composed of heteromodal, paralimbic, and limbic regions, which are collectively linked, in parallel, to other transmodal regions. Interconnections among transmodal areas (e.g., Wernicke area, posterior parietal cortex, hippocampal-enterorhinal complex) enable the integration of distributed perceptual processing systems, resulting in perceptual recognition (i.e., of phenomena such as scenes and events becoming experiences and words taking on meaning) (Mesulam, 2000).

Cortical Networks Classically, five distinct cortical networks have been conceptualized as governing various aspects of cognitive functioning: 1. The language network, which includes transmodal regions or “epicenters” in the Broca and Wernicke areas located in the pars opercularis/triangular portions of the inferior frontal gyrus and posterior aspect of the superior temporal gyrus, respectively 2. Spatial awareness, based in transmodal regions in the frontal eye fields and posterior parietal cortex

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Paralimbic areas 36 19 High-order (heteromodal) it association areas 37 Modality-specific (unimodal) association areas 20 Idiotypic (primary) areas Fig. 10.1 Cortical anatomy and functional subtypes (areas) described by Brodmann’s map of the human brain. The boundaries are not intended to be precise. Much of this information is based on experimental evidence obtained from laboratory animals and remains to be confirmed in the human brain. AA, Auditory association cortex; ag, angular gyrus; A1, primary auditory cortex; B, Broca area; cg, cingulate gyrus; f, fusiform gyrus; FEF, frontal eye fields; ins, insula; ipl, inferior parietal lobule; it, inferior temporal gyrus; MA, motor association cortex; mpo, medial parieto-occipital area; mt, middle temporal gyrus; M1, primary motor area; of, orbitofrontal region; pc, prefrontal cortex; ph, parahippocampal region; po, parolfactory area; ps, peristriate cortex; rs, retrosplenial area; SA, somatosensory association cortex; sg, supramarginal gyrus; spl, superior parietal lobule; st, superior temporal gyrus; S1, primary somatosensory area; tp, temporopolar cortex; VA, visual association cortex; V1, primary visual cortex; W, Wernicke area. (From Mesulam, M.M., 2000. Behavioral neuroanatomy. Large-scale networks, association cortex, frontal syndromes, the limbic system and hemisphere specializations. In: Mesulam, M.M. [Ed.], Principles of Behavioral and Cognitive Neurology. Oxford University Press, New York, p. 13.)

3. The memory and emotional network, located in the hippocampalenterorhinal region and amygdala 4. The executive function–working memory network, based in transmodal regions in the lateral prefrontal cortex and possibly the inferior parietal cortices 5. The face-object recognition network, based in the temporopolar and middle/ventral temporal cortices (Mesulam, 1998)

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Lesions of transmodal cortical areas result in global impairments such as hemineglect, anosognosia, amnesia, and multimodal anomia. Disconnection of transmodal regions from a specific unimodal input will result in selective perceptual impairments such as category-specific anomias, prosopagnosia, pure word deafness, or pure word blindness. The emergence of functional neuroimaging technologies— including task-based (Pan et al., 2011) and resting-state functional

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Fig. 10.2 Coronal section through the basal forebrain of a 25-year-old human brain stained for myelin. The substantia innominata (si) and the amygdaloid complex (a) are located on the undersurface of the brain. c, Head of caudate nucleus; cg, cingulate gyrus; g, globus pallidus; i, insula. (From Mesulam, M.M., 2000. Behavioral neuroanatomy. Largescale networks, association cortex, frontal syndromes, the limbic system and hemisphere specializations. In: Mesulam, M.M. (Ed.), Principles of Behavioral and Cognitive Neurology. Oxford University Press, New York, p. 4.)

connectivity analyses (Zhang and Raichle, 2010)—has over the past several decades allowed for the in vivo inspection of brain networks. Apart from the five networks already described, several additional networks have emerged as particularly important to the understanding of brain–behavior relationships in behavioral neurology and neuropsychiatry: 1. The default mode network (DMN)—which includes areas along the anterior and posterior cortical midline (medial prefrontal cortex, posterior cingulate cortex, precuneus), posterior inferior parietal lobules, and medial temporal lobe—is linked to self-referential processing (Buckner et al., 2008, Raichle, 2010). 2. The salience network—which is anchored in the dorsal anterior cingulate cortex (ACC) and insular cortex—has strong subcortical and limbic connections and is linked with reactions to the external world and homeostasis (Seeley et al., 2007). 3. The parietofrontal mirror neuron system—which includes the parietal lobe and the premotor cortex plus the caudal part of the inferior frontal gyrus—is involved in the recognition of voluntary behavior in other people (Cattaneo and Rizzolatti, 2009). The limbic mirror system, formed by the insula and the anterior mesial frontal cortex, is devoted to the recognition of affective behavior. DMN and parietofrontal mirror neuron system abnormalities have been linked to mentalization deficits including impairments of theory of mind, while the right anterior insula and ACC have been implicated in emotional and self-awareness (Craig, 2009).

Frontosubcortical Networks Five frontosubcortical circuits subserve cognition, emotion, behavior, and movement. Disruption of these networks at the cortical or subcortical level can be associated with similar neuropsychiatric symptoms (Perez et al., 2015). Each of these circuits shares similar nonoverlapping components: (1) frontal cortex; (2) striatum (caudate, putamen, ventral striatum); (3) globus pallidus and substantia nigra; and (4) thalamus (which then projects back to frontal cortex) (Alexander et al., 1986, Bonelli and Cummings, 2007) (Fig. 10.3). Integrative connections also occur to and from other subcortical and distant cortical

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regions related to each circuit. Neurotransmitters such as DA, glutamate, γ-aminobutyric acid (GABA), acetylcholine, norepinephrine, and serotonin are involved in various aspects of neural transmission and modulation in these circuits. The frontosubcortical networks are named according to their site of origin or function. Somatic motor function is mediated by the motor circuit originating in the supplementary motor area. Oculomotor function is governed by the oculomotor circuit originating in the frontal eye fields. Three of the five circuits are intimately involved in cognitive, emotional, and behavioral functions: the dorsolateral prefrontal, the orbitofrontal, and the anterior cingulate circuits. Each circuit has both efferent and afferent connections with adjacent and distant cortical regions. The dorsolateral prefrontal cortex (DLPFC)–subcortical circuit is principally involved in attentional and higher-order cognitive executive functions. These functions include the ability to shift sets, organize, and solve problems, as well as the abilities of cognitive control and working memory. Shifting sets is related to mental flexibility and consists of the ability to move between different concepts or motor plans or the ability to shift between different aspects of the same or related concept. Working memory is the online maintenance and manipulation of information. The DLPFC–subcortical circuit includes the dorsolateral head of the caudate, the lateral mediodorsal globus pallidus interna, and the parvocellular aspects of the mediodorsal and ventral anterior thalamic nuclei. Dysfunction in this circuit has been linked with environmental dependency syndromes (including utilization and imitation behavior), poor organization and planning, mental inflexibility, and working memory deficits. Executive dysfunction is also a principal component of subcortical dementias. Deficits identified in subcortical dementias include slowed information processing, memory retrieval deficits, mood and behavioral changes, gait disturbance, dysarthria, and other motor impairments. Vascular dementias, PD, and HD are a few examples of conditions that affect this circuit. The OFC–subcortical circuit is implicated in socially appropriate and empathic behavior, value-based decision making, mental flexibility, response inhibition, and emotion regulation. It pairs thoughts, memories, and experiences with corresponding visceral and emotional states. The OFC has functional specificity along its anteroposterior and mediolateral axes. The medial OFC has been linked to reward processing and behavioral responses in the context of viscerosomatic evaluations, whereas more lateral regions mediate more external, sensory evaluations including decoding punishment. Anterior subregions process the reward value for more abstract and complex secondary reinforcing factors such as money, whereas more concrete factors such as touch and taste are encoded in the posterior areas. The posteromedial OFC is particularly implicated in evaluating the emotional significance of stimuli (Barbas and Zikopoulos, 2007). The OFC–subcortical connections include the ventromedial caudate, mediodorsal aspects of the

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globus pallidus interna, and the medial ventral anterior and inferomedial aspects of the magnocellular mediodorsal thalamus. OFC dysfunction, depicted in the classic personality change experienced by Phineas Gage following injury of his left medial prefrontal cortex by a metal rod in a construction accident, is associated with impulsivity, disinhibition, irritability, aggressive outbursts, socially inappropriate behavior, and mental inflexibility. Persons with bilateral OFC lesions may manifest “theory of mind” deficits. Theory of mind is a model of how a person understands and infers other people’s intentions, desires, mental states, and emotions (Bodden et al., 2010). Conditions that exhibit OFC and related neurocircuit impairment include schizophrenia (Bora et al., 2009), depression (Price and Drevets, 2010), OCD (Milad and Rauch, 2012), FTD (Adenzato et al., 2010), and HD. Other conditions that may affect this circuit include closed head trauma, rupture of anterior communicating aneurysms, and subfrontal meningiomas. The ACC and its subcortical connections are implicated in motivated behavior, conflict monitoring, cognitive control, and emotion regulation. Regions of the ACC located subgenually and rostral to the genu of the corpus callosum have reciprocal amygdalar connections and are implicated in the regulation of emotion. Dorsal ACC regions are interconnected to lateral and mediodorsal prefrontal regions and are involved in cognitive functions and the behavioral expression of emotional states (Devinsky et al., 1995, Etkin et al., 2011). An important function of the dorsal ACC is the ability to engage in aspects of cognitive control—the ability to pursue and regulate goal-oriented behavior. ACC–subcortical connections include the nucleus accumbens/ ventromedial caudate, ventral globus pallidus, and ventral aspects of the magnocellular mediodorsal and ventral anterior thalamic nuclei. Deficit syndromes linked to the ACC–subcortical circuit include the spectrum of amotivational syndromes (apathy, abulia, akinetic mutism) and cognitive impairments including poor response inhibition, error detection, and goal-directed behavior. Some conditions that may affect this circuit include AD, FTD, PD, HD, head trauma, brain tumors, cerebral infarcts, and obstructive hydrocephalus.

Cerebrocerebellar Networks The cerebellum is engaged in the regulation of cognition and emotion through a feed-forward and feedback loop. The cortex projects to pontine nuclei, which in turn project to the cerebellum. The cerebellum projects to the thalamus, which then projects back to the cortex. Cognitive processing tasks such as language, working memory, and spatial and executive tasks appear to activate the posterior cerebellar lobe. The posterior cerebellar vermis may function as a putative limbic cerebellum, modulating emotional processing (Stoodley and Schmahmann, 2010). Distractibility, executive and working memory problems, impaired judgment, reduced verbal fluency, disinhibition, irritability, anxiety, emotional lability or blunting, obsessive-compulsive behaviors, depression, and psychosis have been reported in association with cerebellar pathology in the context of the cognitive-affective cerebellar syndrome (Schmahmann, 2004).

BIOLOGY OF PSYCHOSIS Schizophrenia is a chronic disintegrative thought disorder where patients frequently experience auditory hallucinations and bizarre or paranoid delusions. Among several etiological hypotheses for schizophrenia, the neurodevelopmental model is one of the most prominent. This model generally posits that schizophrenia results from processes that begin long before clinical symptom onset and is caused by a combination of environmental and genetic factors (Murray and Lewis, 1987; Weinberger, 1987). Several postmortem and neuroimaging studies support this hypothesis with findings of brain developmental

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alterations such as agenesis of the corpus callosum, arachnoid cysts, and other abnormalities in a significant number of schizophrenic patients (Hallak et al., 2007; Kuloglu et al., 2008). Environmental factors are associated with an increased risk for schizophrenia. These factors include being a first-generation immigrant or the child of a first-generation immigrant, urban living, drug use, head injury, prenatal infection, maternal malnutrition, obstetrical complications during delivery, and winter birth (Tandon et al., 2008). Genetic risks are clearly present but not well understood (Smoller 2014). The majority of patients with schizophrenia lack a family history of the disorder. The population lifetime risk for schizophrenia is 1%; it is 10% for first-degree relatives and 4% for second-degree relatives. There is an approximately 50% concordance rate for monozygotic twins as compared with approximately 15% for dizygotic twins. Advancing paternal age increases risk in a linear fashion, which is consistent with the hypothesis that de novo mutations contribute to the genetic risk for schizophrenia. It is most likely that many different genes make small but important contributions to susceptibility. The disease typically manifests only when these genes are combined or certain adverse environmental factors are present. A number of susceptibility genes show an association with schizophrenia: catechol-O-methyl-transferase, neuroregulin 1, dysbindin, disrupted in schizophrenia 1 (DISC1), metabotropic glutamate receptor type 3 gene, and G27/G30 gene complex (Nothen et al., 2010; Tandon et al., 2008). Research in twins and first-degree relatives of patients has shown that genes predisposing to schizophrenia and related disorders affect heritable traits related to the illness. Such traits include neurocognitive functioning, structural MRI brain volume measures, neurophysiological informational processing traits, and sensitivity to stress (van Os and Kapur, 2009). A small proportion of schizophrenia incidence may be explained by genomic structural variations known as copy number variants (CNVs). CNVs consist of inherited or de novo small duplications, deletions, or inversions in genes or regulatory regions. CNV deletions generally show higher penetrance (more severe phenotype) than duplications, and larger CNVs often have higher penetrance and/or more clinical features than smaller CNVs. These genomic structural variations contribute to normal variability, disease risk, and developmental anomalies; they also act as a major mutational mechanism in evolution. The most common CNV disorder, 22q11.2 deletion syndrome (velocardiofacial syndrome), has an established association with schizophrenia. Individuals with 22q11.2 deletions have a 20-fold increased risk for schizophrenia and constitute about 0.9%–1% of schizophrenia patients. When this syndrome is present, genetic counseling is helpful (Bassett and Chow, 2008). Studies are also identifying shared genetic risk for schizophrenia and autism spectrum disorders (McCarroll and Hyman, 2013). A wide variety of neurological conditions, medications, and toxins are associated with psychosis. No consensus is available in the literature regarding the precise anatomical localization of various psychotic syndromes. Evidence from neurochemistry, cellular neuropathology, and neuroimaging studies supports that schizophrenia is a brain disease that affects multiple interacting neural circuits. The two best-known neurotransmitter models offered to explain the various manifestations of schizophrenia are the “dopamine hypothesis” (Howes and Kapur, 2009) and the “glutamate hypothesis.” Schizophrenia has been associated with frontal lobe dysfunction and abnormal regulation of subcortical DA and glutamate systems (Keshavan et al., 2008). Advances in structural and functional neuroimaging techniques over the past 30 years have greatly aided our understanding of neurocircuit alterations in schizophrenia. Structural studies have commonly identified diminished whole brain volume, increased ventricular size, and regional atrophy in hippocampal, prefrontal, superior temporal,

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CHAPTER 10 Depression and Psychosis in Neurological Practice and inferior parietal cortices in schizophrenic patients compared with control groups (Keshavan et al., 2008; Pearlson and Marsh, 1999; Shenton et al., 2001). A reversal of or diminished hemispheric asymmetry has also been characterized. Functional neuroimaging studies have commonly identified decreased cerebral blood flow (CBF) and blood oxygen level–dependent (BOLD) hypoactivation of the prefrontal cortex (including the DLPFC) during cognitive task performance and temporal lobe dysfunction (Brunet-Gouet and Decety, 2006; Keshavan et al., 2008). Schizophrenic patients with prominent negative symptoms have displayed reduced glucose utilization in the frontal lobes. A clinical and neurobiological overlap across schizophrenia, schizoaffective disorder, and bipolar disorder is also increasingly recognized (Clementz et al., 2016). Overall, functional imaging studies suggest that the DLPFC, OFC, ACC, ventral striatum, thalamus, temporal lobe subregions, and cerebellum are sites of prominent functional alterations. Several neurological conditions that may manifest psychosis (e.g., HD, PD, frontotemporal degenerations, stroke) are commonly also associated with frontal and subcortical dysfunction. For example, dorsolateral and mediofrontal hypoperfusion on functional imaging has been demonstrated in a subset of AD patients with delusions (Ismail et al., 2012).

BIOLOGY OF DEPRESSION The intersection of neurology and psychiatry is nowhere more evident than the remarkable comorbidity of psychiatric illness, especially depression, in many neurological disorders, with a 20%–60% prevalence rate of depression in patients with stroke, neurodegenerative diseases, MS, headache, HIV, TBI, epilepsy, chronic pain, obstructive sleep apnea, intracranial neoplasms, and motor neuron disease. Depression amplifies the physiological response to pain (Perez et al., 2015), whereas pain-related symptoms and limitations frequently lead to the emergence of depressive symptoms. In a community-based study, almost 50% of adolescents with chronic daily headaches had at least one psychiatric disorder, most commonly major depression and panic. Women with migraine who have major depression are twice as likely as those with migraine alone to report having been sexually abused when they were children. If the abuse continued past age 12, women with migraine were five times more likely to report depression (Tietjen et al., 2007). Despite the proliferation of antidepressant therapeutics, major depression is often a chronic and/or recurrent condition that remains difficult to treat. Up to 70% of patients taking antidepressants in a primary care setting may be poorly adherent, most often due to adverse side effects during both short- and long-term therapy. Although the heritability of idiopathic depression based on twin studies is estimated to be between 40% and 50% (Levinson, 2006), the genetics of depression have thus far proven difficult to fully elucidate (Fabbri et al., 2018). Depression is a polygenetic condition that does not adhere to simple Mendelian genetics, and genetic mechanisms implicated in depression suggest complex gene–environment interactions. An individual’s genetic makeup may lead to increased susceptibility for the development of depression in the context of adverse environmental (psychosocial) influences. Behavioral genetics research based on stress-diathesis models of depression demonstrates that the risk of depression after a stressful event is enhanced in populations carrying genetic risk factors and is diminished in populations lacking such risk factors. A gene’s contribution to depression may be missed in studies that do not account for environmental interactions and may be revealed only when studied within the context of environmental stressors specifically mediated by that gene (Uher, 2008). Genotype–environment interactions are ubiquitous because genes not only affect the risk for depression by creating susceptibility to specific environmental

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stressors but may also predispose individuals to persistently place themselves in highly stressful environments. Approaches to the study of genetic influences in depression include association studies of candidate genes, genetic linkage studies of pedigrees with a strong family history of depression, and genome-wide association studies. Association studies in depression have focused on monoaminergic candidate genes (Levinson, 2006). An intriguing interaction between polymorphisms in the promoter region of the serotonin transporter (5-HTT) gene and depression as well as an association between 5-HTT promoter region polymorphisms and depression-related neurocircuit activation patterns has emerged. The promoter activity of the 5-HTT gene is modified by sequence elements proximal to the 5′ regulatory region, termed the 5-HTT gene-linked polymorphic region (5-HTTLPR). The short “s” allele of the 5-HTTLPR is associated with lower transcription output of 5-HTT mRNA compared with the long “l” allele. A prospective longitudinal study has demonstrated that individuals with one or two copies of the short allele exhibited more depressive symptoms and suicidality following stressful life events in their early 20s compared with individuals homozygous for the long allele (Caspi et al., 2003; Karg et al., 2011). Genome-wide association studies in depression, including treatment-refractory depression (TRD), have largely failed to identify robust, reproducible findings (Fabbri et al., 2018, Lewis et al., 2010, Wray et al., 2012). This suggests that genome-wide association studies in depression have been underpowered to date. Studies of epigenetic mechanisms in depression, though in their early stages, appear to hold promise in elucidating the mechanisms by which environmental factors affect gene expression. Epigenetics is the study of changes in gene activity caused by factors other than changes in the underlying nucleotide sequence. Whereas the genomic sequence defines the potential genetic repertoire of a given individual, the epigenome delineates which genes in the repertoire are expressed (along with the degree of expression) (Booij et al., 2013). As an example, DNA methylation is one of several epigenetic modifications that influence gene expression. In a pioneering animal study probing the impact of early life experiences on subsequent epigenetic programming, rat pups who experienced high rates of licking and grooming behaviors (positive influences) exhibited decreased methylation at the glucocorticoid receptor transcription factor binding site (Weaver et al., 2004). A postmortem human study examining epigenetic glucocorticoid receptor regulation revealed increased methylation in the neuron-specific glucocorticoid receptor and decreased glucocorticoid receptor mRNA in suicide victims with a history of childhood abuse compared with nonabused suicide victims and nonsuicide controls (McGowan et al., 2009). At the cellular neurobiological level, the potential clinical relevance of neurogenesis in the adult mammalian brain represents a recent major breakthrough in depression studies. Imaging studies have demonstrated a 10%–20% decrease in the hippocampal volume of patients with chronic depression (Colle et al., 2018). Cell proliferation studies using 5-bromo-2′-deoxyuridine injection to label dividing cells show that antidepressants also lead to increased cell numbers in the mammalian hippocampus. This effect is seen with chronic but not acute treatment; the time course of the effect mirrors the known time course of the therapeutic action of antidepressants in humans (approximately 2 weeks for initial effect, upward of 4–8 weeks for maximal benefit) (Czeh et al., 2001; Samuels and Hen, 2011). Although a role for neurogenesis in the pathophysiology of depression appears to be a promising avenue of research, the relevance of animal studies described here with respect to humans remains controversial (Reif et al., 2006). From a systems-level perspective, amygdalar-hippocampal, ACC, OFC, DLPFC, and subcortical regions are implicated in the

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neurobiology of primary and acquired depression (Perez et al., 2016). Increased basal and stimuli-driven amygdalar activity has been extensively characterized in depression (Drevets, 2003). In an early PET imaging study, depressed patients with a family history of depression demonstrated increased activation of the left amygdala; this pattern of amygdalar hyperactivation was also observed in remitted subjects with a family history of depression (Drevets et al., 1992). This suggests that enhanced amygdalar activity potentially represents a trait vulnerability biomarker for depressive illness. A number of studies have specifically linked enhanced amygdalar activity to the negative attentional bias of information processing in depression. Increased amygdalar metabolic activity has also been positively correlated with plasma cortisol levels (Drevets et al., 2002), suggesting a link between elevated amygdalar activity and dysfunction of the hypothalamic–pituitary–adrenal axis. Dysfunction of the prefrontal cortex also plays an important role in the pathophysiology of depression. The subgenual ACC has been implicated in the modulation of negative mood states (Hamani et al., 2011). Several neuroimaging studies characterized elevated baseline subgenual activation in depression (Dougherty et al., 2003; Gotlib et al., 2005; Konarski et al., 2009; Mayberg et al., 2005), whereas other investigations have described reduced subgenual activations (Drevets et al., 1997). Mayberg and colleagues have suggested that depression can be potentially defined phenomenologically as “the tendency to enter into, and inability to disengage from, a negative mood state” (Holtzheimer and Mayberg, 2011). Subgenual ACC dysfunction may play a critical role in the inability to effectively modulate mood states. In addition to the ACC, the OFC and DLPFC exhibit abnormalities in depression. Consistent with OFC lesions linked to increased depression risk, depression severity is inversely correlated with medial and posterolateral OFC activity in neuroimaging studies (Drevets, 2007; Price and Drevets, 2010). Reduced OFC activations may lead to amygdalar disinhibition in depression. Meanwhile, the DLPFC potentially exhibits a lateralized dysfunctional pattern in depression. Though not consistently identified, depressed patients have shown left DLPFC hypoactivity and right DLPFC hyperactivity (Grimm et al., 2008); left DLPFC hypoactivity was linked to negative emotional judgments whereas right DLPFC hyperactivity was associated with attentional deficits. Subcortically, decreased ventral striatum/nucleus accumbens activation has been linked with anhedonia (Epstein et al., 2006; Keedwell et al., 2005; Pizzagalli et al., 2009). In neurological disorders, damage to the prefrontal cortex from stroke or tumor or to the striatum from degenerative diseases such as PD and HD is associated with depression (Charney and Manji, 2004). Functional imaging studies of subcortical disorders such as these reveal that hypometabolism in paralimbic regions, including the anterotemporal cortex and anterior cingulate, correlates with depression (Bonelli and Cummings, 2007). Depression in PD, HD, and epilepsy has been associated with reduced metabolic activity in the OFC and caudate nucleus. Functional imaging studies of untreated depression have been extended to evaluate responses to pharmacological, cognitive-behavioral, and surgical treatments. Clinical improvement after treatment with selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine correlates with increased activity on PET in brainstem and dorsal cortical regions including the prefrontal, parietal, anterior, and posterior cingulate areas and with decreased activity in limbic and striatal regions including the subgenual cingulate (Hamani et al., 2011), hippocampus, insula, and pallidum. These findings are consistent with the prevailing model for the involvement of a limbic-cortical-striatal-pallidal-thalamic circuit in major depression. The same group has shown that imaging can be used to identify patterns of metabolic activity predictive of treatment response. Hypometabolism of the rostral anterior cingulate characterized patients who failed to respond to

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antidepressants, whereas hypermetabolism characterized responders. Dougherty and coworkers (2003) used PET to search for neuroimaging profiles that might predict clinical response to anterior cingulotomy in patients with TRD. Responders displayed elevated preoperative metabolism in the left prefrontal cortex and the left thalamus. A combination of functional imaging and pharmacogenomic technologies might allow subsets of treatment responders to be classified and outcomes to be predicted more precisely than with either technology alone. Goldapple and coinvestigators (2004) used PET to study the clinical response of cognitive-behavioral therapy (CBT) in patients with unipolar depression; they found increases in the hippocampus and dorsal cingulate and decreases in the dorsal, ventral, and medial frontal cortex activity (Goldapple et al., 2004). The authors speculate that the same limbic-cortical-striatal-pallidal-thalamic circuit is involved but that differences in the direction of metabolic changes may reflect different underlying mechanisms of action of CBT and SSRIs. Resting-state metabolism of the right anterior insula as determined by PET has also been identified as a potential treatment-selective biomarker in depression for CBT and SSRI treatment response (McGrath et al., 2013), although reliable neuroimaging biomarkers of treatment response in major depression remain ill defined (Fonseka et al., 2018).

CLINICAL SYMPTOMS AND SIGNS SUGGESTING NEUROLOGICAL DISEASE Many neurological conditions have associated psychiatric symptoms. Psychiatrists and neurologists must be intimately acquainted with features of the clinical history and examination that point to the need for further investigation. Box 10.3 outlines some key features that have historically suggested an underlying neurological condition. eBox 10.4 reviews some key areas of the review of systems that can be helpful when a patient is being assessed for neurological and medical causes of psychiatric symptoms. eTable 10.3 reviews abnormalities in the elemental neurological examination associated with diseases that can exhibit significant neuropsychiatric features.

PSYCHIATRIC MANIFESTATIONS OF NEUROLOGICAL DISEASE Virtually any process that affects the neurocircuits described earlier can result in behavioral changes and psychiatric symptoms at some point. Psychiatric symptoms may be striking and can precede any neurological manifestation by years. eTable 10.4 lists conditions that can be associated with psychosis or depression. Box 10.5 summarizes some key points from the preceding discussion. A general overview and discussion of a number of major categories of neurological and systemic conditions with prominent neuropsychiatric features follows. More detailed information regarding the evaluation, natural history, pathology, and specific treatment recommendations for these conditions is beyond the scope of this chapter.

Stroke and Cerebral Vascular Disease Stroke is the leading cause of neurological disability in the United States and one of the most common causes of acquired behavioral changes in adults. The neuropsychiatric consequences of stroke depend on the location and size of the stroke, preexisting brain pathology, baseline intellectual capacity and functioning, age, and premorbid psychiatric history. Neuropsychiatric symptoms may occur in the setting of first strokes and multi-infarct dementia. In general, interruption of bilateral frontotemporal lobe function is associated with an increased risk of depressive and psychotic symptoms. Specific stroke-related syndromes such as aphasia and visuospatial dysfunction are beyond the

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eBOX 10.4 Review of Systems With Possible Neuropsychiatric Relevance and Related Neurological Conditions Neck Stiffness (meningitis)

General Weight loss (neoplasia, drug abuse) Decreased energy level (multiple sclerosis, neoplasia) Fever/chills (occult systemic or central nervous system infection) Arthritis (vasculitis, connective tissue disease, Lyme disease)

Skin Rash (vasculitis, Lyme disease, sexually transmitted diseases) Birthmarks (phakomatoses)

Head New-onset headaches or change in character/severity (many conditions) Trauma (subdural hematoma, contusion, postconcussive syndrome) Eyes Chronic visual loss (can predispose to visual hallucinations including Charles Bonnet syndrome) Episodic visual loss (amaurosis fugax) Diplopia (brainstem pathology or cranial nerve lesions) Ears Hearing loss (can predispose to auditory hallucinations and paranoia) Nose Anosmia (head trauma, olfactory groove meningioma, neurodegenerative diseases such as Alzheimer and Parkinson diseases) Mouth Oral lesions (nutritional deficiency, seizure, inflammatory disease)

eTABLE 10.3

Symptoms

Cardiovascular Heart disease (ischemic cerebrovascular disease) Hypertension (ischemic cerebrovascular disease) Cardiac arrhythmia (cerebral emboli) Motor Focal weakness (amyotrophic lateral sclerosis, stroke, mass lesion[s]) Gait dysfunction (hydrocephalus, cerebellar/degenerative movement disorders, confusional states) Autonomic Vomiting (neurodegenerative disorder-related dysautonomia, porphyria) Constipation (dysautonomia) Urinary retention or incontinence (dysautonomia, various forms of hydrocephalus, dementias) Impotence (dysautonomia)

Neurological Abnormalities Suggesting Diseases Associated With Psychiatric

Examination Abnormalities

Disease(s) or Underlying Etiology

Vital signs

Marked hypertension Tachypnea Hypoventilation Behavior Alien hand syndrome Cranial nerves Visual field deficit Pupils Argyll Robertson Unilateral dilation Horner syndrome Ophthalmoplegia Vertical gaze palsy Mixed Cornea: Kayser–Fleischer rings Lens: cataracts Fundi Papilledema Optic pallor Extrapyramidal Cerebellar Motor neuron Peripheral nerve Gait Apraxia Spasticity Bradykinesia

Hypertensive encephalopathy, serotonin syndrome, neuroleptic malignant syndrome, preeclampsia Delirium due to systemic infection Hypoxia, alcohol withdrawal, sedative intoxication Corticobasal ganglionic degeneration Stroke, mass, MS, lupus Neurosyphilis Brain herniation, porphyria Stroke, carotid disease, demyelinating disease PSP Wernicke-Korsakoff syndrome, chronic basilar meningitis Wilson disease Chronic steroids, Down syndrome Intracranial mass lesion, MS MS, porphyria, Tay-Sachs Parkinson disease, DLB, HD, stroke, WD, numerous others Alcohol, hereditary degenerative ataxias, paraneoplastic, medication toxicity ALS, FTD with motor neuron disease Adrenomyeloneuropathy, metachromatic leukodystrophy, vitamin B12 deficiency, porphyria Normal pressure hydrocephalus, frontal network dementias Stroke, MS Multi-infarct dementia, PD, PSP, DLB

ALS, Amyotrophic lateral sclerosis; DLB, dementia with Lewy bodies; FTD, frontotemporal dementia; HD, Huntington disease; MS, multiple sclerosis; PD, Parkinson disease; PSP, progressive supranuclear palsy; WD, Wilson disease. @

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eTABLE 10.4

Selected Neurological and Systemic Causes of Depression and/or Psychosis

Category

Disorders

Head trauma

Traumatic brain injury Subdural hematoma Lyme disease Prion diseases Neurosyphilis Viral infections/encephalitides (HIV infection/encephalopathy, herpes encephalitis, cytomegalovirus, Epstein–Barr virus, etc.) Whipple disease Cerebral malaria Encephalitis Systemic infection Systemic lupus erythematosus Sjögren syndrome Temporal arteritis Hashimoto encephalopathy Sydenham chorea Sarcoidosis Primary or secondary cerebral neoplasm Systemic neoplasm Pancreatic cancer Paraneoplastic encephalitis Hepatic encephalopathy Uremic encephalopathy Dialysis dementia Hypo/hyperparathyroidism Hypo/hyperthyroidism Addison disease/Cushing disease Postpartum Vitamin deficiency: vitamin B12, folate, niacin, vitamin C Gastric bypass–associated nutritional deficiencies Hypoglycemia Stroke Multi-infarct dementia Central nervous system vasculitis Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) Alzheimer disease Lewy body disease Frontotemporal dementias Parkinson disease Progressive supranuclear palsy Huntington disease Corticobasal ganglionic degeneration Multisystem atrophy/striatonigral degeneration/olivopontocerebellar atrophy

Infectious

Inflammatory

Neoplastic

Endocrine/acquired metabolic

Vascular

Degenerative

Category

Demyelinating/ dysmyelinating

Inherited metabolic

Epilepsy

Medications

Drugs of abuse

Drug withdrawal syndromes

Toxins Other

Disorders Idiopathic basal ganglia calcifications/ Fahr disease Multiple sclerosis Acute disseminated encephalomyelitis Adrenoleukodystrophy Metachromatic leukodystrophy Wilson disease Tay-Sachs disease Adult neuronal ceroid lipofuscinosis Niemann-Pick type C Acute intermittent porphyria Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes Ictal Interictal Postictal Forced normalization Post epilepsy surgery Analgesics Androgens Antiarrhythmics Anticonvulsants Anticholinergics Antibiotics Antihypertensives Antineoplastic agents Corticosteroids Dopamine agonists Oral contraceptives Sedatives/hypnotics Steroids Alcohol Amphetamines Cocaine Hallucinogens Marijuana MDMA (Ecstasy) Phencyclidine Alcohol Barbiturates Benzodiazepines Amphetamines Heavy metals Inhalants Normal pressure hydrocephalus Ionizing radiation exposure Decompression sickness

HIV, Human immunodeficiency virus; MDMA, 3,4-methylenedioxymethamphetamine.

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CHAPTER 10 Depression and Psychosis in Neurological Practice

Historical Features Suggesting Neurological Disease in Patients With Psychiatric Symptoms

BOX 10.3

BOX 10.5

Presence of Atypical Psychiatric Features Late or very early age of onset Acute or subacute onset Lack of significant psychosocial stressors Catatonia Diminished comportment Cognitive decline Intractability despite adequate therapy Progressive symptoms History of Present Illness Includes New or worsening headache Inattention Somnolence Incontinence Focal neurological complaints such as weakness, sensory changes, incoordination, or gait difficulty Neuroendocrine changes Anorexia/weight loss Patient History Risk factors for cerebrovascular disease or central nervous system infections Malignancy Immunocompromise Significant head trauma Seizures Movement disorder Hepatobiliary disorders Abdominal crises of unknown cause Biological relatives with similar diseases or complaints Unexplained Diagnostic Abnormalities Screening laboratories Neuroimaging studies or possibly imaging of other systems Electroencephalography Cerebrospinal fluid

scope of this chapter; therefore only the abnormalities in mood and emotion after stroke are discussed. A common misconception is that depressive symptoms can be explained as a response to the associated neurological deficits and impairment in function. Evidence supports a higher incidence of depression in stroke survivors than occurs in persons with other equally debilitating diseases. Minor depression is more closely related to the patient’s elemental deficits. Emotional and cognitive disorders may occur independently of or in association with sensorimotor dysfunction in stroke. Poststroke depression (PSD) is the most common neuropsychiatric syndrome, occurring in 30%–50% of survivors at 1 year, with irritability, agitation, and apathy often present as well (Robinson and Jorge, 2016). About 50% of patients with depressive symptoms will meet criteria for a major depressive episode. Although somewhat controversial, onset of depression within the first few weeks after a stroke is most commonly associated with lesions affecting the frontal lobes, especially the prefrontal cortex and head of the caudate (Starkstein et al., 1987). The frequency and severity of depression increase with closer proximity to the frontal poles. Left prefrontal lesions are more commonly associated with acute depression and may be complicated by aphasia, resulting in the patient’s inability

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Key Points

1. Affective and psychotic disorders may occur as a result of neurological disease and be indistinguishable from the idiopathic forms. 2. Neuropsychiatric and cognitive dysfunction can be correlated with altered functioning in anatomical regions. 3. Cortical processing of sensory information proceeds from its point of entry through association areas with progressively more complex interconnections with other regions having sensory, memory, cognitive, emotional, and autonomic information, resulting ultimately in perceptual recognition and emotional meaning for experiences. 4. Frontosubcortical circuits are heavily involved in cognitive, affective, and behavioral functioning. Disruption of frontal circuits at the cortical or subcortical level by various processes can be associated with similar neuropsychiatric symptoms. 5. Features of the patient’s clinical history and examination can be suggestive of a medical or neurological cause of psychiatric symptoms. Many medical and neurological conditions are associated with neuropsychiatric symptoms. Each condition may carry unique implications for prognosis, treatment, and long-term management.

to express the symptoms. Mania is much less common but usually occurs in relation to lesions of the right hemisphere, particularly with involvement of the OFC–subcortical circuit and medial temporal structures (Lee et al., 2019, Perez et al., 2011). Single manic events as well as recurrent manic and depressive episodes have been reported. Nondominant hemispheric strokes may also result in aprosody without associated depression. Currently the standard treatment of PSD is CBT and pharmacotherapy (Wang et al., 2018). Apart from the association between large-territory strokes and depression, the “vascular depression” hypothesis denotes the potential of increased association between cerebrovascular disease and late-life depression (Alexopoulos, 2005; Alexopoulos et al., 1997). Clinically, vascular or late-life depression is characterized by executive deficits, slowed processing speed, psychomotor retardation, lack of insight, and disability out of proportion to depressive symptoms. Cerebrovascular white matter T2 MRI hyperintensities from diabetes, hyperlipidemia, cardiac disease, and hypertension have been linked with this condition. Some studies have localized white matter lesions to the prefrontal cortex and temporal lobe, including particular fiber tracts (e.g., cingulum bundle, uncinate fasciculus [Sheline et al., 2008]). Vascular depression has been associated with poor antidepressant response and higher relapse rates (Alexopoulos et al., 2000). Frontolimbic disconnection and cerebrovascular hypoperfusion are some of the theorized mechanisms linking cerebrovascular disease to late-life depression. Psychosis or psychotic features may present as a rare complication of a single stroke, but the prevalence of these features is not well established. Manifestations may include paranoia, delusions, ideas of reference, hallucinations, or psychosis. Paranoia and psychosis have been reported in association with left temporal strokes resulting in Wernicke aphasia. Other regions producing similar neuropsychiatric symptoms include the right temporoparietal region and the caudate nuclei. Right hemispheric lesions may also be more associated with visual hallucinations and delusions. Reduplicative paramnesia and misidentification syndromes such as Capgras and Fregoli syndromes have also been reported. Reduplicative paramnesia is a syndrome in which patients claim that they are simultaneously in two or more locations. It has been observed to occur in patients with combined lesions of frontal and right temporal lobes but has also been described as due to temporal-limbic-frontal dysfunction (Politis and Loane, 2012). Capgras syndrome is the false belief that someone familiar, usually a

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family member or close friend, has been replaced by an identical-appearing imposter. It has been proposed that this results from right temporal-limbic-frontal disconnection resulting in a disturbance in the ability to recognize familiar people and places (Feinberg et al., 1999). A role for the left hemisphere in generating a fixed false narrative in the context of right lateralized perceptual deficits has also been postulated (Devinsky, 2009). In Fregoli syndrome, the patient believes that a persecutor is able to take on a variety of faces, like an actor. Psychotic episodes can also be a manifestation of complex partial seizures secondary to stroke. Patients with poststroke psychosis are more prone to have comorbid epilepsy than poststroke patients without associated psychosis. Lesions or infarcts of the ventral midbrain can result in a syndrome characterized by well-formed and complex visual hallucinations referred to as peduncular hallucinosis, and novel lesion mapping techniques suggest that subcortical lesions associated with peduncular hallucinosis are all functionally coupled with the extrastriate visual cortex (Boes et al. 2015). Obsessive-compulsive features have also been reported with strokes. These symptoms have been postulated to be due to dysfunction in the orbitofrontal-subcortical circuitry. Consensus criteria for accurately diagnosing vascular cognitive impairments and dementia are lacking (Skrobot et al., 2017). The vascular cognitive impairments can be conceptualized as being made up of three groups: vascular dementia, mixed vascular dementia and AD pathology, and vascular cognitive impairment not meeting the criteria for dementia. These conditions may have variable contributions from mixed forms of small-vessel disease, large-vessel disease, and cardioembolic disease, which accounts for the clinical phenotypic heterogeneity. AD pathology is commonly found in association with cerebrovascular disease pathology, leading to uncertainty with respect to the relative contributions of each in some cases. A temporal relationship between a stroke and the onset of dementia or a stepwise progression of cognitive decline with evidence of cerebrovascular disease on examination and neuroimaging are considered most helpful. No specific neuroimaging profile exists that is diagnostic for pure cerebrovascular disease–related dementia. Vascular dementia may present with prominent cortical, subcortical, or mixed features. Cortical vascular dementia may manifest as unilateral sensorimotor dysfunction; abrupt onset of cognitive dysfunction and aphasia; and difficulties with planning, goal formation, organization, and abstraction. Subcortical vascular dementia often affects frontosubcortical circuitry, resulting in executive dysfunction, cognitive and psychomotor slowing, difficulties with abstraction, apathy, memory problems (recognition and cued recognition relatively intact), impairment of working memory, and decreased ability to perform activities of daily living. Memory difficulties tend to be less severe than in AD. Limited data suggest that cholinesterase inhibitors are beneficial for the treatment of vascular dementia as demonstrated by improvements in cognition, global functioning, and performance of activities of daily living (Chen et al., 2016).

Infectious An expansive list of infections that result in behavioral changes during the early, middle, or late phases of illness or as a result of treatments or subsequent opportunistic infections could be generated. This portion of the present chapter focuses on only a few salient examples with contemporary relevance and illustrative complexity.

Human Immunodeficiency Virus Individuals infected with HIV can be affected by a variety of neuropsychiatric and neurological problems independent of opportunistic infections and neoplasms. These include cognitive impairment, behavioral changes, and sensorimotor disturbances. Neurologists and psychiatrists must anticipate a spectrum of psychiatric phenomena that

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can include depression, paranoia, delusions, hallucinations, psychosis, mania, irritability, and apathy. HIV-associated dementia (HAD) is the term given to the syndrome that presents with bradyphrenia, memory decline, executive dysfunction, impaired concentration, and apathy. These features are compatible with a subcortical dementia with prominent dysfunction in the ganglia of the frontobasal ganglia (Woods et al., 2004). Minor cognitive motor disorder (MCMD) refers to a milder form of this syndrome that has become more common since the advent of highly active antiretroviral therapy (HAART). HAD may be the acquired immunodeficiency virus syndrome (AIDS)–defining illness in up to 10% of patients. It has been estimated to occur in 20%– 30% of untreated adults with AIDS. HAART has reduced its frequency by approximately 50%, but the frequency of pathologically proven HIV encephalitis remains high. Lifetime prevalence of depression in HIV-infected individuals is 22%–45%, with depressed individuals demonstrating reduced compliance with antiretroviral therapy and increased HIV-related morbidity. Antidepressants have been efficacious in treating HAD (Himelhoch and Medoff, 2005). Psychostimulants may also be a helpful adjunct in treating HAD. Evidence suggests that HIV-infected patients with new-onset psychosis usually respond well to typical neuroleptic medications, but they are more sensitive to the side effects of these medications, particularly extrapyramidal symptoms (EPS) and tardive dyskinesias. This sensitivity is thought to be due to HIV’s effect on the basal ganglia, resulting in a loss of dopaminergic neurons. When typical neuroleptics are being prescribed, caution is warranted owing to this sensitivity and the additional possible pharmacological interactions with antiretroviral medications. Atypical neuroleptics are favored. HAART and other medications used in HIV patients can have neuropsychiatric side effects. For example, the nucleoside reverse transcriptase inhibitor zidovudine (AZT) may lead to mania, delirium, or depression. Moreover, many medications used in the treatment of HIV inhibit or induce the cytochrome P450 system, thereby altering psychotropic drug levels. Therefore drug interactions in HIV patients with psychiatric disorders are common and require close monitoring.

Creutzfeldt-Jakob Disease Prion diseases are a group of fatal degenerative disorders of the nervous system caused by a conformational change in the prion protein, a normal constituent of cell membranes. These conditions are characterized by long incubation periods followed by a relatively rapid neurological decline and death (Johnson, 2005). Creutzfeldt-Jakob disease (CJD) is the most common human prion disease but is rare, with an incidence of between 0.5 and 1.5 cases per million people per year. The sporadic form of the disease accounts for about 85% of cases; it typically occurs later in life (mean age, 60 years), and manifests with a rapidly progressive course characterized by cerebellar ataxia, dementia, myoclonus, exaggerated startle reflex, seizures, and psychiatric symptoms progressing to akinetic mutism and complete disability within months after disease onset. Analysis of CSF may prove positive for 14-3-3 protein, which has been shown to have a sensitivity of 92% and a specificity of 80% (Muayqil et al., 2012). Diffusion-weighted imaging may show posterior cortical ribbon or striatal hyperintensities, whereas middleto late-stage sporadic CJD may show periodic sharp-wave complexes on the EEG (Geschwind et al., 2008). Psychiatric symptoms such as personality changes, anxiety, depression, paranoia, obsessive-compulsive features, and psychosis occur in about 80% of patients during the first 100 days of illness (Wall et al., 2005). About 60% present with symptoms compatible with a rapidly progressive dementia. The mean duration of the illness is 6–7 months. The autosomal dominant familial form of CJD accounts for 10%–15% of cases; iatrogenically caused cases account for about 1%.

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New-variant CJD is a new form of acquired spongiform encephalopathy that emerged in 1994 in the United Kingdom. This form has been linked with consumption of infected animal products. Patients with the new variant have a different course characterized by younger age at onset (mean age, 29 years), prominent psychiatric and sensory symptoms, and a longer disease course. Spencer and colleagues reported that 63% demonstrated purely psychiatric symptoms at onset (dysphoria, anxiety, anhedonia), 15% had purely neurological symptoms, and 22% had features of both (Spencer et al., 2002). New-variant CJD may be distinguished from sporadic CJD by hyperintensities in the pulvinar on MRI. Median duration of illness was 13 months; by the time of death, prominent neurological and psychiatric manifestations were universal.

units per day administered as 3–4 million units intravenously every 4 hours or continuous infusion for 10–14 days. An alternative treatment is procaine penicillin G, 2–4 million units intramuscularly daily, with probenecid 500 mg orally, both daily for 10–14 days. A common recommendation to ensure an adequate response and cure is to repeat CSF studies 6 months after treatment.

Neurosyphilis

Thyroid Disease

A resurgence of neurosyphilis has accompanied the AIDS epidemic in the industrialized world. Neurosyphilis may occur in any stage of syphilis. Early neurosyphilis, seen in the first weeks to years of infection, is primarily a meningitic process in which the parenchyma is not typically involved. It can coexist with primary or secondary syphilis and be asymptomatic. Inadequate treatment of early syphilis and coinfection with HIV predispose to early neurosyphilis. Epidemiological studies in HIV-infected patients have documented increased HIV shedding associated with genital ulcers, suggesting that syphilis increases the susceptibility of infected persons to the acquisition and transmission of HIV (Lynn and Lightman, 2004). Symptomatic early neurosyphilis may present with meningitis with or without cranial nerve involvement or ocular changes, meningovascular disease, or stroke. Late neurosyphilis affects the meninges, brain, or spinal cord parenchyma and usually occurs years to decades after primary infection. Manifestations of late neurosyphilis include tabes dorsalis, a rapidly progressive dementia with psychotic features, general paresis (also known as general paralysis of the insane), or both. Pupillary abnormalities are common, the most classic being Argyll Robertson pupils: miotic, irregular pupils showing light-near dissociation (Berger and Dean, 2014). Dementia as a symptom of neurosyphilis is unlikely to improve significantly with treatment, yet the course of the illness can be arrested. The presenting psychiatric symptoms of neurosyphilis can include personality changes, hostility, confusion, hallucinations, expansiveness, delusions, and dysphoria. Symptoms also reported in association with neurosyphilis include explosive temper, emotional lability, anhedonia, social withdrawal, decreased attention to personal affairs, unusual giddiness, histrionicity, hypersexuality, and mania. A significant incidence of depression has been associated with general paresis. There is no uniform consensus for the best approach to diagnosing neurosyphilis. Diagnosis usually depends on various combinations of reactive serological tests, CSF cell count or protein, Venereal Disease Research Laboratories (VDRL) testing of the CSF, and clinical manifestations. Some authorities argue that all patients with syphilis should have CSF examination, since asymptomatic neurosyphilis can be identified only by changes in the CSF. The CSF VDRL is the standard serological test for CSF and is highly specific but insensitive. When reactive in the absence of substantial contamination of CSF with blood, it is usually considered diagnostic. Its titer may be used to assess the activity of the disease and response to treatment. Two tests of CSF may be used to confirm a diagnosis of neurosyphilis: the Treponema pallidum hemagglutination assay (TPHA) and fluorescent treponemal antibody absorption (FTA-ABS) assay. No single serology screen is perfect for diagnosing neurosyphilis. Other indicators of disease activity include CSF abnormalities such as elevated white blood cell count, elevated protein, and increased γ-globulin (IgG) levels. Treatment of neurosyphilis consists of a regimen of aqueous penicillin G, 18–24 million

Hypothyroidism results from a deficiency in circulating thyroxine (T4). It can be due to impaired function at the level of the hypothalamus (tertiary hypothyroidism), the anterior pituitary (secondary hypothyroidism), or the thyroid gland (primary hypothyroidism, the most common cause of hypothyroidism). Neurological symptoms and signs can include headache, fatigue, apathy, inattention, slowness of speech and thought, sensorineural hearing loss, sleep apnea, and seizures. Some of these symptoms may mimic depression. Hypothyroidism can worsen or complicate the course of depression, resulting in a seemingly refractory depression. More rare findings include polyneuropathy, cranial neuropathy, muscle weakness, psychosis (referred to as myxedema madness), dementia, coma, and death. Psychosis typically presents with paranoid delusions and auditory hallucinations. Hyperthyroidism may be due to a number of causes that produce increased serum T4. With mild hyperthyroidism, patients are typically anxious, irritable, emotionally labile, tachycardic, and tremulous. Other symptoms can include apathy, depression, panic attacks, feelings of exhaustion, inability to concentrate, and memory problems. When apathy and depression are present, the term apathetic hyperthyroidism is often used. Thyroid storm results from an abrupt elevation in T4, often provoked by significant stress such as that due to surgery. It can be associated with fever, tachycardia, seizures, and coma; if untreated, it is often fatal. Psychosis and paranoia frequently occur during thyroid storm but are rare with milder hyperthyroidism, as is mania. Many patients will experience complete remission of symptoms 1–2 months after a euthyroid state is obtained, with a marked reduction in anxiety, sense of exhaustion, irritability, and depression. Some authors, however, report an increased rate of anxiety in patients, as well as persistence of affective and cognitive symptoms for several months up to 10 years after a euthyroid state has been established. Steroid-responsive encephalopathy associated with autoimmune thyroiditis (STREAT), also known as Hashimoto encephalopathy, is a rare disorder involving thyroid autoimmunity (Castillo et al., 2006). Antibodies associated with this condition include antithyroid peroxidase antibodies (previously known as antithyroid microsomal antibodies) and antithyroglobulin antibodies. The clinical syndrome may manifest with a progressive or relapsing and remitting course consisting of tremor, myoclonus, transient aphasia, stroke-like episodes, psychosis, seizures, encephalopathy, hypersomnolence, stupor, or coma. Encephalopathy usually develops over 1–7 days. The underlying mechanism of Hashimoto encephalopathy remains under investigation; importantly, levels of thyroid-stimulating hormone can be normal in this disorder. CSF most often shows an elevated protein level with almost no nucleated cells, whereas oligoclonal bands are often present. The EEG is abnormal in almost all cases, showing generalized slowing or frontal intermittent rhythmic δ activity. Triphasic waves, focal slowing, and epileptiform abnormalities may also be seen. MRI of the brain

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Metabolic and Toxic Essentially any metabolic derangement, if severe enough or combined with other conditions, can adversely affect behavior and cognition (eTable 10.5 ). Metabolic disorders should remain within the differential diagnosis when patients with psychiatric symptoms are being evaluated.

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Depression and Psychosis in Neurological Practice

107.e1

Metabolic Disorders That May Cause Psychiatric and Neurological Symptoms

Abnormality

Mood Disorder

Hyperthyroidism Hypothyroidism Hypercortisolism Hypocortisolism Hypercalcemia Hypoglycemia Hyponatremia (SIADH)

+ +++ +++ ++ ++ ++ ++

Mania

Delirium

Dementia

Psychotic Disorder

Anxiety Disorder

Personality Changes

+

++ ++ ++ + ++ +++ ++

+ + + + ++ ++ ++

++ ++ +++ + ++ ++ +

+++

+ + + +

++

+

+

+++

+

+++, Frequent; ++, common; +, rare; SIADH, syndrome of inappropriate antidiuretic hormone secretion. Adapted from Breitbart, W.B., 1989. Endocrine-related psychiatric disorders. In: Holland, J.C., Rowland, J.H. (Eds.), Handbook of Psycho-oncology: Psychological Care of the Patient with Cancer. Oxford University Press, New York, pp. 356––366; and from Breitbart W., Holland, J.C., 1993. Psychiatric Aspects of Symptom Management in Cancer Patients. APA Press, Washington, DC, p. 29.

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is often normal but may reveal hyperintensities on T2-weighted or fluid-attenuated inversion recovery (FLAIR) imaging in the subcortical white matter or at the gray/white matter junction. SPECT may show regions of hypoperfusion. The neurological and psychiatric symptoms respond well to treatment, which generally involves highdose steroids. The associated abnormal findings on EEG, and often the MRI abnormalities, resolve with effective treatment.

Wilson Disease Wilson disease (WD), also known as hepatolenticular degeneration, is an autosomal recessive disorder produced by a mutation on chromosome 13. The gene encodes a transport protein, the mutation of which causes abnormal deposition of copper in the liver, brain (especially the basal ganglia), and the corneas of the eyes. WD typically begins in childhood but in some cases has its onset as late as the fifth or sixth decade. About one-third of patients present with psychiatric symptoms, one-third present with neurological features, and one-third present with hepatic disease. Neurological manifestations are largely extrapyramidal, including chorea, tremor (infrequently including wing beating–like characteristics), and dystonia. Other symptoms include dysphagia, dysarthria, ataxia, gait disturbance, and a fixed (sardonic) smile. Seizures may also occur in a minority of patients. Potential neuropsychiatric symptoms are numerous, with at least half of patients manifesting symptoms early in the disease course. Personality and mood changes are the most common neuropsychiatric features, with depression occurring in approximately 30% of patients. Bipolar spectrum symptoms occur in about 20% of patients. Suicidal ideation is recognized in about 5%–15%. WD patients can present with increased sensitivity to neuroleptics. Other symptoms include irritability, aggression, and psychosis. Cognitively, the profile is consistent with disturbance of the frontosubcortical networks. Despite long-term treatment, about 70% of WD patients develop psychiatric symptoms (Srinivas et al., 2008; Svetel et al., 2009). Diagnosis is suggested by the identification of Kayser-Fleischer (KF) rings in patients with the appropriate clinical picture. The KF ring is a yellow-brown discoloration of the Descemet membrane in the limbic area of the cornea, best visualized with slit-lamp examination. A KF ring is present in 98% of patients with neurological disease and in 80% of all cases of WD. Reduced serum ceruloplasmin levels and elevated 24-hour urine copper excretion are consistent with this disorder. A liver biopsy is sometimes necessary to make the diagnosis. MRI studies may show abnormal T2 signal in the putamen, midbrain, pons, thalamus, cerebellum, and other structures. Atrophy is commonly present. The initial treatment for symptomatic patients is chelation therapy with either penicillamine or trientine. An estimated 20%–50% of patients with neurological manifestations treated with penicillamine experience an acute worsening of their symptoms, and some of these patients do not recover to their pretreatment neurological baseline. Alternatives that may lead to a lower incidence of neurological worsening include trientine or tetrathiomolybdate. Both may be used in combination with zinc therapy. Treatment of presymptomatic patients or maintenance therapy of successfully treated symptomatic patients can be accomplished with a chelating agent or zinc. Early treatment may result in partial improvement of the MRI changes as well as most of the neurological and psychiatric symptoms.

Vitamin B12 and Folic Acid Deficiency The true prevalence of vitamin B12 deficiency in the general population is unknown. The Framingham study demonstrated a prevalence of 12% among elderly persons living in the community. Other studies have suggested that the incidence may be as high as 30%–40% among the sick and institutionalized elderly. The most common sign

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of vitamin B12 deficiency is macrocytic anemia. However, signs and symptoms attributed to the nervous system are diverse and can occur in the absence of anemia or macrocytosis. Furthermore, a normal serum cobalamin level does not exclude the possibility of a clinical deficiency. Serum homocysteine levels, which are elevated in more than 90% of deficiency states, and serum methylmalonic acid levels can be used to verify deficiency states in the appropriate settings. Subacute combined degeneration (SCD) refers to the combination of spinal cord and peripheral nerve pathology associated with vitamin B12 deficiency. Patients often complain of unsteady gait and distal paresthesias. The examination may demonstrate evidence of posterior column, pyramidal tract, and peripheral nerve involvement. Cognitive, behavioral, and psychiatric manifestations can occur in isolation or together with the elemental signs and symptoms. Personality change, cognitive dysfunction, mania, depression, and psychosis have been reported. Prominent psychotic features include paranoid or religious delusions and auditory and visual hallucinations. Dementia is often comorbid with cobalamin deficiency; however, the causative association is unclear. There are few research data to support the existence of reversible dementia due to vitamin B12 deficiency. Cobalamin deficiency–associated cognitive impairment is more likely to improve when it is mild and of short duration. Folate deficiency can produce a clinical picture similar to cobalamin deficiency, although some investigators report that folate deficiency tends to produce more depression, whereas vitamin B12 deficiency tends to produce more psychosis. Elevated serum homocysteine is also seen with a functional folate deficiency state wherein folate utilization is impaired. Repletion of folate if comorbid vitamin B12 deficiency is not first corrected can result in an acute exacerbation of the neuropsychiatric symptoms.

Porphyrias The porphyrias are caused by enzymatic defects in the heme biosynthetic pathway. Porphyrias with neuropsychiatric symptoms include acute intermittent porphyria (AIP), variegated porphyria (VP), hereditary mixed coproporphyria (HMP), and plumboporphyria (extremely rare and autosomal recessive), which may give rise to acute episodes of potentially fatal symptoms such as neurovisceral crisis, abdominal pain, delirium, psychosis, neuropathy, and autonomic instability. AIP, the most common type reported in the United States, follows an autosomal dominant pattern of inheritance and is due to a mutation in the gene for porphobilinogen deaminase. The disease is characterized by attacks that may last days to weeks, with relatively normal function between attacks. Infrequently, the clinical course may exhibit persisting clinical abnormalities with superimposed episodes of exacerbation. The episodic nature, clinical variability, and unusual features of this condition may cause symptoms to be misattributed to somatoform, functional (psychogenic), or other psychiatric disorders. Attacks may be spontaneous but are typically precipitated by a variety of factors such as infection, alcohol use, pregnancy, anesthesia, and numerous medications including antidepressants, anticonvulsants, and oral contraceptives. Porphyric attacks usually manifest with a triad consisting of abdominal pain, peripheral neuropathy, and neuropsychiatric symptoms. Seizures may also occur. Abdominal pain is the most common symptom, which can result in surgical exploration if the diagnosis is unknown. A variety of cognitive and behavioral changes can occur, including anxiety, restlessness, insomnia, depression, mania, hallucinations, delusions, confusion, catatonia, and psychosis. The diagnosis can be confirmed during an acute attack of AIP, HMP, or VP by measuring urine porphobilinogens. Acute attacks are treated with avoidance of precipitating factors (e.g., medications), intravenous hemin, intravenous glucose, and pain control.

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Drug Abuse Common neurological manifestations are broad and include the direct effects of intoxication, side effects, and withdrawal syndromes as well as indirect effects. Direct effects can range from somnolence with sedatives to psychosis from hallucinogens and stimulants. Side effects may be as severe as stroke or vasculitis from stimulant abuse. Withdrawal may be lethal, as in the case of alcohol withdrawal and delirium tremens. Indirect effects can occur as a result of trauma, such as head injury, suffered while under the influence. Substance abuse has a high comorbidity with a variety of psychiatric conditions. Neuropsychiatric manifestations occur with abuse of all classes of drugs and are summarized in eBox 10.6. The behavioral and cognitive manifestations of substance abuse may be transient; in a vulnerable subset of individuals, however, they may be chronic. Growing evidence suggests that drug use (e.g., 3,4-methylenedioxymethamphetamine [MDMA, “ecstasy”]) may promote the development of chronic neuropsychiatric states such as depression and impaired cognition due to changes in structural and functional neuroanatomy (Parrott, 2013). Although the use of Cannabis sativa seems to be neither a sufficient nor a necessary cause of psychosis, it does confer an increased relative risk for developing psychosis in dose-dependent fashion (Marconi et al., 2016).

Systemic Lupus Erythematosus Systemic lupus erythematosus (SLE, lupus) is a multisystem inflammatory disorder that affects all ages, although young females are at a significantly elevated risk. CNS involvement is common, with clinical manifestations seen at some point during the disease course in up to 90% of patients. Primary neurological and psychiatric manifestations of SLE are likely due to a mixture of pathogenic mechanisms that include vascular abnormalities, autoantibodies, and the local production of inflammatory mediators. Secondary neurological and psychiatric manifestations occur as a result of various therapies (e.g., immunosuppression with steroids) or complications of the disease. Neuropsychiatric symptoms are common, often episodic, and may occur in association with steroid treatment, which creates significant dilemmas in management. Depression and anxiety each occur in approximately 25% of SLE patients. Reports of the prevalence of overall mood disturbances range between 16% and 75%, and reports of anxiety disorders occur in 7%–70%. Psychosis is rarer and tends to occur in the context of confusional states. Its overall prevalence has been reported to range from 5% to 8%. The incidence of psychotic symptoms in patients receiving prednisone in doses between 60 and 100 mg/day is approximately 30%. These symptoms are reported to respond favorably to reduction in steroid dose and psychotropic management. Focal or generalized seizures may occur in the setting of active generalized SLE or as an isolated event. The prevalence of seizures ranges from 3% to 51%. Cognitive manifestations of SLE—including temporary, fluctuating, or relatively stable characteristics—eventually occur in up to 75% of patients; these manifestations range from mild attentional difficulties to dementia. In some patients, cognitive performance improves with resolution of any concurrent psychiatric disturbances. Cerebrovascular disease may underlie nonreversible cognitive dysfunction; when progressive, it may cause atrophy and multi-infarct dementia. Many patients with cognitive impairment have no demonstrable vascular lesions on neuroimaging. Cognitive impairment may manifest as subcortical features with deficits in processing speed, attention, learning and memory, conceptual reasoning, and cognitive flexibility. Reports of the prevalence of subclinical cognitive impairment range from 11% to 54% of patients. A number of brain-specific antibodies have been studied as potential diagnostic markers of psychosis associated with neuropsychiatric SLE (NPSLE), but none appear to be specific (Kimura et al., 2010). SLE patients identified

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as having a persistently positive immunoglobulin (Ig)G anticardiolipin antibody over a 5-year period have been demonstrated to have a greater reduction in psychomotor speed than antibody-negative SLE patients. Patients with a persistently elevated immunoglobulin A (IgA) anticardiolipin antibody level have been demonstrated to have poorer performance on tests of conceptual reasoning and executive function than antibody-negative SLE patients. Elevated IgG and IgA anticardiolipin antibody levels may be causative or a marker of long-term subtle deterioration in cognitive function in SLE patients. However, their role in routine evaluation and management remains controversial. Cerebrovascular disease is a well-known cause of neuropsychiatric dysfunction and is reported to occur in 5%–18% of SLE patients. The criteria set most widely used for diagnosing SLE is that developed by the American College of Rheumatology (ACR). An antinuclear antibody (ANA) titer to 1:40 or higher is the most sensitive of the ACR criteria and is present in up to 99% of persons with SLE at some point in their illness. The ANA titer, however, is not specific. It can be positive in several other rheumatological conditions, in nonclinical populations, and in relation to some medication exposures. Anti–double-stranded DNA and anti-Smith antibodies, particularly in high titers, have high specificity for SLE, although their sensitivity is low. The rapid plasma reagin (RPR) test, a syphilis serology, may be falsely positive. Treatment of NPSLE includes corticosteroids and immunosuppressive therapy, including pulse intravenous cyclophosphamide or plasmapheresis when NPSLE is thought to occur secondary to an inflammatory process. Anticoagulation is used in patients with thrombotic disease in the setting of antiphospholipid antibody syndrome.

Multiple Sclerosis MS is an inflammatory demyelinating disease that manifests the pathological hallmark findings of multifocal demyelinated plaques in the brain and spinal cord. MS lesions are typically disseminated throughout the CNS, with a predilection for the optic nerves, brainstem, spinal cord, cerebellum, and periventricular white matter. Its cause remains unknown, but it is thought to be an immune-mediated disorder affecting individuals with a genetic predisposition. The heterogeneity of clinical, pathological, and MRI findings suggest involvement of more than one pathological mechanism. It is the leading cause of nontraumatic disability among young adults. Socioepidemiological studies indicate that MS leads to unemployment within a 10-year disease course in as many as 50%–80% of patients. Females are more affected than males at a 2:1 ratio. It is characterized either by attacks of neurological deficits with variable remittance or by a steadily progressive course of neurological decline. Neuropsychiatric manifestations of MS are common, occurring in up to 60% of patients at some point in their disease. The lifetime prevalence of major depression in MS is approximately 50%. The lifetime prevalence of bipolar disorder is twice the prevalence in the general population. Euphoria may be present in more advanced MS, usually in association with cognitive deficits. Pseudobulbar affect— defined as outbursts of involuntary, uncontrollable, stereotypical episodes of laughing or crying—occurs in varying degrees of severity in approximately 10% of patients. Other symptoms include anxiety, sleep disorder, emotional lability/irritability, apathy, mania, suicidality, and rarely psychosis. Occasionally psychiatric symptoms may present as the major manifestation of an episode of demyelination. The presence of psychiatric symptomatology does not preclude the use of steroids to abbreviate clinical attacks of MS. There is ongoing debate about whether interferon therapy is associated with a higher incidence of depression in MS patients. Clinically, pharmacological and behavioral treatment mirrors the management of depression and psychosis in patients without MS. Recently published guidelines for management

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eBOX 10.6 Potential Behavioral and Cognitive Manifestations of Substance Abuse Depression Panic attacks Anxiety Hallucinations Delusions Paranoia Mania Depersonalization Disinhibition Impulsivity Cognitive deficits: Attention Calculation Executive tasks Memory Fatigue Sedation Autoimmune

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of the psychiatric symptoms of MS suggest that there is insufficient evidence to refute or support the use of antidepressants for depression or anxiety disorders in this population, although a combination of dextromethorphan and quinidine may be considered for the treatment of pseudobulbar affect (Minden et al., 2014). Cognitive impairment is found in approximately 40% of patients. Deficits have been described in working, semantic, and episodic memory as well as in the person’s ability to accurately assess his or her own memory function. Patients may also suffer from impaired attention, cognitive slowing, reduced verbal fluency, and difficulties with abstract reasoning and concept formation. Correlations between cognitive impairment and the MRI location of lesions and indices of total lesion area are actively under investigation (Charil et al., 2003; Reuter et al., 2011). There are few data on the treatment of cognitive dysfunction in MS (Amato et al., 2013). The disease-modifying agent interferon β-1a was noted to be associated with improvements in information-processing and problem-solving abilities over a 2-year longitudinal study. A small trial demonstrated an improvement in complex attention, concentration, and visual memory in a group of patients treated for 1 year with interferon β-1b compared with controls (Barak and Achiron, 2002). Donepezil, 10 mg daily, has been reported to improve verbal learning and memory in some MS patients.

Neoplastic A variety of neoplasms cause cognitive and behavioral disorders. Of particular relevance are mass lesions and paraneoplastic syndromes. Mass lesions can be single or multiple and can be primary to the CNS or metastatic. The most common intracranial primary tumors are astrocytomas (e.g., glioblastoma multiforme), meningiomas, pituitary tumors, vestibular schwannomas, and oligodendrogliomas. Common metastatic tumors include primary lung and breast tumors, melanoma, and renal and colon cancers. The number of patients presenting with a primary psychiatric diagnosis secondary to an unidentified brain tumor is likely to be less than 5%. However, 15%–20% of patients with intracranial tumors may present with neuropsychiatric manifestations before the development of primary neurological problems such as motor or sensory deficits. The behavioral manifestations of mass lesions are diverse and related to a number of factors including direct disruption of local structures or circuits, rate of growth, seizures, and increased intracranial pressure. A relationship between tumor location and specific psychiatric symptoms has not been established. Meningiomas, given their slow growth over years, are classic examples of tumors that can present solely with behavioral manifestations. Common locations include the olfactory groove and sphenoid wings, which can disrupt adjacent limbic structures such as the orbital frontal gyri and medial temporal lobes. Paraneoplastic syndromes represent remote nonmetastatic manifestations of malignancy. Neurological paraneoplastic syndromes are primarily immune-mediated disorders that may develop as a result of antigens shared between the nervous system and tumor cells (Berzero and Psimaras, 2018). The most common primary malignancies that promote neurological paraneoplastic syndromes are ovarian and small-cell lung cancer (SCLC). These syndromes generally develop subacutely, often before the primary malignancy is identified, and may preferentially involve selected regions of the CNS. Typical sites of involvement include muscle, neuromuscular junction, peripheral nerve, cerebellum, and limbic structures. Limbic encephalitis—associated with SCLC, testicular cancer, and ovarian teratomas among other pathologies—produces a significant amnestic syndrome and neuropsychiatric symptoms including agitation, depression, personality changes, apathy, delusions, hallucinations, psychosis, and complex partial and generalized seizures. Anti N-methyl-d-aspartate

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(NMDA) receptor encephalitis associated with antibodies against the NR1-NR2 heterodimer of the receptor has been increasingly recognized as presenting commonly in young women with ovarian teratomas and psychiatric symptoms including anxiety, agitation, bizarre behavior, paranoid delusions, visual or auditory hallucinations, and/ or memory loss. Additional frequently encountered symptoms include seizures, decreased consciousness, dyskinesias, autonomic instability, and hypoventilation (Dalmau and Rosenfeld, 2014). Elevated markers in paraneoplastic syndromes may include (1) intracellular paraneoplastic antigens, such as Hu, associated with SCLC, and Ta and Ma-2 (Hoffmann et al., 2008), associated with testicular cancer; and (2) cell membrane antigens such as the NMDA receptor and voltage-gated potassium channels. Paraneoplastic disorders are often progressive and refractory to therapy, although in some cases significant improvement follows tumor resection and early initiated immunotherapy interventions. Significant neuropsychiatric sequelae can arise from the various chemotherapeutic and radiation therapies used for cancer treatment.

Degenerative Neuropsychiatric symptoms are common in most degenerative disorders that produce significant dementia. In this chapter, the term dementia is used synonymously with the DSM-5 diagnostic category of major neurocognitive disorder; mild cognitive impairment (MCI) is synonymous with mild neurocognitive disorder. The individual presentations of such symptoms are related to a number of factors specific to the disease: location of lesion burden, rate of progression of disease, and factors specific to the individual (e.g., premorbid personality, education level, psychiatric history, social support system, and coping skills). Neurodegenerative diseases are increasingly recognized as involving abnormalities of protein metabolism. About 70% of dementias in the elderly and more than 90% of neurodegenerative dementias can be linked to abnormalities of three proteins: β-amyloid, α-synuclein, and tau. Disorders of protein metabolism have associated neuroanatomical regions of vulnerable cell populations that are related to the clinical manifestations. AD, for example, has associated disorders of β-amyloid and tau. PD, DLB, and multisystem atrophies are synucleinopathies. α-Synuclein is the main component of Lewy bodies, which are a major histological marker seen in PD and DLB. In these disorders, Lewy bodies may be found in the substantia nigra, locus coeruleus, nucleus basalis, limbic system, and transitional and neocortex. FTD, progressive supranuclear palsy (PSP), and corticobasal ganglionic degeneration implicate abnormal tau metabolism in their pathogenesis. Tauopathies are associated with selective involvement of the frontal and temporal cortex and frontosubcortical circuitry.

Alzheimer Disease and Mild Cognitive Impairment Neuropsychiatric symptoms of AD may include agitation, aggression, delusions including paranoia, hallucinations, anxiety, apathy, social withdrawal, reduced speech output, reduction or alteration of long-standing family relationships, and loss of sense of humor. With disease progression, patients often lose awareness (insight) into the nature and severity of their deficits. A review of 100 cases of autopsy-proven AD demonstrated that 74% of patients had behavioral symptoms detected at the time of the initial evaluation. Symptoms included apathy (51%), hallucinations (25%), delusions (20%), depressed mood (6.6%), verbal aggression (36.8%), and physical aggression (17%). The presence of behavioral symptoms at the initial evaluation was associated with greater functional impairment not directly related to the cognitive impairments. Depressive symptoms, dysphoria, or major depression eventually occur in approximately 50% of patients. Psychosis has been reported to occur in 30% to 50% of patients at some time during the course of the illness, more commonly

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CHAPTER 10 Depression and Psychosis in Neurological Practice in the later stages. Mania occurs in less than 5%. Behavioral changes have been shown to be problematic and to precipitate earlier nursing home placement. Social comportment has been viewed as being relatively spared in AD, but subtle personality changes occur in nearly every individual over time. Significant impairment in the ability to recognize facial expressions of emotion and an inability to repeat, comprehend, and discriminate affective elements of language have been reported. It has been hypothesized that 15% of AD patients may have a frontal variant wherein they present with difficulties attributable to frontal lobe circuitry rather than an amnestic syndrome. Impairments in driving ability (Dawson et al., 2009) and decision-making abilities such as medical decision making (Okonkwo et al., 2008) and financial management (Marson et al., 2009) may be present even in early AD. Atypical antipsychotic drugs are widely used to treat psychosis, aggression, and agitation in patients with AD. Efficacy is modest and concerns about safety have emerged, including increased risk of mortality, cerebrovascular events, metabolic derangements, EPS, falls, cognitive worsening, cardiac arrhythmia, and pneumonia, among other symptoms (Steinberg and Lyketsos, 2012). Adverse effects may offset advantages in the efficacy of atypical antipsychotic drugs for the treatment of psychosis, aggression, or agitation in AD patients, particularly if used chronically. Limited evidence suggests that electroconvulsive therapy (ECT) may be effective for the management of severe agitation (Acharya et al., 2015). Early evidence also suggests that dronabinol may be helpful in the management of aggressive behavior in severely demented patients (Woodward et al., 2014). The concept of MCI was developed to characterize a population of individuals exhibiting symptoms that are between normal age-related cognitive decline and dementia. These patients have minimal decline from their prior level of functioning and remain independent. MCI (amnestic single domain) was initially defined as a condition of memory impairment beyond what was expected for age in the absence of impairments in other domains of cognitive functioning such as working memory, executive function, language, and visuospatial ability. This concept has since evolved and now includes four subtypes of impairment that are not of sufficient severity to warrant the diagnosis of dementia. The second type of MCI, called amnestic multiple domain, is associated with memory impairment plus impairment in one or more other cognitive domains. The third subtype is called nonamnestic single domain, and the fourth is known as nonamnestic multiple domain MCI. In many cases the natural history of these subtypes leads to different endpoint conditions. Combining the clinical syndrome with the presumed cause may allow for reliable prediction of outcome of the MCI syndrome. When associated with only memory impairment, MCI may represent normal aging, depression, or progress to AD. Amnestic MCI involving multiple domains has a higher association with depression or progression to AD or vascular dementia. Nonamnestic single-domain MCI may have a higher likelihood of progression to FTD. Nonamnestic multiple-domain MCI may have a higher likelihood of progression to Lewy body dementia or vascular dementia (Petersen and Negash, 2008). In 2008, it was estimated that more than 5 million people in the United States above 71 years of age had MCI. The prevalence of MCI among persons younger than 75 years has been estimated to be 19% and 29% for those older than 85 years. Almost one-third of these individuals have amnestic MCI, which may progress to AD at a rate of 10%–15% per year. The conversion rate of amnestic MCI to dementia over a 6-year period may be as high as 80%. Neuropsychiatric symptoms (also known as mild behavioral impairment) are common in persons with MCI. Depression occurs in 20%, apathy in 15%, and irritability in 15%. Increased levels of agitation and aggression are also present. Almost half of MCI patients demonstrate one of these

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neuropsychiatric symptoms coincident with the onset of cognitive impairment. Impaired awareness of memory dysfunction may also be present to a degree comparable with that found in persons with early AD. Evidence suggests that persons with MCI have an increased risk of motor vehicle accidents when risk factors such as having a history of driving citations, crashes, reduced driving mileage, situational avoidance, or aggression or impulsivity are present. Difficulties with medical decision making have also been identified in some individuals with MCI (Okonkwo et al., 2008).

Frontotemporal Dementia FTD, the most common progressive focal cortical syndrome, is characterized by atrophy of the frontal and anterotemporal lobes. Age at presentation is usually between 45 and 65 years (almost invariably before age 65), and reports of its incidence range from being equal in males and females to (more recently) predominating in males by a ratio of 14:3. The prevalence of FTD is equal to that of AD for early-onset (age real spontaneous object use and worse for transitive rather than intransitive actions.

to demonstrate how to prepare a letter for mailing or a sandwich for eating. The examiner instructs the patient that the imaginary elements needed for the task are laid out in front of them; the patient is then observed to see whether the correct sequence of events is performed. Ideational apraxia manifests as a failure to perform each step in the correct order. If disturbed, the examiner can repeat this testing with a real object, such as providing the patient with a letter and stamp.

Testing for Conceptual Apraxia Patients with conceptual apraxia make content errors and demonstrate the actions of tools or objects other than the one they were asked to pantomime. For example, the examiner shows the patient either pictures or the actual tools or objects and asks the patient to pantomime or demonstrate their use or function. Patients with conceptual apraxia pantomime the wrong use or function, but they are able to imitate gestures without spatiotemporal errors (see Table 11.1).

Testing for Limb-Kinetic Apraxia For limb-kinetic apraxia testing, the examiner asks the patient to perform fine finger movements and looks for evidence of incoordination. For example, the examiner asks the patient to pick up a small coin such as a dime from the table with the thumb and the index finger only. Normally, people use the pincer grasp to pick up a dime by putting a forefinger on one edge of the coin and the thumb on the opposite edge. Patients with limb-kinetic apraxia will have trouble doing this without sliding the coin to the edge of the table or using multiple fingers. Another test involves the patient rotating a nickel between the thumb, index, and middle fingers 10 times as rapidly as they can. Patients with limb-kinetic apraxia are slow and clumsy at these tasks (Hanna-Pladdy et al., 2002). In addition, they may also have disproportionate problems with meaningless gestures. These tasks, particularly the simple coin rotation test, provide valuable information about dexterity skills for ADLs (Foki et al., 2016).

Testing for Callosal Apraxia The examination for callosal apraxias is the same as for the other limb apraxias except that the abnormalities are limited to the nondominant

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hand. The testing for callosal apraxia may reveal a disconnection-variant ideomotor apraxia, a dissociative apraxia, or even a conceptual apraxia in the nondominant limb (Heilman et al., 1997).

PATHOPHYSIOLOGY OF LIMB APRAXIAS Ideomotor apraxia is associated with left hemispheric lesions in a variety of structures including the inferior parietal lobe, the frontal lobe, and the premotor areas, particularly the SMA. There are reports of ideomotor apraxia due to subcortical lesions in the basal ganglia (caudate-putamen), thalamus (pulvinar), and associated white-matter tracts including the corpus callosum. Limb apraxias can be caused by any central nervous system disorder that affects these regions. The different forms of limb apraxia result from cerebrovascular lesions, especially left middle cerebral artery strokes with right hemiparesis and apraxia evident in the left upper extremity. Right anterior cerebral artery strokes and paramedian lesions could produce ideomotor apraxia, disconnection variant. Ideomotor apraxia and limb-kinetic apraxia can be the initial or presenting manifestation of disorders such as corticobasal syndrome, primary progressive aphasia, parietal-variant Alzheimer disease, and other disorders (Rohrer et al., 2010). There are important considerations of hemispheric specialization and handedness on praxis. Early investigators proposed that handedness was related to the hemispheric laterality of the movement formulas. Studies using functional imaging have provided converging evidence that in people who are right-handed, it is the left inferior parietal lobe that appears to store the movement formulas needed for learned skilled movements (Muhlau et al., 2005). However, lefthanded people may demonstrate an ideomotor apraxia from a right hemisphere lesion, because their movement formulas can be stored in their right hemisphere. It is not unusual to see right-handed patients with large left hemisphere lesions who are not apraxic, and there are rare reports of right-handed patients with right hemisphere lesions and limb apraxia (Schell et al., 2014). These findings suggest that hand preference is not entirely determined by the laterality of the movement formulas, and praxis and handedness can be dissociated.

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REHABILITATION FOR LIMB APRAXIAS

RELATED DISORDERS

Because many instrumental and routine ADLs depend on learned skilled movements, patients with limb apraxia usually have impaired functional abilities. The presence of limb apraxia, more than any other neuropsychological disorder, correlates with the level of caregiver assistance required 6 months after a stroke, whereas the absence of apraxia is a significant predictor of return to work after a stroke (Saeki et al., 1995). The treatment of limb apraxia is therefore important for improving the quality of life of the patient. Even though many apraxia treatments have been studied, none has emerged as the standard. There are no effective pharmacotherapies for limb apraxia, and treatments primarily involve rehabilitation strategies. Buxbaum and associates (2008) surveyed the literature on the rehabilitation of limb apraxia and identified 10 studies with 10 treatment strategies: multiple cues, error type reduction, six-stage task hierarchy, conductive education, strategy training, transitive/intransitive gesture training, rehabilitative treatment, error completion, exploration training, and combined error completion and exploration training. Most of these approaches emphasize cueing with multiple modalities, with verbal, visual, and tactile inputs, repetitive learning, and feedback and correction of errors. If possible, rehabilitation techniques should involve activities that are akin to a natural setting (Baak et al., 2015). The timing of rehabilitation may be an important factor as well. Apraxia patients with acute lesions, such as left hemisphere strokes, appear to respond better if the therapy is initiated early (Mutha et al., 2017). Patients with post-stroke apraxia have had generalization of cognitive strategy training to other ADLs (Geusgens et al., 2006), but, unfortunately, many others have not (Bickerton et al., 2006; Shimizu and Tanemura, 2017). Newer technologies such as transcranial stimulation of left parietal cortex or primary motor cortex, can temporarily improve praxis in some patients (Bianchi et al., 2015; Bolognini et al., 2015; Park 2018). Other novel techniques for apraxia rehabilitation include embedding sensors in household tools in order to guide rehabilitation (Hughes et al., 2013), using a videogame-based feedback system to improve pinch and grasp forces (Fusco et al., 2018), and evaluating apraxia with a virtual partner (Candidi et al., 2017). In summary, patients can learn and produce new gestures, and new technologies, including transcranial stimulation, may play a role in rehabilitation, but the re-learned specific movements may not persist or generalize well to contexts outside the rehabilitation setting. Nevertheless, some patients with ideomotor apraxia have improved with gesture-production exercises (Smania et al., 2000), with positive effects lasting 2 months after completion of gesture training (Smania et al., 2006). Patients with apraxia would benefit from referral to a rehabilitation specialist with experience in treating apraxias (Cantagallo et al., 2012; Dovern et al., 2012). Additional practical interventions for the management of limb apraxias involve making environmental changes. This includes removing unsafe tools or implements, providing a limited number of tools to select from, replacing complex tasks with simpler ones that require few or no tools and fewer steps, as well as similar modifications.

Other movement disturbances may be related to or confused with the limb apraxias. The alien limb phenomenon, a potential result of callosal lesions, is the experience that a limb feels foreign and has involuntary semipurposeful movements, such as spontaneous limb levitation. This disorder can occur from neurodegenerative conditions, most notably corticobasal syndrome. Akinesia is the inability to initiate a movement in the absence of motor deficits, and hypokinesia is a delay in initiating a response. Akinesia and hypokinesia can be directional, with decreased initiation of movement in a specific spatial direction or hemifield. Akinesia and hypokinesia result from a failure to activate the corticospinal system due to Parkinson disease and diseases that affect the frontal lobe cortex, basal ganglia, or thalamus. Several other movement disturbances are associated with frontal lobe dysfunction. Motor impersistence is the inability to sustain a movement or posture and occurs with dorsolateral frontal lesions. Magnetic grasp and grope reflexes with automatic reaching for environmental stimuli are primitive release signs. In echopraxia, some patients automatically imitate observed movements. Along with utilization behavior, echopraxia may be part of the environmental dependency syndrome of some patients with frontal lesions. Catalepsy is the maintenance of a body position into which patients are placed (waxy flexibility). Two related terms are mitgehen (“going with”), where patients allow a body part to move in response to light pressure, and mitmachen (“doing with”), where patients allow a body part to be put into any position in response to slight pressure, then return the body part to the original resting position after the examiner releases it. Motor perseveration is the inability to stop a movement or a series of movements after the task is complete. In recurrent motor perseveration, the patient keeps returning to a prior completed motor program, and in afferent or continuous motor perseveration, the patient cannot end a motor program that has just been completed.

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SUMMARY Limb apraxia, or the disturbance of learned skilled movements, is an important but often missed or unrecognized impairment. Clinicians may misattribute limb apraxia to weakness, hemiparesis, clumsiness, or other motor, sensory, spatial, or cognitive disturbance. Apraxia may only be evident on fine, sequential, or specific movements of the upper extremities and requires a systematic praxis examination (Zadikoff and Lang, 2005). Apraxia is an important cognitive disturbance and a salient sign in patients with strokes, Alzheimer disease, corticobasal syndrome, and other conditions. The model of left parietal movement formulas and disconnection syndromes introduced by Liepmann over 100 years ago continues to be compelling today. This model, in the context of a dedicated apraxia examination and analysis for spatiotemporal or content errors, clarifies and classifies the limb apraxias. Although more effective treatments need to be developed, rehabilitation strategies can be helpful interventions for these disturbances. Fortunately, recent advances in technology and rehabilitation continue to enhance our understanding and management of limb apraxias. The complete reference list is available online at https://expertconsult. inkling.com/.

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12 Agnosias Howard S. Kirshner OUTLINE Visual Agnosias, 127 Cortical Visual Disturbances, 127 Cortical Visual Distortions, 128 Balint Syndrome and Simultanagnosia, 128 Visual Object Agnosia, 128 Optic Aphasia, 130 Prosopagnosia, 130 Klüver-Bucy Syndrome, 130

Auditory Agnosias, 131 Cortical Deafness, 131 Pure Word Deafness, 131 Auditory Nonverbal Agnosia, 131 Phonagnosia, 132 Amusia, 132 Tactile Agnosias, 132 Tactile Aphasia, 132 Summary, 132

Agnosias are disorders of recognition. The general public is familiar with agnosia from Oliver Sacks’ patient, who not only failed to recognize his wife’s face but also mistook it for a hat. Sigmund Freud originally introduced the term agnosia in 1891 to denote disturbances in the ability to recognize and name objects, usually in one sensory modality, in the presence of intact primary sensation. Another definition, that of Milner and Teuber in 1968, referred to agnosia as a “normal percept stripped of its meaning.” The agnosic patient can perceive and describe sensory features of an object yet cannot recognize or identify the object. Criteria for the diagnosis of agnosia include: (1) failure to recognize an object; (2) normal perception of the object, excluding an elementary sensory disorder; (3) ability to name the object once it is recognized, excluding anomia as the principal deficit; and (4) absence of a generalized dementia. In addition, agnosias usually affect only one sensory modality, and the patient can identify the same object when presented in a different sensory modality. For example, a patient with visual agnosia may fail to identify a bell by sight but readily identifies it by touch or by the sound of its ring. Agnosias are defined in terms of the specific sensory modality affected—usually visual, auditory, or tactile—or they may be selective for one class of items within a sensory modality, such as color agnosia or prosopagnosia (agnosia for faces). To diagnose agnosia, the examiner must establish that the deficit is not a primary sensory disorder, as documented by tests of visual acuity, visual fields, auditory function, and somatosensory functions, and not part of a more general cognitive disorder, such as aphasia or dementia, as established by the bedside mental status examination. Naming deficits in aphasia or dementia are, with rare exceptions, not restricted to a single sensory modality. Clinically, agnosias seem complex and arcane, yet they are important in understanding the behavior of neurological patients, and they provide fascinating insights into brain mechanisms related to perception and recognition. Part of their complexity derives from the underlying neuropathology; agnosias frequently result from bilateral or diffuse lesions such as hypoxic encephalopathy, multiple strokes, and major head injuries, and agnosic phenomena also play a role in neurodegenerative disorders and dementias, despite the earlier definitions.

Agnosias have aroused controversies since their earliest descriptions. Some authorities have attributed agnosic deficits to primary perceptual loss in the setting of general cognitive dysfunction or dementia. However, abundant case studies argue in favor of true agnosic deficits. In each sensory modality, a spectrum of disorders can be traced from primary sensory dysfunction to agnosia. We approach agnosias by sensory modality, with progression from primary sensory deficits to disorders of recognition.

VISUAL AGNOSIAS Cortical Visual Disturbances Patients with bilateral occipital lobe damage may have complete “cortical” blindness. Some patients with cortical blindness are unaware that they cannot see, and some even confabulate visual descriptions or blame their poor vision on dim lighting or not having their glasses (Anton syndrome, originally described in 1899). Patients with Anton syndrome may describe objects they “see” in the room around them but walk immediately into a wall. The phenomena of this syndrome suggest that the thinking and speaking areas of the brain are not consciously aware of the lack of input from visual centers. Anton syndrome can still be thought of as a perceptual deficit rather than a visual agnosia, but one in which there is unawareness or neglect of the sensory deficit. Such visual unawareness is also frequently seen with hemianopic visual field defects (e.g., in patients with R hemisphere strokes), and it even has a correlate in normal people; we are not conscious of a visual field defect behind our heads, yet we know to turn when we hear a noise from behind. In contrast to Anton syndrome, some cortically blind patients actually have preserved ability to react to visual stimuli, despite the lack of any conscious visual perception—a phenomenon termed blindsight or inverse Anton syndrome (Leopold, 2012; Ro and Rafal, 2006). Blindsight may be considered an agnosic deficit, because the patient fails to recognize what he or she sees. Residual vision is usually absent in blindness caused by disorders of the eyes, optic nerves, or optic tracts. Patients with cortical vision loss may react to more elementary visual stimuli such as brightness, size, and movement, whereas

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they cannot perceive finer attributes such as shape, color, and depth. Subjects sometimes look toward objects they cannot consciously see. One study reported a woman with postanoxic cortical blindness who could catch a ball without awareness of seeing it. Blindsight may be mediated by subcortical connections such as those from the optic tracts to the midbrain. Lesions causing cortical blindness may also be accompanied by visual hallucinations. Irritative lesions of the visual cortex produce unformed hallucinations of lines or spots, whereas those of the temporal lobes produce formed visual images. Visual hallucinations in blindness are referred to as Bonnet syndrome (Teunisse et al., 1996). Although Bonnet originally described this phenomenon in his grandfather, who had ocular blindness, complex visual hallucinations occur more typically with cortical visual loss (Manford and Andermann, 1998). Visual hallucinations can occur during recovery from cortical blindness; positron emission tomography (PET) has shown metabolic activation in the parieto-occipital cortex associated with hallucinations, suggesting hyperexcitability of the recovering visual cortex (Wunderlich et al., 2000). The late Oliver Sacks reported numerous examples of visual hallucinations in his 2012 book, Hallucinations (Sacks, 2012). In practice, we diagnose cortical blindness by the absence of ocular pathology, the preservation of the pupillary light reflexes, and the presence of associated neurological symptoms and signs. In addition to blindness, patients with bilateral posterior hemisphere lesions are often confused and agitated, and have short-term memory loss. Amnesia is especially common in patients with bilateral strokes within the posterior cerebral artery territory, which involves not only the occipital lobe but also the hippocampi and related structures of the medial temporal region. Cortical blindness occurs as a transient phenomenon after traumatic brain injury, in migraine, in epileptic seizures, and as a complication of iodinated contrast procedures such as arteriography. Cortical blindness can develop in the setting of hypoxic-ischemic encephalopathy (Wunderlich et al., 2000), posterior reversible encephalopathy syndrome (PRES), meningitis, systemic lupus erythematosus, dementing conditions such as the Heidenhain variant of Creutzfeldt– Jakob disease, or the posterior cortical atrophy syndrome described in Alzheimer disease and other dementias (Kirshner and Lavin, 2006).

Cortical Visual Distortions Positive visual phenomena frequently develop in patients with visual field defects and even in migraine: distortions of shape called metamorphopsia, scintillating scotomas, irregular shapes (teichopsia, or fortification spectra), macropsia and micropsia, peculiar changes of shape and size known as the Alice in Wonderland syndrome (described by Golden in 1979), achromatopsia (loss of color vision), akinetopsia (loss of perception of motion), palinopsia (perseveration of visual images), visual allesthesia (spread of a visual image from a normal to a hemianopic field), and even polyopia (duplication of objects). All these phenomena are disturbances of higher visual perception rather than agnosias. Two types of color vision deficit are associated with occipital lesions. First, a complete loss of color vision, or achromatopsia, may occur either bilaterally or in one visual hemifield with lesions that involve portions of the visual association cortex (Brodmann areas 18 and 19). Second, patients with pure alexia and lesions of the left occipital lobe fail to name colors, although their color matching and other aspects of color perception are normal. Patients often confabulate an incorrect color name when asked what color an object is. This deficit can be called color agnosia, in the sense that a normally perceived color cannot be properly recognized. Although this deficit has been termed color anomia, these patients can usually name the colors of familiar objects such as a school bus or the inside of a watermelon.

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Balint Syndrome and Simultanagnosia In 1909, Balint described a syndrome in which patients act blind, yet can describe small details of objects in central vision (Rizzo and Vecera, 2002). The disorder is usually associated with bilateral hemisphere lesions, often involving the parietal and frontal lobes. Balint syndrome involves a triad of deficits: (1) psychic paralysis of gaze, also called ocular motor apraxia, or difficulty directing the eyes away from central fixation; (2) optic ataxia, or incoordination of extremity movement under visual control (with normal coordination under proprioceptive control); and (3) impaired visual attention. These deficits result in the perception of only small details of a visual scene, with loss of the ability to scan and perceive the “big picture.” Patients with Balint syndrome literally cannot see the forest for the trees. Some, but not all, patients have bilateral visual field deficits. In bedside neurological examination, helpful tests include asking the patient to interpret a complex drawing or photograph, such as the “Cookie Theft” picture from the Boston Diagnostic Aphasia Examination and the National Institutes of Health Stroke Scale. Partial deficits related to Balint syndrome, including isolated optic ataxia, or impaired visually guided reaching toward an object, have also been described. Optic ataxia likely results from disruption of the transmission of visual information for visual direction of motor acts from the occipital cortex to the premotor areas. This function involves portions of the dorsal occipital and parietal areas as part of the “dorsal visual stream” (Himmelbach et al., 2009). A second partial Balint syndrome deficit is simultanagnosia, or loss of ability to perceive more than one item at a time, first described by Wolpert in 1924. The patient sees details of pictures, but not the whole. Many such patients have left occipital lesions and associated pure alexia without agraphia; these patients can often read “letter-by-letter,” or one letter at a time, but they cannot recognize a word at a glance (see Chapter 13). Robertson and colleagues (1997) emphasized deficient spatial organization as a contributing factor to the perceptual difficulties of a patient with Balint syndrome secondary to bilateral parieto-occipital strokes. Balint syndrome has also been reported in patients with posterior cortical atrophy and related neurodegenerative conditions involving the posterior parts of both hemispheres (Kirshner and Lavin, 2006; McMonagle et al., 2006).

Visual Object Agnosia Visual object agnosia is the quintessential visual agnosia: the patient fails to recognize objects by sight, with preserved ability to recognize them through touch or hearing, in the absence of impaired primary visual perception or dementia (Biran and Coslett, 2003). In 1890, Lissauer distinguished two subtypes of visual object agnosia: apperceptive visual object agnosia, referring to the synthesis of elementary perceptual elements into a unified image, and associative visual object agnosia, in which the meaning of a perceived stimulus is appreciated by recall of previous visual experiences.

Apperceptive Visual Agnosia The first type, apperceptive visual agnosia, is difficult to separate from impaired perception or partial cortical blindness. Patients with apperceptive visual agnosia can pick out features of an object correctly (e.g., lines, angles, colors, movement), but they fail to appreciate the whole object (Grossman et al., 1997). Warrington and Rudge (1995) pointed to the right parietal cortex for its importance in visual processing of objects, and they found this area critical to apperceptive visual agnosia. A patient described by Luria misnamed eyeglasses as a bicycle, pointing to the two circles and a crossbar. Apperceptive visual agnosia can be related to damage to the primary visual cortex by bilateral occipital lesions (Serino et al., 2014). Recent evidence of the functions of specific

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CHAPTER 12 Agnosias cortical areas has included the specialization of the medial occipital cortex for appreciation of color and texture, whereas the lateral occipital cortex is more involved with shape perception. Deficits in these specific visual functions can be seen in patients with visual object agnosia (Cavina-Pratesi et al., 2010). On the other hand, a patient reported by Karnath et al. (2009) had visual form agnosia with bilateral medial occipitotemporal lesions. Another way of analyzing apperceptive visual agnosia is by the focusing of visual attention. Theiss and DeBleser in 1992 distinguished two features of visual attention: a wide-angle attentional lens that sees the figure generally but perceives only gross features (the forest), and a narrow-angle spotlight that focuses on the fine visual details (the trees). They described a patient with a faulty wide-angle attentional beam; she could identify small objects within a drawing but missed what the drawing represented. Fink and colleagues (1996), in PET studies of visual perception in normal subjects, found that right hemisphere sites, particularly the lingual gyrus, activated during global processing of figures, whereas left hemisphere sites, particularly the left inferior occipital cortex, activated during more local processing. The ability of patients with apperceptive visual agnosia to perceive fine details but not the whole picture (missing the forest for the trees) is closely related to Balint syndrome and simultanagnosia. As with most cortical visual syndromes, apperceptive visual agnosia usually occurs in patients with bilateral occipital lesions. It may represent a stage in recovery from complete cortical blindness. Deficits in recognition of visual objects may be especially apparent with recognition of degraded images, such as drawings rather than actual objects. Apperceptive visual agnosia can also be part of dementing syndromes (Kirshner and Lavin, 2006; McMonagle et al., 2006) (Fig. 12.1).

Associative Visual Agnosia Associative visual agnosia—Lissauer’s second type—has to do with recognition of appropriately perceived objects. Some patients can copy or match drawings of objects they cannot name, thus excluding a primary defect of visual perception. Aphasia is excluded because the

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patient can identify the same object presented in the tactile or auditory modality. Patients with associative visual agnosia often have other related recognition deficits such as color agnosia, prosopagnosia, and alexia. Associative visual agnosia is usually associated with bilateral posterior hemisphere lesions, often involving the fusiform or occipitotemporal gyri, sometimes the lingual gyri and adjacent white matter. Jankowiak and colleagues described a patient with bilateral parieto-occipital damage from gunshot injuries. Visual acuity was nearly normal except for bilateral upper “altitudinal” visual field defects. He had difficulty recognizing and naming colors, faces, objects, and pictures. He could copy drawings he could not recognize, and he could draw images from memory or after tachistoscopic presentation. The crux of this patient’s deficit was an inability to match an internal visual percept with representations of visual objects; in other words, he could perceive visual stimuli normally but failed to assign meaning or identity to them. Geschwind postulated in 1965 that visual agnosia results from a disconnection syndrome in which bilateral lesions prevent visual information from the occipital lobes from reaching the left hemisphere language areas. Most but not all cases of associative visual agnosia have involved the fusiform or occipitotemporal gyri bilaterally, presumably interrupting connections between the visual cortex and the language areas for naming, or the medial temporal region for identification from memory. The disconnection hypothesis of visual agnosia is likely an oversimplification of the complexities of visual perception and recognition, but it provides a useful way to remember the syndrome. A recent review divided visual agnosias into those affecting the ventral (or “what”) visual network or stream, including visual object agnosia, cerebral achromatopsia, prosopagnosia (see below), topographagnosia, and pure alexia, versus those affecting the dorsal (or “where”) stream, including akinetopsia (agnosia for movement), simultanagnosia, and optic ataxia (Haque et al., 2018). However, another recent review placed prosopagnosia and topographagnosia (agnosia for landmarks) in the ventral pathway. Orientation agnosia (agnosia for the placement of objects in space) belongs with the dorsal

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Fig. 12.1 T2-weighted magnetic resonance images from a patient with progressive loss of vision, misidentification of objects, and the inability to describe the whole of a picture, mentioning only small details. The clinical diagnosis was posterior cortical atrophy, a neurodegenerative condition. Both A and B show atrophy of the occipital cortex bilaterally, with T2 hyperintensity in the occipital white matter. @

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pathway, along with akinetopsia (Martinaud, 2017). Landmark agnosia can be specific for recently learned landmarks or for all landmarks. The disorder can be distinguished from knowledge of routes. Lesions involve the right temporal lobe and right hippocampus (van der Ham et al., 2017). The ventral stream is thought to be conscious, the dorsal stream unconscious. Yet another recent paper points to greater interaction between the ventral and dorsal streams, from a detailed study of a patient with visual agnosia (Milner, 2017). Rehabilitation of patients with visual agnosia and Balint syndrome has been studied to a limited extent. A recent review suggests that compensatory measures are more effective than restorative attempts in making these patients function better (Heutink et al., 2018).

Optic Aphasia The syndrome of optic aphasia, or optic anomia, is intermediate between agnosias and aphasias. The patient with optic aphasia cannot name objects presented visually but can demonstrate recognition of the objects by pantomiming or describing their use. The preserved recognition of the objects distinguishes optic aphasia from associative visual agnosia. Like visual agnosics, patients with optic aphasia can name objects presented in the auditory or tactile modalities, distinguishing them from anomic aphasics. In optic aphasia, information about the object must reach parts of the cortex involved in recognition, perhaps in the right hemisphere, but the information is not available to the language cortex for naming. This explanation also fits Geschwind’s disconnection hypothesis. Patients with optic aphasia may confabulate incorrect names when asked to name an object they clearly recognize, just as the patient with color agnosia confabulates incorrect color names. The language cortex appears to supply a name from the class of items when specific information is not forthcoming, without the conscious awareness that the information is not correct. Patients with optic aphasia frequently manifest associated deficits of alexia without agraphia and color agnosia, suggesting a left occipital lesion. Optic aphasia bears great similarity to pure alexia without agraphia; just as optic aphasics may recognize objects they cannot name, pure alexics sometimes recognize words they cannot read.

Prosopagnosia Prosopagnosia refers to the inability to recognize faces. Patients fail to recognize close friends and relatives or pictures of famous people, except by memorizing details of shape or hairstyle, but they learn to compensate by identifying a person by voice, mannerisms, gait patterns, and apparel. Prosopagnosia is restricted not only to the visual modality but also to the class of faces. Facial recognition is a complex function. First, patients who cannot match pictures of faces must have defective face processing, or apperceptive prosopagnosia, whereas those who can match faces but simply fail to recognize familiar examples (either friends and relatives or famous personages) have associative prosopagnosia (Barton et al., 2004). There has been some opinion that faces are not a unique perceptual entity but just representative of complex stimuli; however, a study by Busigny and colleagues (2010) found that their patient performed normally in perceptual tasks involving cars, objects, and geometric shapes, while being deficient with faces. Transient prosopagnosia has been reported after focal electrical stimulation of the right inferior occipital gyrus (Jonas et al., 2012). Another aspect of facial recognition is the perception of emotion in facial expressions, a function that appears localized to the right hemisphere. A recent study suggested that white-matter lesions disconnecting the occipital cortex from “emotion-related regions” might be responsible for agnosia for emotional facial expression (Philippi et al., 2009). In clinical studies, prosopagnosia may occur either as an isolated deficit or as part of a more general visual agnosia for objects and colors.

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Faces are likely the most complex and individualized visual displays to recognize, but some patients with visual object agnosia can recognize faces, suggesting that there are specific brain areas devoted to facial recognition. Humphreys (1996) reviewed evidence that living things may be recognized in a different part of the occipital cortex from nonliving things. The anatomical localization of prosopagnosia is similar to that of the other visual agnosias, but we have better knowledge of the anatomy and physiology of face recognition. Most studies have reported bilateral temporo-occipital lesions, often involving the fusiform or occipitotemporal gyri, but cases with unilateral posterior right hemisphere lesions have also been described. There is an occipital face area, presumably involved in facial perception, a fusiform gyrus face area, involved in recognition of faces, and most recently an anterior temporal center that appears to be involved in details of perception that may not be limited strictly to faces (Barton, 2003; Gainotti, 2013). In short, there is a right hemisphere network for facial recognition. A recent study involving both functional magnetic resonance imaging (fMRI) and neuropsychological testing found the inferior occipital (“occipital face area”) lobe critical for the identification of specific individual faces, whereas the “fusiform face area” in the middle fusiform gyrus was involved in other aspects of face perception (Steeves et al., 2009). The disconnection hypothesis has been invoked in prosopagnosia, reflecting interruption of fibers passing from the occipital cortices to the centers where memories of faces are stored. Prosopagnosia also occurs in dementing illnesses such as frontotemporal dementia (Joubert et al., 2004) and posterior cortical atrophy (Kirshner and Lavin, 2006), and impaired facial recognition has also been reported in amnestic mild cognitive impairment (Lim et al., 2011). Two recent reviews discussed the rehabilitation of prosopagnosia (Corrow et al., 2016; Davies-Thompson et al., 2017).

Klüver-Bucy Syndrome Another form of visual agnosia is the psychic blindness syndrome described by Klüver and Bucy in 1939. They reported the syndrome originally in monkeys with bilateral temporal lobectomies, but similar symptoms develop in humans with bilateral temporal lesions (Trimble et al., 1997). An animal may inappropriately try to eat or mate with objects or fail to show customary fear when confronted with a natural enemy. Human Klüver-Bucy patients manifest visual agnosia and prosopagnosia as well as memory loss, language deficits, and changes in behavior such as placidity, altered sexual orientation, and excessive eating. Cases of the human Klüver-Bucy syndrome have been reported with bitemporal damage from surgical ablation, herpes simplex encephalitis, and dementing conditions such as Pick disease. Patients with Klüver-Bucy syndrome appear to have no major deficits of primary visual perception, but connections appear to be disrupted between vision and memory and limbic structures, so visual percepts do not arouse their ordinary associations. A recent review of the Klüver-Bucy syndrome discussed more specific anatomical considerations in both animals and man. Bilateral ventral temporal lobe resections or lobectomies resulted in impaired visual discrimination, which was not seen following lateral temporal resections or unilateral resections. The temporal portion of limbic networks are disrupted in this syndrome, interfering with cortical and subcortical circuits involved in emotional behavior and mood. Bilateral resections of the lateral amygdala resulted in not only the loss of fear that is part of the Klüver-Bucy syndrome but also a “hypersexed state.” Humans usually have partial syndromes, as compared with animals subjected to complete bilateral temporal lobectomy, but this syndrome also involves related deficits such as aphasia and memory loss. The author states that the treatment of these patients is “difficult and often unsatisfactory” (Lanska, 2018).

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CHAPTER 12 Agnosias

AUDITORY AGNOSIAS Like cortical visual syndromes, cortical auditory disorders range from primary auditory syndromes of cortical deafness to partial deficits of recognition of specific types of sound. As with the visual agnosias, most cortical auditory deficits require bilateral cerebral lesions, usually involving the temporal lobes, especially the primary auditory cortices in the Heschl gyri.

Cortical Deafness Profound hearing deficits are seen in patients with acquired bilateral lesions of the primary auditory cortex (Heschl gyrus, Brodmann areas 41 and 42) or of the auditory radiations projecting to the Heschl gyri. In general, unilateral lesions of the auditory cortex have little effect on hearing. Only rarely are patients with bilateral auditory cortex lesions completely deaf, even to loud noises; most retain some pure tone hearing but have deficits in higher-level acoustic processing such as identification of meaningful sounds, temporal sequencing, and sound localization. As in visual agnosia, the cortical hearing deficits blend imperceptibly into the auditory agnosias (Brody et al., 2013). A patient with auditory agnosia can hear noises but not appreciate their meanings, as in identifying animal cries or sounds associated with specific objects, such as the ringing of a bell. Most such patients also cannot understand speech or appreciate music. Auditory agnosias can be divided into (1) pure word deafness, (2) pure auditory nonverbal agnosia, (3) phonagnosia, or the inability to identify persons by their voices (Gainotti, 2011; Hailstone et al., 2010; Polster and Rose,

1998), and (4) pure amusia. Patients may have one or a mixture of these deficits.

Pure Word Deafness The syndrome of pure word deafness involves an inability to comprehend spoken words, with an ability to hear and recognize nonverbal sounds. Pure word deafness often evolves out of an initial deficit of cortical deafness or severe cortical auditory disorder. Pure word deafness has traditionally been explained as a disconnection of both primary auditory cortices from the left hemisphere Wernicke area. Engelien and colleagues (2000) showed activation on PET scanning during auditory stimulation in a patient with extensive bilateral temporal lesions, a phenomenon they referred to as deaf hearing (analogous to blindsight). Unilateral left hemisphere lesions have also been associated with pure word deafness; by Geschwind’s disconnection theory, such a lesion might be strategically placed so as to disconnect both primary auditory cortices from the Wernicke area. Occasionally patients with Wernicke aphasia have more severe involvement of auditory comprehension than reading comprehension, also resembling pure word deafness. In fact, most cases of pure word deafness also have paraphasic speech, further linking the syndrome to Wernicke aphasia (Fig. 12.2).

Auditory Nonverbal Agnosia Auditory nonverbal agnosia refers to patients who have lost the ability to identify meaningful nonverbal sounds but have preserved pure tone hearing and language comprehension. These cases also tend to have bilateral temporal lobe lesions. A reported case had a unilateral

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Fig. 12.2 A computed tomography scan from a patient with extensive bilateral infarctions involving the temporal lobes. The patient could hear pure tones and nonverbal sounds, but she was completely unable to comprehend speech. These 4 slices of a computerized axial tomogram (CT scan) show old strokes affecting the temporal lobes bilaterally, in a patient with cortical deafness. (From Kirshner, H.S., Webb, W.G., 1981. Selective involvement of the auditory-verbal modality in an acquired communication disorder: benefit from sign language therapy, Brain and Language, 13, 161–170.) @

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left temporal lesion with evidence of reorganization of auditory word perception involving the adjacent left and contralateral right temporal cortex (Saygin et al., 2010).

Phonagnosia Phonagnosia is analogous to prosopagnosia in the visual modality; it is a failure to recognize familiar people by their voices. Again, apperceptive deficits can occur in the matching of unfamiliar voices, usually reflecting unilateral or bilateral temporal damage, but failure to recognize a familiar voice may involve a right parietal locus corresponding to the specific area for recognition of voices. Gainotti (2011) reviewed evidence that voice recognition deficits correlated with right anterior temporal lesions, but in many cases this is “multimodal,” affecting recognition of familiar persons not only by voice but also by facial appearance. A related deficit is auditory affective agnosia, or failure to recognize the emotional intonation of speech, usually associated with right hemisphere lesions (Polster and Rose, 1998). Two cases of progressive phonagnosia have been reported in frontotemporal dementia (Hailstone et al., 2010). A recently published case report of a bird enthusiast with semantic dementia described very specific impairments of bird call recognition, whereas the patient could recognize human faces and voices. There were also very focal deficits in bird knowledge referable to bird names and habitats (Muhammed, et al., 2018).

Amusia The loss of musical abilities after focal brain lesions is another complex topic, reflecting the complexity of musical appreciation and analysis (Alossa and Castelli, 2009). Traditional lesion-deficit analysis has suggested that recognition of melodies and musical tones is a right temporal function, whereas analysis of learned or skilled aspects of pitch, rhythm, and tempo involves the left temporal lobe. In a study of patients with temporal lobe lesions and epilepsy, those with left hemisphere lesions were more impaired in temporal sequencing of music as well as speech (Samson et al., 2001). The left hemisphere is likely more activated when a trained musician listens to music, as compared with an untrained listener. In a study of PET brain imaging during musical performance in 10 professional pianists, sight-reading of music activated both visual association cortices and the superior parietal lobes, areas distinct from those utilized in reading words. Listening to music activated both secondary auditory cortices, and playing music activated frontal and cerebellar areas. The authors commented that widespread as these areas were, the study did not examine the whole musical experience, let alone the pleasure afforded by music. The composer, Maurice Ravel, whose case was originally described in 1948 by Alajouanine, suffered a progressive fluent aphasia that gradually took his ability to read or write music but spared his capacity to listen to and appreciate it. Another study also reported progressive musical dysfunction in two professional musicians with dementing illness. A recently described patient with resection of a right temporoparietal tumor had a loss of sad or happy music perception but preserved meter and beat (Baird et al., 2014).

TACTILE AGNOSIAS As we have seen with the syndromes of cortical loss of visual and auditory perception, a range of somatosensory deficits is seen with cortical lesions. Patients with lesions of the parietal cortex may have preserved ability to feel pinprick, temperature, vibration, and proprioception, yet they fail to identify objects palpated by the contralateral hand or to recognize numbers or letters written on the opposite side of the body. These deficits, called astereognosis and agraphesthesia, represent deficits of cortical sensory loss rather than agnosias. Alternatively, they could be considered as apperceptive tactile agnosias. Rarely, patients who can

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describe the shape and features of a palpated object, yet cannot identify the object, have been reported. The patient can readily identify the object by sound or sight, thereby fulfilling the criteria for associative tactile agnosia (Bottini et al., 1995). Caselli (1991a) investigated 84 patients with unilateral hemisphere lesions for deficits in tactile perception. Seven patients had tactile agnosia for objects palpated by the contralateral hand. These deficits occurred in the absence of primary somatosensory loss. Some patients had severe hemiparesis or hemianopia yet performed well in tactile object recognition, but patients with neglect secondary to right hemisphere lesions tended to have more severe deficits. A second study reported that only patients with neglect had bilateral tactile object recognition deficits, whereas patients with left parietal lesions had tactile agnosia only for items in the right hand (Caselli, 1991b). However, the study did not include patients with bilateral lesions, and agnosia in the visual and auditory modalities is clearly more profound when bilateral lesions are present. The mechanisms of tactile agnosia may vary. First, appreciation of shape may be a property of the sensory cortex. In the studies of Bottini and colleagues (1995), matching of shapes (an apperceptive task) was more sensitive to right hemisphere damage, whereas matching of meaningful shapes (the associative task) was more sensitive to left hemisphere lesions. Second, the right parietal cortex is also involved in spatial and topographical functions, and spatial disorders may account for some of the tactile recognition deficits of patients with right parietal lesions. Third, attentional deficits and neglect seen with right hemisphere lesions may increase the lack of tactile recognition. Fourth, disconnection syndromes may be involved in tactile agnosia. The famous 1962 patient of Geschwind and Kaplan with a lesion of the corpus callosum could not identify objects with the left hand, by speech, but could point to the correct object in a group. Patients with surgical section of the corpus callosum have similar deficits; these patients can feel the object with the left hand but cannot name it, presumably because the callosal lesion disconnects the right parietal cortex from left hemisphere language centers.

Tactile Aphasia Tactile aphasia is an inability to name a palpated object despite intact recognition of the object and intact naming when the object is presented in another sensory modality. This syndrome is closely analogous to optic aphasia and has been recognized only rarely.

SUMMARY Agnosias are disorders of sensory perception and recognition. The cortical mechanisms of the agnosias span a spectrum from primary sensory cortical deficits to disorders of the association cortex, or disconnection syndromes between cortical areas. Recognition of objects requires not only primary sensation but also association of the perceived item with previous sensory experiences and associative memories. The agnosias open a window into the brain’s ability to perceive and recognize aspects of the world around us. The complete reference list is available online at https://expertconsult.inkling.com/.

Acknowledgment Portions of this chapter appeared in Kirshner, H.S., 2002. Agnosias, in: Behavioral neurology: Practical science of mind and brain. ButterworthHeinemann, Boston, pp. 137–158.

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13 Aphasia and Aphasic Syndromes Howard S. Kirshner, Stephen M. Wilson OUTLINE Symptoms and Differential Diagnosis of Disordered Language, 134 Bedside Language Examination, 135 Differential Diagnosis of Aphasic Syndromes, 136 Broca Aphasia, 136 Aphemia, 137 Wernicke Aphasia, 137 Pure Word Deafness, 138 Global Aphasia, 139 Conduction Aphasia, 139 Anomic Aphasia, 140 Transcortical Aphasias, 140

Subcortical Aphasias, 141 Pure Alexia Without Agraphia, 141 Alexia With Agraphia, 142 Aphasic Alexia, 143 Agraphia, 144 Language in Right Hemisphere Disorders, 144 Language in Dementing Diseases, 145 Investigation of the Aphasic Patient, 145 Clinical Tests, 145 Differential Diagnosis, 147 Recovery and Rehabilitation of Aphasia, 148

The study of language disorders involves the analysis of that most human of attributes, the ability to communicate through common symbols. Language has provided the foundation of human civilization and learning, and its study has been the province of philosophers as well as physicians. When language is disturbed by neurological disorders, analysis of the patterns of abnormality has practical usefulness in neurological diagnosis. Historically, language was the first higher cortical function to be correlated with specific sites of brain damage. It continues to serve as a model for the practical use of a cognitive function in the localization of brain lesions and for the understanding of human cortical processes in general. Aphasia is defined as a disorder of language that is acquired secondary to brain damage. This definition, adapted from Alexander and Benson (1997), separates aphasia from several related disorders. First, aphasia is distinguished from congenital or developmental language disorders. Second, aphasia is a disorder of language rather than speech. Speech is the articulation and phonation of language sounds; language is a complex system of communicative symbols and rules for their use. Aphasia is distinguished from motor speech disorders, which include dysarthria, dysphonia (voice disorders), stuttering, and apraxia of speech. Dysarthrias are disorders of muscular control of speech. Dysarthria may result from mechanical disturbance of the tongue or larynx or from neurological disorders, including dysfunction of the muscles, neuromuscular junction, cranial nerves, bulbar anterior horn cells, corticobulbar tracts, cerebellar connections, or basal ganglia. Dysarthrias are discussed in Chapter 14. Apraxia of speech is a syndrome of misarticulation of phonemes, especially consonant sounds. Unlike dysarthria, in which certain phonemes are consistently distorted, apraxia of speech contains inconsistent distortions and substitutions of phonemes. The disorder is called an apraxia because there is no primary motor deficit in articulation of individual phonemes. Clinically, speech-apraxic patients produce inconsistent articulatory errors, usually worse on the initial phonemes of a word and with polysyllabic utterances. Apraxia of speech, so defined, is commonly involved in speech production difficulty in the aphasias.

Third, aphasia is distinguished from disorders of thought. Thought involves the mental processing of images, memories, and perceptions, usually but not necessarily involving language symbols. Psychiatric disorders derange thought and alter the content of speech without affecting its linguistic structure. Schizophrenic patients, for example, may manifest bizarre and individualistic word choices, with loose associations and a loss of organization in discourse, together with vague or unclear references and communication failures (Docherty et al., 1996). Elementary language and articulation, however, are intact. Abnormal language content in psychiatric disorders is therefore not considered aphasia because the disorder is one of thought rather than one of language. Language disorders associated with diffuse brain diseases, such as encephalopathies and dementias, do qualify as aphasias, but the involvement of other cognitive functions distinguishes them from aphasia secondary to focal brain lesions. An understanding of language disorders requires an elementary review of linguistic components. Phonemes are the smallest distinctive sound units; morphology is the use of appropriate word endings and connector words for grammatical categories such as tenses, possessives, and singular versus plural; semantics refers to word meanings; the lexicon is the internal dictionary; and syntax is the grammatical construction of phrases and sentences. Discourse refers to the use of these elements to create organized and logical expression of thoughts. Pragmatics refers to the proper use of speech and language in a conversational setting, including pausing while others are speaking, taking turns properly, and responding to questions. Specific language disorders affect one or more of these elements. Language processes have a clear neuroanatomical basis. In simplest terms, the reception and processing of spoken language take place in the auditory system, beginning with the cochlea and proceeding through a series of way stations to the auditory cortex, Heschl gyrus, in each superior temporal gyrus. The decoding of sounds into linguistic information involves the left superior temporal gyrus and sulcus. The recognition of the role of the left temporal cortex in linking sound to meaning dates back to Wernicke (1874) and has been refined over the

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Superior temporal gyrus Temporal lobe Broca’s area Wernicke’s area Fig. 13.1 The lateral surface of the left hemisphere, showing a simplified gyral anatomy and the relationships between Wernicke area and Broca area. Not shown is the arcuate fasciculus, which connects the two cortical speech centers via the deep, subcortical white matter.

last few decades based on numerous studies using the diverse methodologies of cognitive neuroscience. For both repetition and spontaneous speech, auditory information is transmitted via direct and indirect dorsal pathways to Broca area in the posterior inferior frontal gyrus. This area of cortex “programs” the neurons in the adjacent motor cortex, subserving the mouth and larynx, from which descending axons travel to the brainstem cranial nerve nuclei. The inferior parietal lobule, especially the supramarginal gyrus, may also be involved in encoding of speech sounds for production. These anatomical relationships are shown in Figs. 13.1 and 13.2. Reading requires the perception of visual language stimuli by the occipital cortex, followed by processing into auditory language information. Writing involves the activation of motor neurons projecting to the arm and hand. A French study of 107 stroke patients, investigated with aphasia testing and magnetic resonance imaging (MRI) scans, confirmed the general themes of nearly 150 years of clinical aphasia research: frontal lesions caused nonfluent aphasia, whereas posterior temporal lesions affected comprehension (Kreisler et al., 2000). These pathways, and doubtless others, constitute the cortical circuitry for language comprehension and expression. In addition, other cortical centers involved in cognitive processes project into the primary language cortex, influencing the content of language. Finally, subcortical structures play increasingly recognized roles in language functions. The thalamus, a relay for the reticular activating system, appears to alert the language cortex, and lesions of the dominant thalamus frequently produce fluent aphasia. Nuclei of the basal ganglia involved in motor functions, especially the caudate nucleus and putamen, participate in expressive speech. No wonder, then, that language disorders are seen with a wide variety of brain lesions and are important in practical neurological diagnosis and localization. In almost all right-handed people, and in a majority of left-handers as well, clinical syndromes of aphasia result from left hemisphere lesions. Rarely, aphasia may result from a right hemisphere lesion in a righthanded patient, a phenomenon called crossed aphasia (Bakar et al., 1996).

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Fig. 13.2 Coronal plane diagram of the brain, indicating the inflow of auditory information from the ears to the primary auditory cortex in both superior temporal regions (xxx) and then to the Wernicke area (ooo) in the left superior temporal gyrus. The motor outflow of speech descends from the Broca area (B) to the cranial nerve nuclei of the brainstem via the corticobulbar tract (dashed arrow). In actuality, the Broca area is anterior to the Wernicke area, and the two areas would not appear in the same coronal section.

SYMPTOMS AND DIFFERENTIAL DIAGNOSIS OF DISORDERED LANGUAGE Muteness, a total loss of speech, may represent severe aphasia (see the section Aphemia, a rare syndrome, later in this chapter). Muteness can also be a sign of dysarthria; frontal lobe dysfunction with akinetic

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CHAPTER 13 Aphasia and Aphasic Syndromes mutism; severe extrapyramidal system dysfunction, as in Parkinson disease; non-neurological disorders of the larynx and pharynx; or even psychogenic syndromes, such as catatonia. Caution must therefore be taken in diagnosing the mute patient as aphasic. A good rule of thumb is that if the patient can write or type and the language form and content are normal, the disorder is probably not aphasic in origin. If the patient cannot speak or write but makes apparent effort to vocalize, and if there is also evidence of deficient comprehension, aphasic muteness is likely. Associated signs of a left hemisphere injury, such as right hemiparesis, also aid in diagnosis. Finally, if the patient gradually begins to make sounds containing paraphasic errors, aphasia can be identified with confidence. Halting and effortful speech is a symptom of aphasia, but also of motor speech disorders, such as dysarthria or stuttering, and it may be a manifestation of a psychogenic disorder (see under Differential Diagnosis of Causes of Aphasia, later in this chapter; Binder et al., 2012). A second rule of thumb is that if one can transcribe the utterances of an effortful speaker into normal language, the patient is not aphasic. Effortful speech occurs in many aphasia syndromes for varying reasons, including difficulty in speech initiation, imprecise articulation of phonemes, deficient syntax, or word-finding difficulty. Anomia, or inability to produce a specific name, is generally a reliable indicator of language disorder, although it may also reflect memory loss. Anomia is manifest in aphasic speech by word-finding pauses and circumlocutions or use of a phrase where a single word would suffice. Paraphasic speech refers to the presence of errors in the patient’s speech output. Paraphasic errors are divided into literal or phonemic errors, involving substitution of an incorrect sound (e.g., shoon for spoon), and verbal or semantic errors, involving substitution of an incorrect word (e.g., fork for spoon). A related language symptom is perseveration, the inappropriate repetition of a previous response. Occasionally, aphasic utterances involve nonexistent word forms called neologisms. A pattern of paraphasic errors and neologisms that so contaminate speech that the meaning cannot be discerned is called jargon. Another cardinal symptom of aphasia is the failure to comprehend the speech of others. Most aphasic patients also have difficulty with comprehension and production of written language (reading and writing). Fluent, paraphasic speech usually makes an aphasic disorder obvious. The chief differential diagnosis here involves aphasia, psychosis, acute encephalopathy or delirium, and dementia. Aphasic patients are usually not confused or inappropriate in behavior; they do not appear agitated or misuse objects, with occasional exceptions in acute syndromes of Wernicke or global aphasia. By contrast, most psychotic patients speak in an easily understood, grammatically appropriate manner, but their behavior and speech content are abnormal. Only rarely do schizophrenics speak in “clang association” or “word salad” speech. Sudden onset of fluent, paraphasic speech in a middle-aged or elderly patient should always be suspected of representing a left hemisphere lesion with aphasia. Patients with acute encephalopathy or delirium may manifest paraphasic speech and “higher” language disorders, such as inability to write, but the grammatical expression of language is less disturbed than is its content. These language symptoms, moreover, are less prominent than accompanying behavioral disturbances, such as agitation, hallucinations, drowsiness, or excitement, and cognitive difficulties, such as disorientation, memory loss, and delusional thinking. Chronic encephalopathies, or dementias, pose a more difficult diagnostic problem because involvement of the language cortex produces readily detectable language deficits, especially involving

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Bedside Language Examination

1. Spontaneous speech a. Informal interview b. Structured task c. Automatic sequences 2. Naming 3. Auditory comprehension 4. Repetition 5. Reading a. Reading aloud b. Reading comprehension 6. Writing a. Spontaneous sentences b. Writing to dictation c. Copying

naming, reading, and writing. These language disorders (see Language in Dementing Diseases, later in this chapter) differ from aphasia secondary to focal lesions mainly by the involvement of other cognitive functions, such as memory and visuospatial processes.

BEDSIDE LANGUAGE EXAMINATION The first part of any bedside examination of language is the observation of the patient’s speech and comprehension during the clinical interview. A wealth of information about language function can be obtained if the examiner pays deliberate attention to the patient’s speech patterns and responses to questions. In particular, minor word-finding difficulty, occasional paraphasic errors, and higher-level deficits in discourse planning and in the pragmatics of communication, such as turn-taking in conversation and the use of humor and irony, can be detected principally during the informal interview. D. Frank Benson and Norman Geschwind popularized a bedside language examination of six parts, updated by Alexander and Benson (1997) (Box 13.1). This examination provides useful localizing information about brain dysfunction and is well worth the few minutes it takes. The first part of the examination is an analysis of spontaneous speech. A speech sample may be elicited by asking the patient to describe the weather or the reason for coming to the doctor. If speech is sparse or absent, recitation of lists, such as counting or listing days of the week, may be helpful. The most important variable in spontaneous speech is fluency: fluent speech flows rapidly and effortlessly; nonfluent speech is uttered in single words or short phrases, with frequent pauses and hesitations. Attention should first be paid to such elementary characteristics as initiation difficulty, articulation, phonation or voice volume, rate of speech, prosody or melodic intonation of speech, and phrase length. Second, the content of speech utterances should be analyzed in terms of the presence of word-finding pauses, circumlocutions, and errors such as literal and verbal paraphasias and neologisms. Naming, the second part of the bedside examination, is tested by asking the patient to name objects, object parts, pictures, colors, or body parts. A few items from each category should be tested because anomia can be specific to word classes. Proper names of persons are often affected severely. The examiner should ask questions to be sure that the patient recognizes the items or people that he or she cannot name. Auditory comprehension is tested first by asking the patient to follow a series of commands of one, two, and three steps. An example of

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a one-step command is “stick out your tongue”; a two-step command is “hold up your left thumb and close your eyes.” Successful following of commands ensures adequate comprehension, at least at this simple level, but failure to follow commands does not automatically establish a loss of comprehension. The patient must hear the command, understand the language the examiner speaks, and possess the motor ability to execute it, including the absence of apraxia. Apraxia (see Chapter 11 for full discussion) is defined operationally as the inability to carry out a motor command despite normal comprehension and normal ability to carry out the motor act in another context, such as to imitation or with use of a real object. Because apraxia is difficult to exclude with confidence, it is advisable to test comprehension by tasks that do not require a motor act, such as yes–no questions, or by commands that require only a pointing response. The responses to nonsense questions (e.g., “Do you vomit every day?”) quickly establish whether the patient comprehends. Nonsense questions often produce surprising results, given the tendency of some aphasics to cover up comprehension difficulty with social chatter. Repetition of words and phrases should be deliberately tested. Dysarthric patients have difficulty with rapid and variable sequences of consonants, such as “Methodist Episcopal,” whereas people with aphasia have particular difficulty with grammatically complex sentences. The phrase “no ifs, ands, or buts” is especially challenging for individuals with aphasia. Often, they can repeat familiar or “high-probability” phrases much better than unfamiliar ones. Reading should be tested both aloud and for comprehension. The examiner should carry a few printed commands to facilitate a rapid comparison of auditory with reading comprehension. Of course, the examiner must have some idea of the patient’s premorbid reading ability. Writing, the element of the bedside examination most often omitted, not only provides a further sample of expressive language but also allows an analysis of spelling, which is not possible with spoken language. A writing specimen may be the most sensitive indicator of mild aphasia, and it provides a permanent record for future comparison. Spontaneous writing, such as a sentence describing why the patient has come for examination, is especially sensitive for the detection of language difficulty. When spontaneous writing fails, writing to dictation and copying should be tested as well. Finally, the neurologist combines the results of the bedside language examination with those of the rest of the mental status examination and of the neurological examination in general. These “associated signs” help to classify the type of aphasia and to localize the responsible brain lesion.

DIFFERENTIAL DIAGNOSIS OF APHASIC SYNDROMES Broca Aphasia In 1861, the French physician Paul Broca described a nonfluent speech disorder in two patients, one of whom could say only “tan.. tan”. He proposed the term aphemia, but aphasia was adopted. In Broca aphasia, the speech pattern is nonfluent; on bedside examination, the patient speaks hesitantly, often producing the principal, meaning-containing nouns and verbs but omitting small grammatical words and morphemes. This pattern is called agrammatism or telegraphic speech. An example is “wife come hospital.” Patients with acute Broca aphasia may be mute or may produce only single words, often with dysarthria and apraxia of speech. They make many phonemic errors, inconsistent from utterance to utterance, with substitution of phonemes usually differing only slightly from the correct target (e.g., p for b). Naming is deficient, but the patient often

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TABLE 13.1

Aphasia

Bedside Features of Broca

Feature

Syndrome

Spontaneous speech Naming Comprehension

Nonfluent, mute, or telegraphic, sometimes dysarthric Impaired Intact (mild difficulty with complex grammatical phrases) Impaired Often impaired (“third alexia”) Impaired (dysmorphic, dysgrammatical) Right hemiparesis Right hemisensory loss ± Apraxia of left limbs

Repetition Reading Writing Associated signs

manifests a “tip of the tongue” phenomenon, getting out the first letter or phoneme of the correct name. Paraphasic errors in naming are more frequently of literal than verbal type. Auditory comprehension seems intact, but detailed testing usually reveals some deficiency, particularly in the comprehension of complex syntax. For example, sentences with embedded clauses involving prepositional relationships cause difficulty for patients with Broca aphasia in comprehension as well as in expression (“The rug that Bill gave to Betty tripped the visitor”). This may reflect the demands that these types of sentences make on working memory and other functions that depend on the frontal lobe. A study of grammatical comprehension in normal subjects with positron emission tomography (PET) scanning did show activation of the left frontal, Broca area during this function (Caplan et al., 1998). Repetition is hesitant in these patients, resembling their spontaneous speech. Reading is often impaired, despite relatively preserved auditory comprehension. Patients with Broca aphasia may have difficulty with syntax in reading, just as in auditory comprehension and speech. Writing is virtually always deficient in Broca aphasia. Most patients have a right hemiparesis, necessitating use of the nondominant, left hand for writing, but this left-handed writing is far more abnormal than the awkward renditions of a normal right-handed subject. Many patients can scrawl only a few letters. Associated neurological deficits of Broca aphasia include right hemiparesis, hemisensory loss, and apraxia of the oral apparatus and the nonparalyzed (typically left) limbs. Apraxia in response to motor commands is important to recognize because it may be mistaken for comprehension disturbance. Comprehension should be tested by responses to yes-no questions or commands to point to an object. The common features of Broca aphasia are listed in Table 13.1. An important clinical feature of Broca aphasia is its frequent association with depression (Robinson 1997). Patients with Broca aphasia are typically aware of and frustrated by their deficits. At times, they become withdrawn and refuse help or therapy. Usually, the depression lifts as the deficit recovers, but it may be a limiting factor in rehabilitation. The lesions responsible for Broca aphasia usually include the traditional Broca area in the posterior part of the inferior frontal gyrus, along with damage to adjacent cortex and subcortical white matter. Most patients with lasting Broca aphasia, including Broca original cases, have much larger left frontoparietal lesions, including most of the territory of the upper division of the left middle cerebral artery. Such patients typically evolve from global to Broca aphasia over weeks to months. Patients who manifest Broca aphasia immediately after their strokes, by contrast, have smaller lesions of the inferior frontal region, and their deficits generally resolve quickly.

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Fig. 13.3 Magnetic resonance imaging scans from a patient with Broca aphasia. In this patient, the cortical Broca area, subcortical white matter, and the insula were all involved in the infarction. The patient made a good recovery.

In computed tomography (CT) scan analyses at the Boston Veterans Administration Medical Center, lesions restricted to the lower precentral gyrus produced only dysarthria and mild expressive disturbance. Lesions involving the traditional Broca area (Brodmann areas 44 and 45) resulted in difficulty initiating speech, and lesions combining Broca area, the lower precentral gyrus, and subcortical white matter yielded the full syndrome of Broca aphasia (Alexander et al., 1990). In studies by the same group, damage to two subcortical white matter sites—the rostral subcallosal fasciculus deep to the Broca area and the periventricular white matter adjacent to the body of the left lateral ventricle—was required to cause permanent nonfluency. Fig. 13.3 shows an MRI scan from a case of Broca aphasia.

Aphemia This rare syndrome, not much discussed currently, involves transient muteness in patients with isolated lesions centered on the left frontal Broca area, its subcortical white matter, or the inferior precentral gyrus. Aphemia may not classify as a language disorder if writing is normal.

Wernicke Aphasia Wernicke aphasia may be considered a syndrome opposite to Broca aphasia, in that expressive speech is fluent, but comprehension is impaired. The speech pattern is effortless and sometimes even excessively fluent (logorrhea). A speaker of a foreign language might notice nothing amiss, but a listener who shares the patient’s language detects speech empty of meaning, containing verbal paraphasias, neologisms, and jargon productions. In milder cases, the intended meaning of an utterance may be discerned, but the sentence goes awry with paraphasic substitutions. Naming in Wernicke aphasia is deficient, often with bizarre, paraphasic substitutions for the correct name. Auditory comprehension is impaired, sometimes even for simple nonsense questions. Repetition is impaired; whispering a phrase in the patient’s ear, as in a hearing test, may help cue the patient to attempt repetition. Reading comprehension is usually affected similarly to auditory

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TABLE 13.2

Aphasia Feature

Syndrome

Spontaneous speech

Fluent, with paraphasic errors Usually not dysarthric Sometimes logorrheic Impaired (often bizarre paraphasic misnaming) Impaired Impaired Impaired for comprehension, reading aloud Well-formed, paragraphic ± Right hemianopia Motor, sensory signs usually absent

Naming Comprehension Repetition Reading Writing Associated signs

comprehension, but occasional patients show greater deficits in one modality versus the other. The discovery of relatively spared reading ability in Wernicke aphasics is important in allowing these patients to communicate. Writing is also impaired, but in a manner quite different from that of Broca aphasia. The patient usually has no hemiparesis and can grasp the pen and write easily. Written productions are even more abnormal than oral ones, however, in that spelling errors are also evident. Writing samples are especially useful in the detection of mild Wernicke aphasia. Associated signs are limited in Wernicke aphasia; most patients have no elementary motor or sensory deficits, although a partial or complete right homonymous hemianopia may be present. The characteristic bedside examination findings in Wernicke aphasia are summarized in Table 13.2. The psychiatric manifestations of Wernicke aphasia are quite different from those of Broca aphasia. Depression is less common; many Wernicke aphasics seem unaware of or unconcerned about their communicative deficits. With time, some patients become angry or

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A

B Fig. 13.4 Axial and coronal magnetic resonance imaging slices (A and B), and an axial positron emission tomographic (PET) scan view (C) of an elderly woman with Wernicke aphasia. There is a large left superior temporal lobe lesion. The onset of the deficit was not clear, and the PET scan was useful in showing that the lesion had reduced metabolism, favoring a stroke over a tumor.

paranoid about the inability of family members and medical staff to understand them. This behavior, similarly to depression, may hinder rehabilitative efforts. The lesions of patients with Wernicke aphasia are usually centered on the posterior portion of the superior temporal gyrus, extending into the inferior parietal lobule and middle temporal gyrus Kertesz et al., 1993). Fig. 13.4 shows a typical example. In the acute phase, the ability to match a spoken word to a picture is quantitatively related to decreased perfusion of the Wernicke area on perfusion-weighted MRI, indicating less variability during the acute phase than after recovery has taken place (Hillis et al., 2001). Recent literature (see Binder, 2015; Bonilha et al., 2017) has suggested that auditory comprehension is subserved by wider regions of the left temporal lobe. Electrical stimulation @

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of the Wernicke area produces consistent interruption of auditory comprehension, supporting the importance of this region for decoding auditory language (Boatman et al., 1995). A receptive speech area in the left inferior temporal gyrus has also been suggested by electrical stimulation studies and by a few descriptions of patients with seizures involving this area (Kirshner et al., 1995). In terms of vascular anatomy, Wernicke aphasia is generally associated with the inferior division of the left middle cerebral artery.

Pure Word Deafness Pure word deafness is a rare but striking syndrome of isolated loss of auditory comprehension and repetition, without any abnormality of speech, naming, reading, or writing. Hearing for pure tones and for D1 F CD @ 2C @ C

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nonverbal noises, such as animal cries, is intact. Most cases have mild aphasic deficits, especially paraphasic speech. Classically, the anatomical substrate is a bilateral lesion, isolating Wernicke area from input from the primary auditory cortex, in the bilateral Heschl gyri. Pure word deafness is thus an example of a “disconnection syndrome,” in which the deficit results from loss of white matter connections rather than of gray matter language centers. Some cases of pure word deafness, however, have unilateral, left temporal lesions, if the lesion is placed such as to disconnect Wernicke area from primary auditory cortex of both hemispheres.

Global Aphasia Global aphasia may be thought of as a summation of the deficits of Broca aphasia and Wernicke aphasia. Speech is nonfluent or mute, but comprehension is also poor, as are naming, repetition, reading, and writing. Most patients have dense right hemiparesis, hemisensory loss, and often hemianopia, although occasional patients have little hemiparesis. Milder aphasic syndromes in which all modalities of language are affected are often called mixed aphasias. The lesions of patients with global aphasia are usually large, involving both the inferior frontal and the superior temporal regions and often much of the parietal lobe in between. This lesion represents most of the territory of @

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the left middle cerebral artery. Patients in whom the superior temporal gyrus is spared tend to recover their auditory comprehension and to evolve toward the syndrome of Broca aphasia. Recovery in global aphasia may be prolonged; global aphasics may recover more during the second 6 months than during the first 6 months after a stroke (Sarno and Levita, 1979). Characteristics of global aphasia are presented in Table 13.3.

Conduction Aphasia Conduction aphasia is a theoretically important syndrome that can be remembered by its striking deficit of repetition. Most patients have relatively fluent spontaneous speech but make literal paraphasic errors and hesitate frequently for self-correction. Naming may be impaired, but auditory comprehension is preserved. Repetition may be disturbed to seemingly ridiculous extremes, such that a patient who can express himself or herself at a sentence level and comprehend conversation may be unable to repeat even single words. One such patient could not repeat the word “boy” but said “I like girls better.” Reading and writing are somewhat variable, but reading aloud may share some of the same difficulty as repeating. Associated deficits include hemianopia in some patients; right-sided sensory loss may be present, but right hemiparesis is usually mild or absent. Some patients have limb apraxia, creating a D1 F CD @ 2C @ C

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TABLE 13.3

Aphasia

Common Neurological Problems

Bedside Features of Global

TABLE 13.5

Aphasia

Bedside Features of Anomic

Feature

Syndrome

Feature

Syndrome

Spontaneous speech Naming Comprehension Repetition Reading Writing Associated signs

Mute or nonfluent Impaired Impaired Impaired Impaired Impaired Right hemiparesis Right hemisensory loss Right hemianopia

Spontaneous speech

Fluent, some word-finding pauses, circumlocution Impaired Intact Intact Intact Intact, except for anomia Variable or none

Naming Comprehension Repetition Reading Writing Associated signs

Anomic Aphasia Bedside Features of Conduction Aphasia TABLE 13.4 Feature

Syndrome

Spontaneous speech Naming Comprehension Repetition Reading

Fluent, hesitancy, literal paraphasic errors Moderately impaired Intact Impaired + Reading aloud moderately impaired; reading comprehension largely intact Variable deficits + Apraxia of left limbs + Right hemiparesis, usually mild + Right hemisensory loss + Right hemianopia

Writing Associated signs

misimpression that comprehension is impaired. Bedside examination findings in conduction aphasia are summarized in Table 13.4. The lesions of conduction aphasia usually involve either the superior temporal or the inferior parietal regions. Benson and associates suggested that patients with limb apraxia have parietal lesions, whereas those without apraxia have temporal lesions (Benson et al., 1973). Conduction aphasia may represent a stage of recovery in patients with Wernicke aphasia in whom the damage to the superior temporal gyrus is not complete. Conduction aphasia has been advanced as a classical disconnection syndrome. Wernicke originally postulated that a lesion disconnecting the Wernicke and Broca areas would produce this syndrome; Geschwind later pointed to the arcuate fasciculus, a white matter tract traveling from the deep temporal lobe, around the sylvian fissure to the frontal lobe, as the site of disconnection. Anatomical involvement of the arcuate fasciculus is present in most, if not all, cases of conduction aphasia, but some doubt has been raised about the importance of the arcuate fasciculus to conduction aphasia or even to repetition (Bernal and Ardila, 2009). In cases of conduction aphasia, there is usually also cortical involvement of the supramarginal gyrus or temporal lobe. The supramarginal gyrus appears to be involved in auditory immediate memory and in phoneme perception related to word meaning, as well as phoneme generation (Hickok and Poeppel, 2000). Lesions in this area are associated with conduction aphasia and phonemic paraphasic errors. Others have pointed out that lesions of the arcuate fasciculus do not always produce conduction aphasia. Another theory of conduction aphasia has involved a defect in auditory verbal short-term (or what most neurologists would call immediate) memory.

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Anomic aphasia refers to aphasic syndromes in which naming, or access to the internal lexicon, is the principal deficit. Spontaneous speech is normal except for the pauses and circumlocutions produced by the inability to name. Comprehension, repetition, reading, and writing are intact, except for the same word-finding difficulty in written productions. Anomic aphasia is common but less specific in localization than other aphasic syndromes. Isolated, severe anomia may indicate focal left hemisphere pathology. Alexander and Benson (1997) refer to the angular gyrus as the site of lesions producing anomic aphasia, but lesions there usually produce other deficits as well, including alexia and the four elements of Gerstmann syndrome: agraphia, right-left disorientation, acalculia, and finger agnosia, or the inability to identify fingers. Isolated lesions of the temporal lobe can produce pure anomia. Inability to produce nouns is characteristic of temporal lobe lesions, whereas inability to produce verbs occurs more with frontal lesions (Damasio, 1992). Even specific classes of nouns may be selectively affected in some cases of anomic aphasia. Anomia is also seen with mass lesions elsewhere in the brain, and in diffuse degenerative disorders, such as Alzheimer disease (AD). Anomic aphasia is also a common stage in the recovery of many aphasic syndromes. Anomic aphasia thus serves as an indicator of left hemisphere or diffuse brain disease, but it has only limited localizing value. The typical features of anomic aphasia are presented in Table 13.5.

Transcortical Aphasias The transcortical aphasias are syndromes in which repetition is normal, presumably because the causative lesions do not disrupt the perisylvian language circuit from the Wernicke area through the arcuate fasciculus to the Broca area. Instead, these lesions disrupt connections from other cortical centers into the language circuit (hence the name “transcortical”). The transcortical syndromes are easiest to think of as analogues of the syndromes of global, Broca, and Wernicke aphasias, with intact repetition. In addition, because transcortical aphasias spare the perisylvian language circuit, they are often associated with watershed lesions, in the anterior frontal region between the anterior cerebral artery (ACA) and middle cerebral artery (MCA) distribution, or in the parietal region, between the MCA and posterior cerebral artery (PCA) distributions. Mixed transcortical aphasia, or the syndrome of the isolation of the speech area, is a global aphasia in which the patient repeats, often echolalically, but has no propositional speech or comprehension. This syndrome is rare, occurring predominantly in large, watershed infarctions of the left hemisphere or both hemispheres that spare the perisylvian cortex, or in advanced dementias. Transcortical motor aphasia is an analogue of Broca aphasia in which speech is hesitant or telegraphic, comprehension is relatively spared, but repetition is fluent. This syndrome occurs with lesions in

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Bedside Features of Transcortical Aphasias TABLE 13.6

Feature

Isolation Syndrome

Speech

Nonfluent, echolalic Naming Impaired Comprehension Impaired Repetition Intact Reading Impaired Writing Impaired

Transcortical Transcortical Motor Sensory Nonfluent

Fluent, echolalic

Impaired Intact Intact ± Intact ± Intact

Impaired Impaired Intact Impaired Impaired

the frontal lobe, anterior to the Broca area, in the deep frontal white matter, or in the medial frontal region, in the vicinity of the supplementary motor area. All of these lesion sites are within the territory of the anterior cerebral artery, separating this syndrome from the aphasia syndromes of the middle cerebral artery (Broca, Wernicke, global, and conduction). The third transcortical syndrome, transcortical sensory aphasia, is an analogue of Wernicke aphasia in which fluent, paraphasic speech, paraphasic naming, impaired auditory and reading comprehension, and abnormal writing coexist with normal repetition. This syndrome is relatively uncommon, occurring in strokes of the left temporo-occipital area and in dementias. Bedside examination findings in the transcortical aphasias are summarized in Table 13.6.

Subcortical Aphasias A current area of interest in aphasia research involves the “subcortical” aphasias. Although all the syndromes discussed so far are defined by behavioral characteristics that can be diagnosed on the bedside examination, the subcortical aphasias are defined by lesion localization in the basal ganglia, thalamus, or deep cerebral white matter. As knowledge about subcortical aphasia has accumulated, two major groups of aphasic symptomatology have been described: aphasia with thalamic lesions and aphasia with lesions of the subcortical white matter and basal ganglia. Left thalamic hemorrhages frequently produce a Wernicke-like fluent aphasia, with better comprehension than cortical Wernicke aphasia. A fluctuating or “dichotomous” state has been described, alternating between an alert state with nearly normal language and a drowsy state in which the patient mumbles paraphasically and comprehends poorly. Luria has called this a quasi-aphasic abnormality of vigilance, in that the thalamus plays a role in alerting the language cortex. Whereas some skeptics have attributed thalamic aphasia to pressure on adjacent structures and secondary effects on the cortex, cases of thalamic aphasia have been described with small ischemic lesions, especially those involving the paramedian or anterior nuclei of the thalamus, in the territory of the tuberothalamic artery. Because these lesions produce little or no mass effect, such cases indicate that the thalamus and its connections play a definite role in language function (Carrerra and Bogousslavsky, 2006). A case report found fluent aphasia in a left-handed patient with a right thalamic hemorrhage, raising the possibility that language dominance extends to the level of the thalamus (Kirshner & Kistler, 1982). Lesions of the left basal ganglia and deep white matter also cause aphasia. As in thalamic aphasia, the first syndromes described were in basal ganglia hemorrhages, especially those involving the putamen, the most common site of hypertensive intracerebral hemorrhage. Here, the aphasic syndromes are more variable but most commonly involve global or Wernicke-like aphasia. As in thalamic lesions,

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ischemic strokes have provided better localizing information. The most common lesion is an infarct involving the anterior putamen, caudate nucleus, and anterior limb of the internal capsule. Patients with this lesion have an “anterior subcortical aphasia syndrome” involving dysarthria, decreased fluency, mildly impaired repetition, and mild comprehension disturbance (Mega and Alexander, 1994). This syndrome most closely resembles Broca aphasia, but with greater dysarthria and less language dysfunction. Fig. 13.5 shows an example of this syndrome. More restricted lesions of the anterior putamen, head of caudate, and periventricular white matter produce hesitancy or slow initiation of speech but little true language disturbance. More posterior lesions involving the putamen and deep temporal white matter, referred to as the temporal isthmus, are associated with fluent, paraphasic speech and impaired comprehension resembling Wernicke aphasia (Naeser et al., 1990). Small lesions in the posterior limb of the internal capsule and adjacent putamen cause mainly dysarthria, but mild aphasic deficits may occasionally occur. Finally, larger subcortical lesions involving both the anterior and the posterior lesion sites produce global aphasia. A wide variety of aphasia syndromes can thus be seen with subcortical lesion sites. Nadeau and Crosson (1997) presented an anatomical model of basal ganglia and deep white matter involvement in speech and language, based on the known motor functions and fiber connections of these structures. Controversy has followed the identification of the insula as a source of speech production; Dronkers (1996) suggested this based on a lesion overlap analysis of cases of apraxia of speech. Hillis and colleagues (2004), however, showed that in acute aphasia, the left frontal cortex, and not the insula, is related to apraxia of speech. In clinical terms, subcortical lesions do produce aphasia, although less commonly than cortical lesions do, and the language characteristics of subcortical aphasias are often atypical. The presentation of a difficult-to-classify aphasic syndrome, in the presence of dysarthria and right hemiparesis, should lead to suspicion of a subcortical lesion.

Pure Alexia Without Agraphia Alexia, or acquired inability to read, is a form of aphasia, according to the definition given at the beginning of this chapter. The classic syndrome of alexia, pure alexia without agraphia, was described by the French neurologist Dejerine in 1892. This syndrome may be thought of as a linguistic blindfolding: patients can write but cannot read their own writing. On bedside examination, speech, auditory comprehension, and repetition are normal. Naming may be deficient, especially for colors. Patients initially cannot read at all; as they recover, they learn to read letter by letter, spelling out words laboriously. They cannot read words at a glance, as normal readers do. By contrast, they quickly understand words spelled orally to them, and they can spell normally. Some patients can match words to pictures, indicating that some subconscious awareness of the word is present, perhaps in the right hemisphere. Associated deficits include a right hemianopia or right upper quadrant defect in nearly all patients and, frequently, a deficit of shortterm memory. There is usually no hemiparesis or sensory loss. The causative lesion in pure alexia is nearly always a stroke in the territory of the left posterior cerebral artery, with infarction of the medial occipital lobe, often the splenium of the corpus callosum, and often the medial temporal lobe. Dejerine postulated a disconnection between the intact right visual cortex and left hemisphere language centers, particularly the angular gyrus. (Fig. 13.6 is an adaptation of Dejerine’s original diagram.) Geschwind later rediscovered this disconnection hypothesis. Although Damasio and Damasio (1983) found splenial involvement in only 2 of 16 cases, they postulated a disconnection within the deep

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Fig. 13.5 Magnetic resonance imaging (MRI) scan slices in the axial, coronal, and sagittal planes from a patient with subcortical aphasia. The lesion is an infarction involving the anterior caudate, putamen, and anterior limb of the left internal capsule. The patient presented with dysarthria and mild, nonfluent aphasia with anomia, with good comprehension. The advantage of MRI in permitting visualization of the lesion in all three planes is apparent.

white matter of the left occipital lobe. As in the disconnection hypothesis for conduction aphasia, the theory fails to explain all the behavioral phenomena, such as the sparing of single letters. A deficit in short-term memory for visual language elements, or an inability to perceive multiple letters at once (simultanagnosia), can also explain many features of the syndrome. Typical findings of pure alexia without agraphia are presented in Table 13.7 (Fig. 13.7).

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Alexia With Agraphia The second classic alexia syndrome, alexia with agraphia, described by Dejerine in 1891, may be thought of as an acquired illiteracy, in which a previously educated patient is rendered unable to read or write. The oral language modalities of speech, naming, auditory comprehension, and repetition are largely intact, but many cases manifest a fluent, paraphasic speech pattern with impaired naming. This syndrome thus

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Right visual field

Left eye

Right eye

Optic chiasm

Splenium Angular gyrus

Left visual cortex Fig. 13.6 Horizontal brain diagram of pure alexia without agraphia, adapted from that of Dejerine in 1892. Visual information from the left visual field reaches the right occipital cortex but is “disconnected” from the left hemisphere language centers by the lesion in the splenium of the corpus callosum.

Fig. 13.7 Fluid attenuated inversion recovery (FLAIR) magnetic resonance image of an 82-year-old male patient with alexia without agraphia. The infarction involves the medial occipital lobe and the splenium of the corpus callosum, within the territory of the left posterior cerebral artery.

TABLE 13.7 Bedside Features of Pure Alexia Without Agraphia

With Agraphia

Feature

Syndrome

Feature

Syndrome

Spontaneous speech Naming Comprehension Repetition Reading

Intact ± Impaired, especially colors Intact Intact Impaired (some sparing of single letters) Intact Right hemianopia or superior quadrantanopia Short-term memory loss Motor, sensory signs usually absent

Spontaneous speech Naming Comprehension Repetition Reading Writing Associated signs

Fluent, often some paraphasia + Impaired Intact, or less impaired than reading Intact Severely impaired Severely impaired Right hemianopia Motor, sensory signs often absent

Writing Associated signs

TABLE 13.8

overlaps Wernicke aphasia, especially in cases in which reading is more impaired than auditory comprehension. Associated deficits include right hemianopia and elements of Gerstmann syndrome: agraphia, acalculia, right–left disorientation, and finger agnosia. The lesions typically involve the inferior parietal lobule, especially the angular gyrus. Etiologies include strokes in the territory of the angular branch of the left middle cerebral artery or mass lesions in the same region. Characteristic features of the syndrome of alexia with agraphia are summarized in Table 13.8.

Aphasic Alexia In addition to the two classic alexia syndromes, many patients with aphasia have associated reading disturbance. Neurolinguists and cognitive psychologists have divided alexias according to breakdowns in specific stages of the reading process. The linguistic

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concepts of surface structure versus the deep meanings of words have been instrumental in these new classifications. Four patterns of alexia (or dyslexia) have been recognized: letter-by-letter reading, deep, phonological, and surface dyslexia. Fig. 13.8 diagrams the steps in the reading process and the points of breakdown in the four syndromes. Letter-by-letter reading is equivalent to pure alexia without agraphia. Deep dyslexia is a severe reading disorder in which patients recognize and read aloud only familiar words, especially concrete, imageable nouns and verbs. They make semantic or visual errors in reading and fail completely in reading nonsense syllables or nonwords. Word reading is not affected by word length or by regularity of spelling; one patient, for example, could read “ambulance” but not “am.” Most cases have severe aphasia, with extensive left frontoparietal damage. Phonological dyslexia is similar to deep dyslexia, with poor reading of nonwords, but single nouns and verbs are read in a nearly normal fashion, and semantic errors are rare. The fourth type, surface dyslexia, involves spared ability to read by grapheme-phoneme conversion but

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inability to recognize long words, at a glance, or irregular words. These patients can read nonsense syllables but not words of irregular spelling, such as “colonel” or “yacht.” Their errors tend to be phonological rather than semantic or visual (e.g., pronouncing rough and though alike). Written input 2,3 Visual memory images (orthographic lexicon)

1 3

2 Concepts (semantic store)

Sound images (phonological lexicon)

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Grapheme-phoneme transformation

Agraphia Similarly to reading, writing may be affected either in isolation (pure agraphia) or in association with aphasia (aphasic agraphia). In addition, writing can be impaired by motor disorders, by apraxia, and by visuospatial deficits. Isolated agraphia has been described with left frontal or parietal lesions. Agraphias can be analyzed in the same way as the alexias (Fig. 13.9). Thus, phonological agraphia involves the inability to convert phonemes into graphemes or to write pronounceable nonsense syllables, in the presence of ability to write familiar words. Deep dysgraphia is similar to phonological agraphia, but the patient can write nouns and verbs better than articles, prepositions, adjectives, and adverbs. In lexical or surface dysgraphia, patients can write regularly spelled words and pronounceable nonsense words but not irregularly spelled words. These patients have intact phoneme-grapheme conversion but cannot write by a whole-word or “lexical” strategy.

LANGUAGE IN RIGHT HEMISPHERE DISORDERS

2,3 1 Motor speech images (articulatory programs) 1,2,3 Spoken output

Fig. 13.8 Neurolinguistic Model of the Reading Process. According to evidence from the alexias, there are three separate routes to reading: 1 is the phonological (or grapheme-phoneme conversion) route; 2 is the semantic (or lexical-semantic-phonological) route; and 3 is the nonlexical phonological route. In deep dyslexia, only route 2 can operate; in phonological dyslexia, 3 is the principal pathway; in surface dyslexia, only 1 is functional. (Adapted with permission from Margolin, D.I., 1991. Cognitive neuropsychology. Resolving enigmas about Wernicke aphasia and other higher cortical disorders. Arch. Neurol. 48, 751–765.)

Language and communication disorders are important even in patients with right hemisphere disease. First, some patients, especially left-handed patients, may have right hemisphere language dominance and may develop aphasic syndromes from right hemisphere lesions. Second, rare right-handed patients develop aphasia after right hemisphere strokes, a phenomenon called “crossed aphasia” (Bakar et al., 1996). Third, even right-handed persons with typical left hemisphere dominance for language have subtly altered language function after right hemisphere damage. Such patients are not aphasic, in that the fundamental mechanisms of speech production, repetition, and comprehension are undisturbed. Affective aspects of language are impaired, however, such that the speech sounds flat and unemotional; the normal prosody, or emotional intonation, of speech is lost. Syndromes of loss of emotional aspects of speech are termed aprosodias. Motor aprosodia involves loss of expressive emotion with preservation of emotional comprehension; sensory aprosodia involves loss of comprehension of affective language, also called affective agnosia. More than

Thoughts

Spoken language

Auditory words

1

3 2

Semantics

Phonemes 3

Phoneme-grapheme transformation

2

3 1 Written graphemes

Written words

Fig. 13.9 Neurolinguistic Model of Writing and the Agraphias. In deep agraphia, only the semantic (phonological-semantic-lexical) route (1) is operative; in phonological agraphia, route (2), the nonlexical phonological route produces written words directly from spoken words; in surface agraphia, only route (3), the phoneme-grapheme pathway, can be used to generate writing. @

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just emotion, stress and emphasis within a sentence are also affected by right hemisphere dysfunction. More importantly, such vital aspects of human communication as metaphor, humor, sarcasm, irony, and related constituents of language that transcend the literal meaning of words are especially sensitive to right hemisphere dysfunction. These deficits significantly impair patients in the pragmatics of communication. In other words, right hemisphere–damaged patients understand what is said, but not how it is said. They may have difficulty following a complex story (Rehak et al., 1992). Such higher-level language deficits are related to the right hemisphere disorders of inattention and neglect, discussed in Chapters 4 and 45.

semantic dementia usually reflect different forms of frontotemporal lobar degeneration (FTLD), whereas logopenic progressive aphasia is most commonly due to Alzheimer pathology with an atypical anatomical distribution. Progressive nonfluent aphasias are often tauopathies, in familial cases related to mutations on chromosome 17 (Heutink et al., 1997), while semantic dementia may be related to ubiquitin deposition and mutations in the progranulin gene, with production of TDP43 (Baker et al., 2006; Cruts et al., 2006). Another neurodegenerative diseases that can present with language abnormalities or PPA is corticobasal degeneration (Kertesz et al., 2000, Litvan et al., 1998). Creutzfeldt– Jakob disease can present with a rapidly progressive aphasia.

LANGUAGE IN DEMENTING DISEASES

INVESTIGATION OF THE APHASIC PATIENT

Language impairment is commonly seen in patients with dementia. Despite considerable variability from patient to patient, two patterns of language dissolution can be described. The first, the common presentation of AD, involves early loss of memory and general cognitive deterioration. In these patients, mental status examinations are most remarkable for deficits in short-term memory, insight, and judgment, but language impairments can be found in naming and in discourse, with impoverished language content and loss of abstraction and metaphor. The mechanics of language—grammatical construction of sentences, receptive vocabulary, auditory comprehension, repetition, and oral reading—tend to remain preserved until later stages. By aphasia testing, patients with early AD have anomic aphasia. In later stages, language functions become more obviously impaired. In terms of the components of language mentioned earlier in this chapter, the semantic aspects of language tend to deteriorate first, then syntax, and finally phonology. Reading and writing—the last-learned language functions—are among the first to decline. Auditory comprehension later becomes deficient, whereas repetition and articulation remain normal. The language profile may then resemble that of transcortical sensory or Wernicke aphasia. In terminal stages, speech is reduced to the expression of simple biological wants; eventually, even muteness can develop. By this time, most patients are institutionalized or bedridden. The second pattern of language dissolution in dementia, less common than the first, involves the gradual onset of a progressive aphasia, often without other cognitive deterioration. Auditory comprehension is involved early in the illness, and specific aphasic symptoms are evident, such as paraphasic or nonfluent speech, misnaming, and errors of repetition. These deficits worsen gradually, mimicking the course of a brain tumor or mass lesion rather than a typical dementia (Grossman et al., 1996; Mesulam, 2001, 2003; Mesulam et al., 2014). The syndrome is referred to as “primary progressive aphasia (PPA).” MRI or CT scans may show focal atrophy in the left perisylvian region, while EEG studies may show focal slowing. PET has shown prominent areas of decreased metabolism in the left hemisphere regions. Three variants of PPA are commonly recognized (Gorno-Tempini et al., 2011). Progressive nonfluent aphasia involves deficits in speech production and grammar, resembling Broca aphasia. Semantic dementia (Hodges and Patterson, 2007; Snowden et al., 1989) is a progressive fluent aphasia with impaired naming and loss of understanding of even single words. In reading, these patients may have a surface alexia pattern. The third variant of PPA, logopenic progressive aphasia, involves anomia and some repetition difficulty, with intact single-word comprehension (Gorno-Tempini et al., 2008). These three patterns of PPA are associated with different patterns of atrophy on MRI and hypometabolism on PET: progressive nonfluent aphasia is associated with left frontal and insular atrophy; semantic dementia is associated with bilateral anterior temporal atrophy; logopenic progressive aphasia is associated with left posterior temporal and inferior parietal atrophy (Diehl et al., 2004; Josephs et al., 2010). Progressive nonfluent aphasia and @

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Clinical Tests The bedside language examination is useful in forming a preliminary impression of the type of aphasia and the localization of the causative lesion. Follow-up examinations are also helpful; as in all neurological diagnosis, the evolution of a neurological deficit over time is the most important clue to the specific disease process. For example, an embolic stroke and a brain tumor might both produce Wernicke aphasia, but strokes occur suddenly, with improvement thereafter, whereas tumors produce gradually worsening aphasia. In addition to the bedside examination, a large number of standardized aphasia test batteries have been published. The physician should think of these tests as more detailed extensions of the bedside examination. They have the advantage of quantitation and standardization, permitting comparison over time and, in some cases, even a diagnosis of the specific aphasia syndrome. Research on aphasia depends on these standardized tests. For neurologists, the most helpful battery is the Boston Diagnostic Aphasia Examination, or its Canadian adaptation, the Western Aphasia Battery. Both tests provide subtest information analogous to the bedside examination, and are therefore meaningful to neurologists, as well as aphasia syndrome classification. The Porch Index of Communicative Ability quantifies performance in many specific functions, allowing comparison over time. Other aphasia tests are designed to evaluate specific language areas. For example, the Boston Naming Test provides a large graded set of naming stimuli, while the Token Test evaluates higher-level comprehension deficits. Further information on neuropsychological tests can be found in Chapter 43. Further diagnosis of the aphasic patient rests on the confirmation of a brain lesion by neuroimaging (Fig. 13.10). The advent of CT and MRI (discussed in Chapter 40) revolutionized the localization of aphasia by permitting “real-time” delineation of a focal lesion in a living patient; previously, the physician had to outlive the patient to obtain a clinical–pathological correlation at autopsy. MRI scanning provides better resolution of areas difficult to see on CT, such as the temporal cortex adjacent to the petrous bones, and more sensitive detection of tissue pathology, such as early changes of infarction. The anatomical distinction of cortical from subcortical aphasia is best made by MRI. Acute strokes are visualized early on diffusion-weighted MRI. The EEG is helpful in aphasia in localizing seizure discharges, interictal spikes, and slowing seen after destructive lesions, such as traumatic contusions and infarctions. The EEG can provide evidence that aphasia is an ictal or postictal phenomenon and can furnish early clues to aphasia secondary to mass lesions or to herpes simplex encephalitis. In research applications, electrophysiological testing via subdural grid and depth electrodes, or stimulation mapping of epileptic foci in preparation for epilepsy surgery, has aided in the identification of cortical areas involved in language. Cerebral arteriography is useful in the diagnosis of aneurysms, arteriovenous malformations (AVMs), arterial occlusions, vasculitis, D1 F CD @ 2C @ C

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B Fig. 13.10 Coronal T1-weighted magnetic resonance imaging scans of a patient with primary progressive aphasia. Note the marked atrophy of the left temporal lobe. A, Axial fluoro-2-deoxyglucose positron emission tomography (FDG PET). B, Tomographic scan showing extensive hypometabolism in the left cerebral hemisphere, especially marked in the left temporal lobe.

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CHAPTER 13 Aphasia and Aphasic Syndromes and venous outflow obstructions. In preparation for epilepsy surgery, the Wada test, or infusion of amobarbital through an arterial catheter, is useful in the determination of language dominance. Other, related studies by language activation with functional MRI (fMRI) or PET now rival the Wada test for the study of language dominance (AbouKhalil and Schlaggar, 2002). Single-photon emission CT (SPECT), PET, and functional MRI (see Chapter 40) are contributing greatly to the study of language. Patterns of brain activation in response to language stimuli have been recorded in neurologically normal research participants as well as individuals with aphasia, and these studies have broadly confirmed the localizations based on pathology such as stroke over the past 140 years (Posner et al., 1988). In addition, these techniques can be used to map areas of the brain that activate during language functions after insults such as strokes, and the pattern of recovery can be studied. Some such studies have indicated right hemisphere activation in patients recovering from aphasia, whereas others have concluded that return to function of left hemisphere language regions is necessary for full recovery. An fMRI study (Saur et al., 2006) has suggested dysfunction in the language cortex shortly after an ischemic insult, followed by increased activation of right frontal cortex, and then a shift back to the more normal pattern of left hemisphere activation. These techniques provide the best correlation between brain structure and function currently available and should help advance our understanding of language disorders and their recovery.

DIFFERENTIAL DIAGNOSIS Vascular lesions, especially ischemic strokes, are the most common causes of aphasia. Historically, most research studies in aphasia have used stroke patients because stroke is an “experiment” of nature in which one area of the brain is damaged, while the rest remains theoretically intact. Strokes are characterized by the abrupt onset of a neurological deficit in a patient with vascular risk factors. The precise temporal profile is important: most embolic strokes are sudden and maximal at onset, whereas thrombotic strokes typically wax and wane or increase in steps. The bedside aphasia examination is helpful in delineating the vascular territory affected. For example, the sudden onset of Wernicke aphasia nearly always indicates an embolus to the inferior division of the left middle cerebral artery. Global aphasia may be caused by an embolus to the middle cerebral artery stem, thrombosis of the internal carotid artery, or even a hemorrhage into the deep basal ganglia. Whereas most aphasic syndromes involve the territory of the left middle cerebral artery, transcortical motor aphasia is specific to the anterior cerebral territory, and pure alexia without agraphia is specific to the posterior cerebral artery territory. The clinical features of the aphasia are thus of crucial importance to the vascular diagnosis. Hemorrhagic strokes are also an important cause of aphasia, most commonly the basal ganglionic hemorrhages associated with hypertension. The deficits tend to worsen gradually over minutes to hours, in contrast to the sudden or stepwise onset of ischemic strokes. Headache, vomiting, and obtundation are more common with hemorrhages. Because hemorrhages compress cerebral tissue without necessarily destroying it, the ultimate recovery from aphasia is often better in hemorrhages than in ischemic strokes, although hemorrhages are more often fatal. Other etiologies of intracerebral hemorrhage include anticoagulants, head injury, blood dyscrasias, thrombocytopenia, and bleeding into structural lesions, such as infarctions, tumors, AVMs, and aneurysms. Hemorrhages from AVMs mimic strokes, with abrupt onset of focal neurological deficit. Ruptured aneurysms, on the other hand, present with severe headache and stiff neck or with coma; most

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patients have no focal deficits, but delayed deficits (e.g., aphasia) may develop secondary to vasospasm. Lobar hemorrhages may occur in elderly patients without hypertension. These hemorrhages occur near the cortical surface, sometimes extending into the subarachnoid space, and they may be recurrent. Pathological studies have shown amyloid deposition in small arterioles, or cerebral amyloid angiopathy. A final vascular cause of aphasia is cerebral vasculitis (see Chapter 70). Traumatic brain injury is a common cause of aphasia. Cerebral contusions, depressed skull fractures, and hematomas of the intracerebral, subdural, and epidural spaces all cause aphasia when they disrupt or compress left hemisphere language structures. Trauma tends to be less localized than ischemic stroke, and thus, aphasia is often admixed with the general effects of the head injury, such as depressed consciousness, encephalopathy or delirium, amnesia, and other deficits. Head injuries in young people may be associated with severe deficits but excellent long-term recovery. Language deficits, especially those involving discourse organization, can be found in most cases of significant closed head injury (Chapman et al., 1992). Gunshot wounds produce focal aphasic syndromes, which rival stroke as a source of clinical-anatomical correlation. Subdural hematomas are infamous for mimicking other neurological syndromes. Aphasia is occasionally associated with subdural hematomas overlying the left hemisphere, but it may be mild and may be overlooked because of the patient’s more severe complaints of headache, memory loss, and drowsiness. Tumors of the left hemisphere frequently present with aphasia. The onset of the aphasia is gradual, and other cognitive deficits may be associated because of edema and mass effect. Aphasia secondary to an enlarging tumor may thus be difficult to distinguish from a diffuse encephalopathy or early dementia. Any syndrome of abnormal language function should therefore be investigated for a focal, dominant hemisphere lesion. Infections of the nervous system may cause aphasia. Brain abscesses can mimic tumors in every respect, and those in the left hemisphere can present with progressive aphasia. Chronic infections, such as tuberculosis or syphilis, can result in focal abnormalities that run the entire gamut of central nervous system symptoms and signs. Herpes simplex encephalitis has a predilection for the temporal lobe and orbital frontal cortex, and aphasia can be an early symptom, along with headache, confusion, fever, and seizures. Aphasia is often a permanent sequela in survivors of herpes encephalitis. Acquired immunodeficiency syndrome (AIDS) can cause language disorders. Opportunistic infections can cause focal lesions anywhere in the brain, and the neurotropic human immunodeficiency virus agent itself produces a dementia (AIDS dementia complex), in which language deficits play a part. Aphasia is frequently caused by degenerative central nervous system diseases. Reference has already been made to the focal, progressive aphasia in patients with FTLD and progressive nonfluent aphasia or atypical AD with logopenic primary progressive aphasia as compared with the more diffuse cognitive deterioration characteristic of AD. Language dysfunction in AD may be more common in familial cases and may predict poor prognosis. Cognitive deterioration in patients with Parkinson disease may also include language deterioration similar to that of AD, although Parkinson disease tends to involve more fluctuation in orientation and greater tendency to active visual hallucinations and acting out of dreams (Rapid Eye Movement [REM] sleep behavior disorder). Corticobasal degeneration is also associated with PPA and FTD, as noted earlier. A striking abnormality of speech (i.e., initial stuttering followed by true aphasia and dementia) has been described in the dialysis dementia syndrome. This disorder may be associated with spongiform degeneration of the frontotemporal cortex, similar to Creutzfeldt–Jakob disease. Paraphasic substitutions and

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nonsense speech are also occasionally encountered in acute encephalopathies, such as hyponatremia or lithium toxicity. Another cause of aphasia is seizures. Seizures can be associated with aphasia in children as part of the Landau-Kleffner syndrome or in adults as either an ictal or postictal Todd phenomenon. Epileptic aphasia is important to recognize, in that anticonvulsant drug therapy can prevent the episodes, and unnecessary investigation or treatment for a new lesion, such as a stroke, can be avoided. As mentioned earlier, localization of language areas in epileptic patients has contributed greatly to the knowledge of language organization in the brain. A new language area, the basal temporal language area (BTLA), was discovered through epilepsy stimulation studies, and only later confirmed in patients with spontaneous seizures (Kirshner et al., 1995). Another transitory cause of aphasia is migraine. Wernicke aphasia may be seen in a migraine attack, usually with complete recovery over a few hours. Occasional patients may have recurrent episodes of aphasia associated with migraine (Mishra et al., 2009). Finally, aphasia can be psychogenic, often associated with stuttering or stammering. A recent report (Binder et al., 2012) concerned three patients with stuttering or stammering, letter reversals (e.g. “low the mawn” instead of “mow the lawn”), and naming difficulty after minor head injuries. In all three, language productions were inconsistent; for example, when a subject became angry, the speech productions were much more normal. All three failed neuropsychological tests designed to detect a lack of effort (such as a digit span of only two). Patients failed to improve on easier speech production tasks such as speaking in unison, shouting, or speaking while finger-tapping. In addition, whereas developmental stutterers generally have difficulty only with the initial phoneme of a phrase, psychogenic stutterers, but also some acquired cases of stuttering, may hesitate on any word of a phrase.

RECOVERY AND REHABILITATION OF APHASIA Patients with aphasia from acute disorders, such as stroke, generally show spontaneous improvement over days, weeks, and months. In general, the greatest recovery occurs during the first few weeks and months with a decelerating time course. While a commonly stated dogma is that patients reach a plateau after 6 months to a year, several recent studies have clearly demonstrated that many patients continue to make gains years after a stroke. The aphasia type often changes during recovery: global aphasia evolves into Broca aphasia, and Wernicke aphasia into conduction or anomic aphasia (Pashek and Holland, 1988). Language recovery may be mediated by shifting of functions to the right hemisphere or to adjacent left hemisphere regions. As mentioned earlier, studies of language activation using fMRI and PET are advancing our understanding of the neuroanatomy of language recovery (Heiss et al., 1999; Thompson and den Ouden, 2008). These studies suggest that aphasia recovers best when left hemisphere areas, either in the direct language cortex or in adjacent areas, recover function. Right hemisphere activation seems to be a “second best” type of recovery. In addition, a study of patients in the very acute phase of aphasia, with techniques of diffusion and perfusion-weighted MRI, has suggested less variability in the correlation of comprehension impairment with left temporal ischemia than has been suggested from testing of chronic aphasia, after recovery and compensation have commenced (Hillis et al., 2001). Speech-language therapy, provided by speech-language pathologists, attempts to facilitate language recovery by a variety of

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techniques and to help the patient compensate for lost functions (see Chapter 57). Some of the main approaches that are commonly used include script training, response elaboration training, constraint-induced aphasia therapy, speech entrainment, and melodic intonation therapy. In script training, individuals rehearse personally relevant scripts for commonly encountered situations (e.g., visiting a coffee shop) in order to increase independence in communication. Response elaboration training involves clinicians using a cueing hierarchy to support patients in producing increasingly longer utterances by building on prior successful responses. Constraint-induced aphasia therapy involves minimizing the use of gesture or other alternative forms of communication in order to encourage practice with producing language. Speech entrainment depends on the surprisingly preserved ability of some patients with aphasia to speak along with an audiovisual model (i.e., hearing and watching the lips of another talker). This facilitation can be leveraged in support of script training and in the hope of promoting generalization to unsupported situations. Melodic intonation therapy is based on the premise of the right hemisphere’s involvement in prosodic aspects of language, which can provide a substrate for recovery when the left hemisphere is damaged. There is robust evidence for the efficacy of speech-language therapy in randomized controlled trials. Some patients may also benefit from using an Augmentative and Alternative Communication (AAC) device to communicate. The recent explosion of mobile computing technology has led to a proliferation of high-quality applications that allow nonverbal patients to communicate common and personally relevant concepts. A new approach to language rehabilitation is the use of pharmacological agents to improve speech. Albert and colleagues (1988) first reported that the dopaminergic drug bromocriptine promotes spontaneous speech output in transcortical motor aphasia. Several other studies have supported the drug in nonfluent aphasias, although a recent controlled study showed no benefit (Ashtary et al., 2006). Stimulant drugs are also being tested in aphasia rehabilitation. In a double-blind, placebo-controlled, parallel-group study, Berthier et al. (2009) observed the effect of memantine and constraint-induced aphasia therapy (CIAT) on chronic poststroke aphasia. Memantine and CIAT alone improved aphasia compared with placebo, but the best and most durable outcomes were observed when memantine and CIAT were combined. As new information accumulates on the neurochemistry of cognitive functions, other pharmacological therapies may be forthcoming. Finally, stimulation techniques such as transcranial magnetic stimulation (Martin et al., 2009; Wong and Tsang, 2013) and direct cortical stimulation (Monti et al., 2013) are being applied to patients with aphasia, and several early trials indicate benefit from these techniques (Fridriksson et al., 2018; Saxena and Hillis, 2017; Tippett et al., 2014).

Acknowledgment The authors would like to thank Sarah Schneck, MS, CCC-SLP, in the Department of Hearing and Speech Sciences, Vanderbilt University Medical Center, for assistance, especially with the discussion about speech and language therapy. The complete reference list is available online at https://expertconsult. inkling.com/.

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14 Dysarthria and Apraxia of Speech Howard S. Kirshner OUTLINE Motor Speech Disorders, 149 Dysarthrias, 149 Apraxia of Speech, 150 Oral or Buccolingual Apraxia, 151

Aphemia, 151 “Foreign Accent Syndrome”, 151 Acquired Stuttering, 151 Opercular Syndrome, 151

MOTOR SPEECH DISORDERS Motor speech disorders are syndromes of abnormal articulation, the motor production of speech, without abnormalities of language. A patient with a motor speech disorder should be able to produce normal expressive language in writing and to comprehend both spoken and written language. If a listener transcribes into print or type the speech of a patient with a motor speech disorder, the text should read as normal language. Motor speech disorders include dysarthrias, disorders of speech articulation, apraxia of speech, a motor programing disorder for speech, and four rarer syndromes: aphemia, foreign accent syndrome, acquired stuttering, and the opercular syndrome. Duffy (1995), in an analysis of speech and language disorders at the Mayo Clinic, reported that 46.3% of the patients had dysarthria, 27.1% aphasia, 4.6% apraxia of speech, 9% other speech disorders (such as stuttering), and 13% other cognitive or linguistic disorders.

Dysarthrias Dysarthrias involve the abnormal articulation of sounds or phonemes, or more precisely, abnormal neuromuscular activation of the speech muscles, affecting the speed, strength, timing, range, or accuracy of movements involving speech (Duffy, 1995). The most consistent finding in dysarthria is the distortion of consonant sounds. Dysarthria is neurogenic, related to dysfunction of the central nervous system, nerves, neuromuscular junction, or muscle, with a contribution of sensory deficits in some cases. Speech abnormalities secondary to local, structural problems of the palate, tongue, or larynx do not qualify as dysarthrias. Dysarthria can affect not only articulation but also phonation, breathing, or prosody (emotional tone) of speech. Total loss of ability to articulate is called anarthria. Like the aphasias, dysarthrias can be analyzed in terms of the specific brain lesion sites associated with specific patterns of speech impairment. Analysis of dysarthria at the bedside is useful for the localization of neurological lesions and the diagnosis of neurological disorders. An experienced examiner should be able to recognize the major types of dysarthria, rather than referring to “dysarthria” as a single disorder. The examination of speech at the bedside should include repeating syllables, words, and sentences. Repeating consonant sounds (such as /p/, /p/, /p/) or shifting consonant sounds (/p/, /t/, /k/) can help to identify which consonants consistently cause trouble. The Mayo Clinic classification of dysarthria (Duffy, 1995), widely used in the United States, includes six categories: (1) flaccid, (2) spastic and “unilateral upper motor neuron,” (3) ataxic, (4) hypokinetic, (5) hyperkinetic, and (6) mixed dysarthria. These types of dysarthria are summarized in Table 14.1.

Flaccid dysarthria is associated with disorders involving lower motor neuron weakness of the bulbar muscles, such as polymyositis, myasthenia gravis, and bulbar poliomyelitis. The speech pattern is breathy and nasal, with indistinctly pronounced consonants. In the case of myasthenia gravis, the patient may begin reading a paragraph with normal enunciation, but by the end of the paragraph the articulation is soft, breathy, and frequently interrupted by labored respirations. Spastic dysarthria occurs in patients with bilateral lesions of the motor cortex or corticobulbar tracts, such as bilateral strokes. The speech is harsh or “strain-strangle” in vocal quality, with reduced rate, low pitch, and consonant errors. Patients often have the features of “pseudobulbar palsy,” including dysphagia, exaggerated jaw jerk and gag reflexes, and easy laughter and crying (emotional incontinence, pseudobulbar affect, or pathological laughter and crying). Another variant is the “opercular syndrome,” described later in this chapter. A milder variant of spastic dysarthria, “unilateral upper motor neuron” dysarthria, is associated with unilateral upper motor neuron lesions (Duffy, 1995). This type of dysarthria has features similar to those of spastic dysarthria, only in a less severe form. Unilateral upper motor neuron dysarthria is one of the commonest types of dysarthria, occurring in patients with unilateral strokes. Strokes, depending on their location, can also cause mixed patterns of dysarthria (see later). There is considerable evidence for the efficacy of speech therapy for poststroke dysarthria (Mackenzie, 2011). Ataxic dysarthria or “scanning speech,” associated with cerebellar disorders, is characterized by one of two patterns: irregular breakdowns of speech with explosions of syllables interrupted by pauses, or a slow cadence of speech, with excessively equal stress on every syllable. The second pattern of ataxic dysarthria is referred to as “scanning speech.” A patient with ataxic dysarthria, attempting to repeat the phoneme /p/ as rapidly as possible, produces either an irregular rhythm, resembling popcorn popping, or a very slow rhythm. Causes of ataxic dysarthria include cerebellar strokes, tumors, multiple sclerosis, and cerebellar degenerations. Hypokinetic dysarthria, the typical speech pattern in Parkinson disease, is notable for decreased and monotonous loudness and pitch, rapid rate, and occasional consonant errors. In a study of brain activation by positron emission tomography (PET) methodology (Liotti et al., 2003), premotor and supplementary motor area activations were seen in untreated patients with Parkinson disease and hypokinetic dysarthria but not in normal subjects. Following a voice treatment protocol, these premotor and motor activations diminished, whereas right-sided basal ganglia activations increased. Hypokinetic dysarthria

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Common Neurological Problems

Classification of the Dysarthrias

Type

Localization

Auditory Signs

Diseases

Flaccid

Lower motor neuron

Stroke, myasthenia gravis

Spastic

Bilateral upper motor neuron

Breathy, nasal voice, imprecise consonants Strain-strangle, harsh voice, slow rate, imprecise consonants Consonant imprecision, slow rate, harsh voice quality Irregular articulatory breakdowns, excessive and equal stress Rapid rate, reduced loudness, monopitch and monoloudness Prolonged phonemes, variable rate, inappropriate silences, voice stoppages Amyotrophic strain-strangle, harsh voice, slow rate, imprecise consonants

Unilateral upper motor neuron Ataxic

Cerebellum

Hypokinetic

Extrapyramidal

Hyperkinetic

Extrapyramidal

Spastic and flaccid

Hypernasality, lower motor neuron

Bilateral strokes, tumors, primary lateral sclerosis Stroke, tumor Stroke, degenerative disease Parkinson disease Dystonia, Huntington disease

Upper lateral sclerosis, multiple strokes

Adapted from Duffy, J.R., 1995. Motor Speech Disorders: Substrates, Differential Diagnosis, and Management. Mosby, St. Louis; and from Kirshner, H.S., 2002. Behavioral Neurology: Practical Science of Mind and Brain. Butterworth-Heinemann, Boston.

responds both to behavioral therapies and to pharmacological treatment of Parkinson disease, although the efficacy of speech therapy in Parkinson disease has not been proved (Herd et al., 2012). Hyperkinetic dysarthria, a pattern in some ways opposite to hypokinetic dysarthria, is characterized by marked variation in rate, loudness, and timing, with distortion of vowels, harsh voice quality, and occasional, sudden stoppages of speech. This speech pattern is seen in hyperkinetic movement disorders such as Huntington disease and dystonia musculorum deformans. The final category, mixed dysarthria, involves combinations of the other five types. One common mixed dysarthria is a spastic-flaccid dysarthria seen in amyotrophic lateral sclerosis (ALS). The ALS patient has the harsh, strain-strangle voice quality of spastic dysarthria, combined with the breathy and hypernasal quality of flaccid dysarthria. Multiple sclerosis may feature a spastic-flaccid-ataxic or spastic-ataxic mixed dysarthria, in which slow rate or irregular breakdowns are added to the other characteristics seen in spastic and flaccid dysarthria. A recent publication found that tongue movements were particularly affected by multiple sclerosis (Mefford et al., 2019). Wilson disease can involve hypokinetic, spastic, and ataxic features. The management of dysarthria includes speech therapy techniques for strengthening muscles, training more precise articulations, slowing the rate of speech to increase intelligibility, or teaching the patient to stress specific phonemes. Devices such as pacing boards to slow articulation, palatal lifts to reduce hypernasality, amplifiers to increase voice volume, communication boards for subjects to point to pictures, and augmentative communication devices and computer techniques can be used when the patient is unable to communicate in speech. Surgical procedures such as a pharyngeal flap to reduce hypernasality or vocal fold Teflon injection or transposition surgery to increase loudness may help the patient to speak more intelligibly. In Parkinson disease, most patients have elements of dysarthria and dysphonia, and treatment can include speech therapy, drug treatment, deep brain stimulation, and even surgical options (Baumann et al., 2018; Dashtipour et al., 2018;). Deep brain stimulation may improve motor speech, although with variations depending on location and frequency of stimulation (Morello et al., 2020).

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Apraxia of Speech Apraxia of speech is a disorder of the programing of articulation of sequences of phonemes, especially consonants (Ziegler et al., 2012). The motor speech system makes errors in selection of consonant phonemes, in the absence of any “weakness, slowness or incoordination” of the muscles of speech articulation (Wertz et al., 1991). The term “apraxia of speech” implies that the disorder is one of a skilled, sequential motor activity (as in other apraxias), rather than a primary motor disorder. Hillis and colleagues (2004) gave a more informal definition of apraxia of speech, in terms of a patient who “knows what he or she wants to say and how it should sound” yet cannot articulate it properly. Consonants are frequently substituted rather than distorted, as in dysarthria. Patients have special difficulty with polysyllabic words and consonant shifts, as well as in initiating articulation of a word. Errors are inconsistent from one attempt to the next, in contrast to the consistent distortion of phonemes in dysarthria. This inconsistency can be documented by asking the patient to repeat a difficult word such as “catastrophe” five times. The four cardinal features of apraxia of speech are: (1) effortful, groping, or “trial-and error” attempts at speech, with efforts at self-correction; (2) dysprosody; (3) inconsistencies in articulation errors; and (4) difficulty with initiating utterances. Usually the patient has the most difficulty with the first phoneme of a polysyllabic utterance. The patient may make an error in attempting to produce a word on one trial, a different error the next time, and a normal utterance the third time. Apraxia of speech is rare in isolated form, but it frequently contributes to the speech and language deficit of Broca aphasia. A patient with apraxia of speech, in addition to aphasia, will often write better than he or she can speak, and comprehension is relatively preserved. Dronkers (1996) and colleagues have presented evidence from computed tomography (CT) and magnetic resonance imaging (MRI) scans indicating that, although the anatomical lesions vary, patients with apraxia of speech virtually always have damage in the left hemisphere insula, whereas patients without apraxia of speech do not. However, this “overlapping lesion” approach to brain localization can be misleading. Moreover, recent MRI correlations of apraxia of speech in acute stroke patients by Hillis and colleagues (2004) have

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CHAPTER 14 Dysarthria and Apraxia of Speech

pointed to the traditional Broca area in the left frontal cortex as the site of apraxia of speech and as the site where programing of articulation takes place. Recent publications have drawn attention to primary progressive apraxia of speech as a progressive disorder, related to primary progressive aphasia and frontotemporal dementia (Croot et al., 2012; Duffy and Josephs, 2012; Utianski et al., 2018). See Chapter 13 for a discussion of primary progressive aphasia and frontotemporal dementia. Testing of patients for speech apraxia includes the repetition of sequences of phonemes (pa/ta/ka), as discussed previously under testing for dysarthria. Repetition of a polysyllabic word (e.g., “catastrophe” or “television”) is especially likely to elicit apraxic errors, and having the subject repeat the same word five times will bring out the inconsistency in the apraxic utterances.

Oral or Buccolingual Apraxia Apraxia of speech is not the same as oral-buccal-lingual apraxia or ideomotor apraxia for learned movements of the tongue, lips, and larynx. Oral apraxia can be elicited by asking a subject to lick his or her upper lip, smile, or stick out the tongue. Oral apraxia is discussed in Chapter 13, Aphasia and Aphasic Syndromes. Both oral apraxia and apraxia of speech can coexist with Broca aphasia.

Aphemia Another differential diagnosis with both apraxia of speech and dysarthria is the syndrome of aphemia. Broca first used the term “aphemie” to designate the syndrome later called “Broca aphasia,” but in recent years the term has been reserved for a syndrome of near muteness, with normal comprehension, reading, and writing. Aphemia is clearly a motor speech disorder rather than an aphasia, if written language and comprehension are indeed intact. Patients are often anarthric, with no speech whatever, and then effortful, nonfluent speech emerges. Some patients have persisting dysarthria, with dysphonia and sometimes distortions of articulation that sound similar to foreign accents (see next section). Alexander et al. (1990) associated pure anarthria with lesions of the face area of motor cortex. Functional imaging studies also suggest that articulation is mediated at the level of the primary motor face area (Riecker et al., 2000), and disruption of speech articulation can be produced by transcranial magnetic stimulation over the motor face area (Epstein et al., 1999). Controversy remains as to whether aphemia is equivalent to apraxia of speech, as suggested by Alexander et al. (1989). In general, aphemia is likely to involve lesions in the vicinity of the primary motor cortex and perhaps Broca area.

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“Foreign Accent Syndrome” The “foreign accent syndrome” is an acquired form of motor speech disorder, related to the dysarthrias, in which the patient acquires a dysfluency resembling a foreign accent, usually after a unilateral stroke (Kurowski et al., 1996; Marien et al., 2019; Takayama et al., 1993). Lesions may involve the motor cortex of the left hemisphere. The disorder can also be mixed with aphasia.

Acquired Stuttering Another uncommon motor speech disorder following acquired brain lesions is a pattern resembling developmental stuttering, referred to as “acquired” or “cortical stuttering.” Acquired stuttering involves hesitancy in producing initial phonemes, with an associated dysrhythmia of speech. Acquired stuttering clearly overlaps with apraxia of speech but may lack the other features of apraxia of speech discussed earlier. Acquired stuttering has been described most often in patients with left hemisphere cortical strokes (Franco et al., 2000; Turgut et al., 2002), but the syndrome has also been reported with subcortical lesions including infarctions of the pons, basal ganglia, and subcortical white matter (Ciabarra et al., 2000). Stuttering-like dysfluencies can also occur in acquired apraxia of speech (Bailey et al., 2017). Acquired stuttering can also be psychogenic; Binder and colleagues (2012) discuss ways of detecting psychogenic acquired stuttering. A more general review of psychogenic speech and language abnormalities was recently published by Barnett and colleagues (2019). They believed that no uniform set of criteria exists for the reliable diagnosis of functional speech disorder.

Opercular Syndrome The opercular syndrome, also called Foix-Chavany-Marie syndrome or cheiro-oral syndrome (Bakar et al., 1998; Bogousslavsky et al., 1991), is a severe form of pseudobulbar palsy in which patients with bilateral lesions of the perisylvian cortex or subcortical connections become completely mute. These patients can follow commands involving the extremities but not the cranial nerves; for example, they may be unable to open or close their eyes or mouth or smile voluntarily, yet they smile when amused, yawn spontaneously, and even utter cries in response to emotional stimuli. The ability to follow limb commands shows that the disorder is not an aphasic disorder of comprehension. The discrepancy between automatic activation of the cranial musculature and inability to perform the same actions voluntarily has been called an “automatic-voluntary dissociation.” The complete reference list is available online at https://expertconsult.inkling.com/.

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15 Neurogenic Dysphagia Delaram Safarpour, Kaveh Sharzehi, Ronald F. Pfeiffer

OUTLINE Normal Swallowing, 152 Neurophysiology of Swallowing, 153 Mechanical Dysphagia, 153 Neuromuscular Dysphagia, 154 Oculopharyngeal Muscular Dystrophy, 154 Myotonic Dystrophy, 154 Other Muscular Dystrophies, 155 Inflammatory Myopathies, 155 Mitochondrial Disorders, 155 Myasthenia Gravis, 155 Neurogenic Dysphagia, 156

Stroke, 156 Multiple Sclerosis, 158 Parkinson Disease, 159 Other Basal Ganglia Disorders, 159 Amyotrophic Lateral Sclerosis, 160 Cranial Neuropathies, 160 Brainstem Processes, 161 Cervical Spinal Cord Injury, 161 Other Processes, 161 Evaluation of Dysphagia, 161

The mechanics of swallowing are like those of an elegant wristwatch. On the surface, this appears to be a simple, perhaps even pedestrian process, but it is actually both tremendously complex and remarkably fascinating. Humans swallow approximately 500 times daily (Shaw and Martino, 2013). Normally, swallowing occurs unobtrusively and is afforded scant attention. Malfunction can go completely unnoticed for a time; but when it finally becomes manifest, serious—sometimes catastrophic—consequences can ensue. Impaired swallowing, or dysphagia, can originate from disturbances in the mouth, pharynx, or esophagus that may be generated by mechanical, musculoskeletal, or neurogenic mechanisms. Although mechanical dysphagia is an important topic, this chapter primarily focuses on neuromuscular and neurogenic causes of dysphagia, because processes in these categories are most likely to be encountered by the neurologist. Dysphagia is surprisingly common and has been reported to be present in 3% of the general population and in 10% of individuals over age 65. Dysphagia occurs quite frequently in neurological patients and can occur in a broad array of neurological or neuromuscular conditions. It has been estimated that neurogenic dysphagia develops in approximately 400,000 to 800,000 people per year, and that dysphagia is present in roughly 50% of inhabitants of long-term care units. Moreover, dysphagia can lead to superimposed problems such as inadequate nutrition, dehydration, recurrent upper respiratory infections, and frank aspiration with consequent pneumonia and even asphyxia. It thus constitutes a formidable and frequent problem confronting the neurologist in everyday practice.

NORMAL SWALLOWING Swallowing is a surprisingly complicated and intricate phenomenon. It comprises a mixture of voluntary and reflex, or automatic, actions engineered and carried out by some of the more than 30 pairs of

muscles within the oropharyngeal, laryngeal, and esophageal regions along with five cranial nerves and two cervical nerve roots that, in turn, receive directions from centers within the central nervous system (Sasegbon and Hamdy, 2017; Shaw and Martino, 2013). Reflex swallowing is coordinated and carried out at a brainstem level, where centers act directly on information received from sensory structures within the oropharynx and esophagus. A differentiation can be made between voluntary swallowing, which occurs when a person desires to eat or drink during the awake and aware state, and spontaneous swallowing in response to accumulated saliva in the mouth (Ertekin, 2011). Volitional swallowing is, not surprisingly, accompanied by additional activity that originates not only in motor and sensory cortices but also in other cerebral structures (Hamdy et al., 1999; Sasegbon and Hamdy, 2017; Zald and Pardo, 1999). The process of swallowing can conveniently be broken down into three or four distinct stages or phases: oral (which some subdivide into oral preparatory and oral propulsive), pharyngeal, and esophageal. These components have also been distilled into what have been designated the horizontal and vertical subsystems, reflecting the direction of bolus flow in each component (when the individual is upright while swallowing). The horizontal subsystem comprises the oral phase of swallowing and is largely volitional in character; the vertical subsystem comprises the pharyngeal and esophageal phases, which are primarily under reflex control. In the oral preparatory phase, food is taken into the mouth and, if needed, chewed. Saliva is secreted to provide both lubrication and the initial “dose” of digestive enzymes; the food bolus is then formed and shaped by the tongue. In the oral propulsive phase, the tongue propels the bolus backward to the pharyngeal inlet where, in a piston-like action, it delivers the bolus into the pharynx. This initiates the pharyngeal phase, in which a cascade of intricate, extremely rapid, and exquisitely coordinated movements sealoff the nasal passages and protects the trachea while the cricopharyngeal muscle, which functions

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CHAPTER 15 Neurogenic Dysphagia as the primary component of the upper esophageal sphincter (UES), relaxes and allows the bolus to enter the esophagus. As an example of the intricacy of movements during this phase of swallowing, the UES, prompted in part by traction produced by elevation of the larynx, actually relaxes just prior to arrival of the food bolus, creating suction that assists in guiding the bolus into the esophagus. The bolus then enters the esophagus, where peristaltic contractions usher it distally and, on relaxation of the lower esophageal sphincter, into the stomach. Swallowing is synchronized with respiration, such that expiration rather than inspiration immediately follows a swallow, thus reducing the risk of aspiration—another example of the finely tuned coordination involved in the swallowing mechanism (Mehanna and Jankovic, 2010).

NEUROPHYSIOLOGY OF SWALLOWING Central control of swallowing has traditionally been ascribed to brainstem structures, with cortical supervision and modulation emanating from the inferior precentral gyrus. However, positron emission tomography (PET), transcranial magnetic stimulation (TMS), and functional magnetic resonance imaging (fMRI) studies of volitional swallowing reveal a considerably more complex picture in which a broad network of brain regions is active in the control and execution of swallowing. It is perhaps not surprising that in PET studies, the strongest activation of volitional swallowing occurs in the lateral motor cortex within the inferior precentral gyrus, wherein lie the cortical representations of tongue and face. There is disagreement among investigators, however, in that some have noted bilaterally symmetrical activation of the lateral motor cortex (Zald and Pardo, 1999) whereas others have noted a distinctly asymmetrical activation, at least in some of the subjects tested (Hamdy et al., 1999). Additional and perhaps somewhat surprising brain areas also are activated during volitional swallowing (Hamdy et al., 1999; Sasegbon and Hamdy, 2017; Schaller et al., 2006; Zald and Pardo, 1999). The supplementary motor area may play a role in preparing for volitional swallowing, and the anterior cingulate cortex may be involved with monitoring autonomic and vegetative functions. Another area of activation during volitional swallowing is the anterior insula, particularly on the right. It has been suggested that this activation may provide the substrate that allows gustatory and other intraoral sensations to modulate swallowing. Lesions in the insula may also increase the swallowing threshold and delay the pharyngeal phase of swallowing (Schaller et al., 2006). PET studies also consistently demonstrate distinctly asymmetrical left-sided activation of the cerebellum during swallowing. This activation may reflect cerebellar input concerning the coordination, timing, and sequencing of swallowing. Activation of putamen has also been noted during volitional swallowing, but it has not been possible to differentiate this activation from that seen with tongue movement alone. Within the brainstem, swallowing appears to be regulated by central pattern generators that contain the programs directing the sequential movements of the various muscles involved (Steuer and Guertin, 2019). The dorsomedial pattern generator resides in the medial reticular formation of the rostral medulla and the reticulum adjacent to the nucleus tractus solitarius and is involved with the initiation and organization of the swallowing sequence (Schaller et al., 2006). A second central pattern generator, the ventrolateral pattern generator, lies near the nucleus ambiguus and its surrounding reticular formation (Schaller et al., 2006). It serves primarily as a connecting pathway to motor nuclei such as the nucleus ambiguus and the dorsal motor nucleus of the vagus, which directly control motor output to the pharyngeal musculature and proximal esophagus. The enteric nervous system also

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plays a role in controlling esophageal function, apparently involving both motor and sensory components (Woodland et al., 2013). It has become evident that a large network of structures participates in the act of swallowing, especially volitional swallowing. The presence of this network presumably accounts for the broad array of neurological disease processes that can produce dysphagia as a part of the clinical picture.

MECHANICAL DYSPHAGIA Structural abnormalities—both within and adjacent to the mouth, pharynx, and esophagus—can interfere with swallowing on a strictly mechanical basis despite fully intact and functioning nervous and musculoskeletal systems (Box 15.1). Within the mouth, macroglossia, temporomandibular joint dislocation, certain congenital anomalies, and intraoral tumors can impede effective swallowing and produce mechanical dysphagia. Pharyngeal function can be compromised by processes such as retropharyngeal tumor or abscess, cervical anterior

BOX 15.1

Mechanical Dysphagia

Oral Amyloidosis Congenital abnormalities Intraoral tumors Lip injuries: Burns Trauma Macroglossia Scleroderma Temporomandibular joint dysfunction Xerostomia: Sjögren syndrome Pharyngeal Cervical anterior osteophytes Infection: Diphtheria Thyromegaly Retropharyngeal abscess Retropharyngeal tumor Zenker diverticulum Esophageal Aberrant origin of right subclavian artery Caustic injury Esophageal carcinoma Esophageal diverticulum Esophageal infection: Candida albicans Cytomegalovirus Herpes simplex virus Varicella zoster virus Esophageal intramural pseudodiverticula Esophageal stricture Esophageal ulceration Esophageal webs or rings Gastroesophageal reflux disease Hiatal hernia Metastatic carcinoma Posterior mediastinal mass Thoracic aortic aneurysm

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osteophyte formation, Zenker diverticulum, or thyroid gland enlargement. An even broader array of structural lesions can interfere with esophageal function, including malignant or benign esophageal tumors, metastatic carcinoma, esophageal stricture from numerous causes, vascular abnormalities such as aortic aneurysm or aberrant origin of the subclavian artery, or even primary gastric abnormalities such as hiatal hernia or complications from gastric banding procedures. Gastroesophageal reflux can also produce dysphagia. However, individuals with these problems are more likely to be seen by the gastroenterologist than the neurologist.

NEUROMUSCULAR DYSPHAGIA A variety of neuromuscular disease processes of diverse etiology can involve the oropharyngeal and esophageal musculature and produce dysphagia as part of their broader neuromuscular clinical picture (Box 15.2). Certain muscular dystrophies, inflammatory myopathies, and mitochondrial myopathies can all display dysphagia, as can disease processes affecting the myoneural junction, such as myasthenia gravis (MG).

Oculopharyngeal Muscular Dystrophy Oculopharyngeal muscular dystrophy (OPMD) is a rare disorder that has a worldwide distribution. It was initially described and is most frequently encountered in individuals with a French-Canadian ethnic background, although its highest reported prevalence is among the Bukhara Jews in Israel (Abu-Baker and Rouleau, 2007). OPMD is the consequence of a GCG trinucleotide repeat expansion in the polyadenylate-binding protein nuclear 1 gene (PABPN1; also known as

BOX 15.2

Neuromuscular Dysphagia

Oropharyngeal Inflammatory myopathies: Dermatomyositis Inclusion body myositis Polymyositis Mitochondrial myopathies: Kearns-Sayre syndrome MNGIE Muscular dystrophies: Duchenne Facioscapulohumeral Limb girdle Myotonic Oculopharyngeal Neuromuscular junction disorders: Botulism Lambert-Eaton syndrome Myasthenia gravis Tetanus Scleroderma Stiff man syndrome Esophageal Amyloidosis Inflammatory myopathies: Dermatomyositis Polymyositis Scleroderma MNGIE, Myoneurogastrointestinal encephalomyopathy.

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poly[A]-binding protein 2 [PABP2]) on chromosome 14. The inheritance pattern of OPMD is primarily autosomal dominant, although a rare autosomal recessive form has been described. OPMD is unique among the muscular dystrophies because of its appearance in older individuals, with symptoms typically first appearing between ages 40 and 60. It is characterized by slowly progressive ptosis, dysphagia, and proximal limb weakness. Facial weakness, changes in voice quality, and excessive fatigue may develop; impaired cognitive function also has been described (Waito et al., 2018). Because of the ptosis, patients with OPMD may assume an unusual posture characterized by raised eyebrows and extended neck. Dysphagia in OPMD is due to impaired function of the oropharyngeal musculature. Impaired swallow efficiency due to reduced pharyngeal constriction, speed of hyoid movement, and degree of airway closure may lead to oral and nasal regurgitation, aspiration, postswallow pharyngeal residue, and esophageal retention (Waito et al., 2018). Although it evolves slowly over many years, OPMD may eventually result not only in difficulty or discomfort with swallowing but also in weight loss, malnutrition, and aspiration. No specific treatment for the muscular dystrophy itself is available, but both cricopharyngeal myotomy and botulinum toxin injection into the cricopharyngeal muscle are effective in diminishing dysphagia in the setting of OPMD. However, both worsened dysphagia and dysphonia may be complications of botulinum toxin injections (Youssof et al., 2014).

Myotonic Dystrophy Myotonic dystrophy is an autosomal dominant disorder whose phenotypic picture includes not only skeletal muscle but also cardiac, ophthalmological, endocrinological, and even central nervous system involvement. It is the most common form of adult-onset muscular dystrophy. Mutations at two distinct locations are associated with the clinical picture of myotonic dystrophy. Type 1 myotonic dystrophy is due to a CTG expansion in the myotonic dystrophy protein kinase (DMPK) gene on chromosome 19; type 2 is the consequence of a CCTG repeat expansion in the zinc finger protein 9 (ZNF9) gene on chromosome 3. Gastrointestinal (GI) symptoms develop in more than 50% of individuals with the clinical phenotype of myotonic dystrophy. These may be the most disabling component of the disorder in 25% of individuals with type 1 myotonic dystrophy, and GI symptoms may actually antedate the appearance of other neuromuscular features. Subjective dysphagia is one of the most prevalent GI features and has been reported in 37%−56% of patients (Ertekin et al., 2001b). Coughing when eating, suggestive of aspiration, may occur in 33%. Objective measures paint a picture of even more pervasive impairment, demonstrating disturbances in swallowing in 70%–80% of persons with myotonic dystrophy (Ertekin et al., 2001b). In one study, 75% of patients asymptomatic for dysphagia were still noted to have abnormalities on objective testing (Marcon et al., 1998). A variety of abnormalities in objective measures of swallowing have been documented in myotonic dystrophy. Abnormal cricopharyngeal muscle activity is present in 40% of patients during electromyographic (EMG) testing (Ertekin et al., 2001b). Impaired esophageal peristalsis has also been noted in affected individuals studied with esophageal manometry. On videofluoroscopic testing, incomplete relaxation of the UES and esophageal hypotonia were the most frequently noted abnormalities (Marcon et al., 1998). Both muscle weakness and myotonia are felt to play a role in the development of dysphagia in persons with myotonic dystrophy (Ertekin et al., 2001b); in at least one study, a correlation was noted between the size of the CTG repeat expansion and the number of radiological abnormalities in myotonic patients

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CHAPTER 15 Neurogenic Dysphagia (Marcon et al., 1998). In a systematic review of oropharyngeal dysphagia in type 1 myotonic dystrophy, Pilz and colleagues identified pharyngeal pooling, decreased pharyngeal contraction amplitude, and reduced UES resting pressure as the primary findings responsible for dysphagia (Pilz et al., 2014). Cognitive dysfunction also may predispose individuals with myotonic dystrophy to be less aware of dysphagia and less likely to employ measures such as proper diet and eating methods to minimize it (Umemoto et al., 2012).

Other Muscular Dystrophies Although less well characterized, dysphagia also occurs in other types of muscular dystrophy. Difficulty swallowing and choking while eating occur with increased frequency in children with Duchenne muscular dystrophy. Dysphagia has also been documented in patients with limb-girdle dystrophy and facioscapulohumeral dystrophy (FSHD). Dysphagia associated with reduced cheek compression strength and reduced endurance of cheek compression and anterior tongue elevation is evident in 25% of patients with FSHD (Mul et al., 2019).

Inflammatory Myopathies Dermatomyositis and polymyositis are the most frequently occurring of the inflammatory myopathic disorders. Both are characterized by progressive, usually symmetrical weakness affecting proximal muscles more prominently than distal. Fatigue and myalgia also may occur. Malignant disease is associated with the disorder in 10%–15% of patients with dermatomyositis and 5%–10% of those with polymyositis. Among individuals older than age 65 with these inflammatory myopathies, more than 50% are found to have cancer. Although dysphagia can develop in both conditions, it more frequently is present in dermatomyositis; when present, it is more severe. Dysphagia is present in 20%–55% of individuals with dermatomyositis but in only 18% with polymyositis (Parodi et al., 2002). The risk of dysphagia in dermatomyositis is associated with the presence of internal malignancy and anti–transcription intermediary factor 1γ (TIF-1γ) antibody (Mugii et al., 2016). It is the consequence of involvement of striated muscle in the pharynx and proximal esophagus. Involvement of pharyngeal and esophageal musculature in polymyositis and dermatomyositis is an indicator of poor prognosis and can be the source of significant morbidity. A 1-year mortality rate of 31% has been reported in individuals with inflammatory myopathy and dysphagia (Williams et al., 2003), although other investigators have reported a 1-year survival rate of 89% (Oh et al., 2007). Dysphagia in persons with inflammatory myopathy may be due to restrictive pharyngoesophageal abnormalities such as cricopharyngeal bar, Zenker diverticulum, and stenosis. In fact, in one study of 13 patients with inflammatory myopathy, radiographic constrictions were noted in 9 (69%) individuals, compared with 1 of 17 controls with dysphagia of neurogenic origin (Williams et al., 2003). Aspiration was also more common in the patients with myositis (61% vs. 41%). The resulting dysphagia can be severe enough to require enteral feeding. Acute total obstruction by the cricopharyngeal muscle has been reported in dermatomyositis, necessitating cricopharyngeal myotomy. Other investigators have reported improvement in 50% of individuals 1 month following cricopharyngeal bar disruption; improvement was still present in 25% at 6 months (Williams et al., 2003). The reason for the formation of restrictive abnormalities in inflammatory myopathy is uncertain, but it may be that long-standing inflammation of the cricopharyngeus muscle impedes its compliance and ability to open fully (Williams et al., 2003). Dysphagia also may develop in inclusion body myositis and may even be the presenting symptom. In the late stages of the disorder, the frequency of dysphagia may actually exceed that seen in

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dermatomyositis and polymyositis. In a group of individuals in whom inclusion-body myositis mimicked and was confused with motor neuron disease, dysphagia was present in 44% (Dabby et al., 2001). In another study, dysphagia was documented in 37 of 57 (65%) patients with inclusion-body myositis (Cox et al., 2009). Abnormal function of the UES, probably due to inflammatory involvement of the cricopharyngeal muscle with consequent reduced compliance, was documented in 37%. A focal inflammatory myopathy involving the pharyngeal muscles and producing isolated pharyngeal dysphagia also has been described in individuals older than age 69. It has been suggested that this is a distinct clinical entity characterized by cricopharyngeal hypertrophy, although polymyositis localized to the pharyngeal musculature has been reported. Dysphagia in both dermatomyositis and polymyositis may respond to corticosteroids and other immunosuppressive drugs, and these remain the mainstay of treatment. Intravenous immunoglobulin (IVIG) therapy has produced dramatic improvement in dysphagia in individuals who were unresponsive to steroids. Although inclusion-body myositis usually responds poorly to these agents, there are reports of long-lasting stabilization of dysphagia with either intravenous or subcutaneous immunoglobulin therapy (Pars et al., 2013). More often, cricopharyngeal myotomy is necessary (Oh et al., 2007).

Mitochondrial Disorders The mitochondrial disorders are a family of diseases that develop as a consequence of dysfunction in the mitochondrial respiratory chain. Most are the result of mutations in mitochondrial deoxyribonucleic acid (DNA) genes, but nuclear DNA mutations may be responsible in some. Mitochondrial disorders are by nature multisystemic, but myopathic and neurological features often predominate, and symptoms may vary widely even between individuals within the same family. In addition to the classic constellation of symptoms—including progressive external ophthalmoplegia, retinitis pigmentosa, cardiac conduction defects, and ataxia—individuals with Kearns-Sayre syndrome also may develop dysphagia. Severe abnormalities of pharyngeal and upper esophageal peristalsis have been documented in this disorder. Cricopharyngeal dysfunction is common and impaired deglutitive coordination may develop. Dysphagia has also been described in other mitochondrial disorders, but these descriptions are only anecdotal and formal study has not been undertaken.

Myasthenia Gravis MG is an autoimmune disorder characterized by the production of autoantibodies directed against the α1 subunit of the nicotinic postsynaptic acetylcholine receptors at the neuromuscular junction, causing destruction of the receptors and a reduction in their number. The clinical consequence of this process is the development of fatigable muscle weakness that progressively increases with repetitive muscle action and improves with rest. MG occurs more frequently in women than in men. Although symptoms can develop at any age, the reported mean age of onset in women is between 28 and 35 years and in men between 42 and 49 years. Although myasthenic symptoms remain confined to the extraocular muscles in approximately 20% of patients, more widespread muscle weakness becomes evident in most individuals. Initial involvement of the bulbar musculature, sometimes labeled laryngeal MG and characterized by dysphagia or dysarthria, is surprisingly common in MG (Yang et al., 2019). Bulbar involvement is evident from the beginning in approximately 6%–30% of MG patients (Koopman et al., 2004); with disease progression, most eventually develop bulbar symptoms such as dysphagia and dysarthria. It is important to recognize, however, that swallowing function may be

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abnormal even without the presence of symptomatic dysphagia in individuals with MG (Umay et al., 2018). Dysphagia in MG can be due to dysfunction at the oral, pharyngeal, or even esophageal levels, and many patients experience it at multiple levels. In a study of 20 myasthenic patients experiencing dysphagia, abnormalities in the oral preparatory phase were evident in 13 individuals (65%), oral phase dysphagia in 18 (90%), and pharyngeal phase involvement in all 20 (100%; Koopman et al., 2004). Oral phase involvement can be due to fatigue and weakness of the tongue or masticatory muscles. In MG patients with bulbar symptoms, repetitive nerve stimulation studies of the hypoglossal nerve have demonstrated abnormalities, as have studies utilizing EMG of the masticatory muscles recorded while chewing. Pharyngeal dysfunction is also common in MG patients who have dysphagia, as demonstrated by videofluoroscopy (VFS). Aspiration, often silent, may be present in 35% or more of these individuals; in elderly patients the frequency of aspiration may be considerably higher. Bedside speech pathology assessment is not a reliable predictor of aspiration (Koopman et al., 2004). Motor dysfunction involving the striated muscle of the proximal esophagus also has been documented in MG. In one study that used testing with esophageal manometry, 96% of patients with MG demonstrated abnormalities such as decreased amplitude and prolongation of the peristaltic wave in this region. Cricopharyngeal sphincter pressure was also noted to be reduced. It is important to remember that dysphagia can also precipitate myasthenic crisis in individuals with MG. In fact, in one study, dysphagia was considered to be a major precipitant of myasthenic crisis in 56% of patients (Koopman et al., 2004).

NEUROGENIC DYSPHAGIA A variety of disease processes originating in the central and peripheral nervous systems can disrupt swallowing mechanisms and produce dysphagia. Processes affecting cerebral cortex, subcortical white matter, subcortical gray matter, brainstem, spinal cord, and peripheral nerves can all elicit dysphagia as a component of the clinical picture (Box 15.3). In addition, oropharyngeal dysphagia is reported in 23% of independently living elderly (Serra-Prat et al., 2011). The term presbyphagia describes multifactorial changes of swallowing physiology associated with aging. These changes are more likely to be related to stroke and neurodegenerative disorders in older individuals; in patients younger than age 60, oncological or other neurological pathologies are more probable (Baijens et al., 2016). In individuals with neurogenic dysphagia, prolonged swallow response, delayed laryngeal closure, and weak bolus propulsion combine to increase the risk of aspiration and the likelihood of malnutrition.

Stroke Stroke is the fifth leading cause of death, claiming 133,000 lives annually; it is the number one cause of adult disability in the United States. Each year, close to 800,000 people experience a new or recurrent stroke. On average, every 40 seconds, someone in the United States has a stroke. The mechanism of stroke is ischemic in 87% of cases; of the remaining cases, 10% are due to intracerebral hemorrhage and 3% the result of subarachnoid hemorrhage. Although stroke can occur at any age, its prevalence increases with advancing age in both males and females, and 75% of strokes occur in individuals older than 75 years. Dysphagia develops in 28%–65% of individuals following acute stroke, and its presence is associated with increased likelihood of severe disability or death (Falsetti et al., 2009; Runions et al., 2004; Schaller et al., 2006). This wide range reflects differences in the manner of assessment of dysphagia, the setting, and the timing of the test used. Although many stroke patients recover swallowing spontaneously in

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the early days after stroke, 11%–50% will continue to have dysphagia at 6 months (Mann et al., 2000; Martino et al., 2005). Aspiration and pneumonia are the most widely recognized complications of dysphagia

BOX 15.3

Neurogenic Dysphagia

Oropharyngeal Arnold-Chiari malformation Basal ganglia disease: Biotin responsive Corticobasal degeneration DLB HD Multiple system atrophy Neuroacanthocytosis PD PSP WD Central pontine myelinolysis Cerebral palsy Drug related: Cyclosporine Tardive dyskinesia Vincristine Infectious: Brainstem encephalitis Diphtheria Epstein-Barr virus Listeria Poliomyelitis Progressive multifocal leukoencephalopathy Rabies Mass lesions: Abscess Hemorrhage Metastatic tumor Primary tumor Motor neuron diseases: ALS MS Peripheral neuropathic processes: Charcot-Marie-Tooth disease Guillain-Barré syndrome (Miller Fisher variant) Spinocerebellar ataxias Stroke Syringobulbia Esophageal Achalasia Autonomic neuropathies: Diabetes mellitus Familial dysautonomia Paraneoplastic syndromes Basal ganglia disorders: PD Chagas disease Esophageal motility disorders Scleroderma ALS, Amyotrophic lateral sclerosis; DLB, dementia with Lewy bodies; HD, Huntington disease; MS, multiple sclerosis; PD, Parkinson disease; PSP, progressive supranuclear palsy; WD, Wilson disease.

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CHAPTER 15 Neurogenic Dysphagia following stroke, but undernourishment and even malnutrition also occur with surprising frequency (Finestone and Greene-Finestone, 2003). Using screening assessment tools, there is evidence that 12%–41% of stroke survivors are at risk of malnutrition at 6 months (Brynningsen et al., 2007) and 11% at 16–18 months (Jönsson et al., 2008). Poststroke dysphagia is an independent predictor of poor outcome, institutionalization, and significant costs (Kumar et al., 2012). The risk of developing pneumonia is three times higher in stroke patients with dysphagia; in patients with confirmed aspiration, the risk is elevated 11-fold (Smithard et al., 2007). The individual cost of pneumonia and associated mortality in a large retrospective US study of stroke patients was quantified as $27,633 (Wilson, 2012). Finestone and Greene-Finestone (2003) have delineated a number of warning signs that can alert physicians to the presence of poststroke dysphagia. Some are obvious and others more subtle. They include drooling, excessive tongue movement or spitting food out of the mouth, poor tongue control, pocketing of food in the mouth, facial weakness, slurred speech, coughing or choking while eating, regurgitation of food through the nose, wet or “gurgly” voice after eating, hoarse or breathy voice, complaints of food sticking in the throat, absence or delay of laryngeal elevation, prolonged chewing, prolonged time to eat or reluctance to eat, and recurrent pneumonia. Although it is commonly perceived that the presence of dysphagia following stroke indicates a brainstem localization for the stroke, this is not necessarily so. Impaired swallowing has been documented in a significant proportion of strokes involving cortical and subcortical structures. The pharyngeal phase of swallowing is primarily impaired in brainstem infarction; in hemispheric strokes, the most striking abnormality is often a delay in initiation of voluntary swallowing. Strokes involving the right hemisphere tend to produce more impairment of pharyngeal motility, whereas left hemispheric lesions have a greater effect on oral stage function (Ickenstein et al., 2005). Dysphagia has been reported as the sole manifestation of infarction in both medulla and cerebrum. Approximately 50%–55% of patients with lesions in the posterior inferior cerebellar artery distribution with consequent lateral medullary infarction (Wallenberg syndrome) develop dysphagia (Teasell et al., 2002). The fact that unilateral medullary infarction can produce bilateral disruption of the brainstem’s swallowing centers suggests that they function as one integrated center. Infarction in the distribution of the anteroinferior cerebellar artery can also result in dysphagia. Following stroke within the cerebral hemispheres, dysphagia can develop by virtue of damage to either cortical or subcortical structures involved with volitional swallowing. Cortical reorganization then plays a key role in swallowing recovery. The mechanism of swallowing recovery after stroke was studied in 28 hemispheric stroke patients using VFS and TMS. After hemispheric stroke, nondysphagic subjects displayed greater pharyngeal cortical representation in the contralesional hemisphere compared with dysphagic subjects. TMS follow-up data at 1 and 3 months indicated that subjects who recovered swallowing function had significantly greater pharyngeal representation in the unaffected hemisphere compared with baseline. These findings highlight the importance of the contralesional hemisphere in swallowing recovery and suggest that bilateral hemispheric damage is more likely to produce dysphagia (Cohen et al., 2016). Bilateral infarction of the frontoparietal operculum may result in the anterior operculum syndrome (Foix-Chavany-Marie syndrome), which is characterized by inability to perform voluntary movements of the face, jaw, tongue, and pharynx but with fully preserved involuntary movements of the same muscles. Impairment of volitional swallowing may be a component of this syndrome. Although tongue deviation is classically associated with medullary lesions damaging the hypoglossal nucleus, it has also been

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documented in almost 30% of persons with hemispheric infarctions. When present in hemispheric stroke, tongue deviation is always associated with facial weakness and dysphagia is present in 43% of affected patients. Individuals with subcortical strokes have a higher incidence of dysphagia and aspiration than those with cortical damage. In one study, more than 85% of individuals with unilateral subcortical strokes demonstrated videofluoroscopic evidence of delayed initiation of the pharyngeal stage of swallowing; in 75%, some radiographic aspiration was noted. Using magnetoencephalography (MEG), Teismann and colleagues compared swallowing activation in subacute stroke patients with and without dysphagia with healthy controls. Increased contralesional activity was predictive of no dysphagia in this study, suggesting that neuroplasticity plays an important role in the recovery of swallowing function (Teismann et al., 2011). Aspiration is a potentially life-threatening complication of stroke. Studies have documented its occurrence in 30%–55% of stroke patients. In one study, videofluoroscopic evidence of aspiration was observed in 36% of patients with unilateral cerebral stroke, 46% with bilateral cerebral stroke, 60% with unilateral brainstem stroke, and 50% with bilateral brainstem lesions. Other studies have suggested that the incidence of aspiration in brainstem strokes may be considerably higher—more than 80%—and that subcortical strokes may result in aspiration in 75% of cases. Kemmling and colleagues (2013) have reported that individuals with right peri-insular strokes have an increased risk of developing hospital-acquired pneumonia and suggest that this may be related to impairment in host immunity due to autonomically induced immunosuppression rather than being a direct consequence of aspiration secondary to dysphagia. Additionally, two symptom mapping studies showed a strong association between dysphagia and right hemispheric opercular and primary sensorimotor cortex strokes (Galovic et al., 2013; Suntrup et al., 2015). In individuals with left hemispheric middle cerebral artery stroke, the presence of aphasia or buccofacial apraxia is a highly significant predictor of dysphagia (Somasundaram et al., 2014). Individuals with signs of aspiration within the first 72 hours following acute stroke have a 12-fold higher risk of being dependent on a feeding tube 3 months later (Ickenstein et al., 2012). On the other hand, aspiration in dysphagic patients may not be associated with obvious signs such as a cough response or overt swallowing difficulty. In fact, silent aspiration (aspiration with absence of any outward signs of distress) occurs in over 2%–25% of patients (Ramsey et al., 2005). Furthermore, an absent gag reflex does not help to differentiate those aspirating from those who are not (Finestone and Greene-Finestone, 2003). In one study, only 44% of patients with suspected oropharyngeal dysphagia following stroke had an impaired gag reflex, and only 47% coughed during oral feeding (Terré and Mearin, 2006). Therefore the employment of objective testing measures to detect the presence and predict the risk of aspiration has been advocated. Dysphagia after stroke can be diagnosed by clinical bedside assessments or instrumentally. Instrumental assessment utilizing modified barium swallow testing with VFS is considered the gold standard in the diagnosis of dysphagia but requires specialist staff and equipment and may not be possible within the first few hours after stroke; clinical bedside assessment is the only option in these cases (Cohen et al., 2016). Simple bedside techniques such as a water-swallowing test have been advocated as practical though somewhat less sensitive alternatives. Ickenstein and colleagues (2010) emphasize the value of a stepwise assessment of swallowing in patients admitted to the hospital with stroke, with the assessment beginning on the first day of admission. The first step is a modified swallowing assessment performed by the nursing staff on the day of admission; the second step is a clinical

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swallowing examination performed within 72 hours of admission by a swallowing therapist; the third step is performance of flexible transnasal swallowing endoscopy performed by a physician within 5 days of admission. Appropriate diet and treatment are then determined after each step. Employment of such a stepwise assessment of dysphagia resulted in a significant reduction in the rate of pneumonia and in antibiotic consumption in a stroke unit (Ickenstein et al., 2010). Instrumental methods of assessment of dysphagia include the videofluoroscopic swallowing study (VFS) and fiberoptic endoscopic evaluation of swallowing (FEES). VFS involves swallowing a radiological contrast agent. It is an expensive test, requires travel to a radiology suite, and it involves radiation. Hence it is impractical to perform VFS in every case. In FEES, a laryngoscope is passed transnasally to the hypopharynx to view the larynx and pharynx. The FEES study enables assessment of anatomy, secretions, and of food and drink management. The equipment is portable, sitting is not essential, and the procedure can be performed at the bedside. However, FEES and VFS are not routinely available in many hospitals worldwide. When available, these two instrumental assessments are consistent and interchangeable. They are the only two assessments that can diagnose aspiration reliably. Swallowing often improves spontaneously in the days and weeks after stroke. Improvement is more likely to occur after cortical strokes compared with those of brainstem origin; the improvement is probably the result of compensatory reorganization of undamaged brain areas (Schaller et al., 2006). Given this natural ability of the brain to reorganize, there has been increased interest in the therapeutic potential of neuromodulation to treat oropharyngeal dysphagia. One of these methods is transcranial direct current stimulation (tDCS), which promotes brain plasticity by tonic stimulation. A recent double-blind randomized study in 60 patients with acute dysphagic stroke showed that those who received tDCS over the contralesional swallowing motor cortex had more rapid rehabilitation of acute poststroke dysphagia. Early intervention seemed to be beneficial in this study. Nasogastric tube feeding can temporarily provide adequate nutrition and buy time until swallowing improves sufficiently to allow oral feeding, but it entails some risks itself, such as increasing the possibility of reflux with consequent aspiration. For individuals in whom significant dysphagia persists after stroke, placement of a percutaneous endoscopic gastrostomy (PEG) tube may become necessary. Ickenstein and colleagues (2005) documented this necessity in 77 of 664 (11.6%) stroke patients admitted to their rehabilitation hospital. Continued need for a PEG tube after discharge from the unit carried with it a somber prognosis. Various methods of behavioral swallowing therapy have traditionally been used in managing persistent poststroke dysphagia. However, the treatment landscape may be changing. Early application of neuromuscular electrical stimulation therapy in conjunction with traditional dysphagia therapy appears to be more effective in improving swallowing function than traditional therapy by itself (Lee et al., 2014). The combination of bilateral repetitive TMS and traditional therapy may also be more effective than traditional therapy alone (Momosaki et al., 2014). In individuals who experience dysfunction of the UES poststroke, a single botulinum toxin injection into the cricopharyngeal muscle may afford an improvement in swallowing that may last for up to 12 months, although care must be taken in choosing appropriate patients (Terré et al., 2013). In a small percentage of individuals, however, placement of a PEG tube will be necessary. In an individual patient data meta-analysis of three randomized controlled trials of pharyngeal electrical stimulation (PES) for poststroke dysphagia, reduced radiological aspiration, reduced dysphagia, and reduced length of hospital stay were documented (Scutt et al.,

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2015). However, a subsequent large randomized controlled trial involving 162 patients did not demonstrate benefit for the procedure, although possible undertreatment was suggested as a potential explanation for the absence of benefit (Bath et al., 2016). Reduction in salivary substance P has been associated with reduced swallowing frequency poststroke (Niimi et al., 2018). In another study in which PES (which increases salivary substance P levels) was performed on 23 tracheotomized stroke patients who could not be decannulated due to severe dysphagia, 61% were decannulated after the first treatment cycle and success in achieving decannulation was closely correlated with increased salivary substance P levels (Muhle et al., 2017). Dysphagia can also develop in the setting of other cerebrovascular processes. Within the anterior circulation, dysphagia has been reported with carotid artery aneurysms. Within the posterior circulation, processes such as elongation and dilatation of the basilar artery, posterior inferior cerebellar artery aneurysm, intracranial vertebral artery dissections, giant dissecting vertebrobasilar aneurysms, and cavernous malformations within the medulla may produce dysphagia in addition to other symptoms. Dysphagia is also a potential complication of carotid endarterectomy, not on the basis of stroke but due to laryngeal or cranial nerve injury. In one study, careful otolaryngologic examination demonstrated such deficits in almost 60% of patients postoperatively (Monini et al., 2005). Most deficits were mild and transient, but some persistent impairment was noted in 17.5% of those studied, and 9% required some rehabilitative procedures. Some investigators recommend careful evaluation and early rehabilitation to improve swallowing function at 1 and 3 months after the procedure (Masiero et al., 2007).

Multiple Sclerosis MS is an inflammatory demyelinating disease of the central nervous system that primarily though not exclusively affects young adults. The mean age of onset is approximately age 30. In its most common guise, MS is characterized by exacerbations and remissions, although some individuals may follow a chronic progressive course right from the start. The etiology of MS is uncertain but an autoimmune process is presumed. Dysphagia is a frequent problem that presents challenges for the management of MS patients. Survey studies report subjective difficulty swallowing in approximately 38% of adults with MS (Alali et al., 2018; Levinthal et al., 2013), but studies utilizing objective measures, such as swallowing videoendoscopy, demonstrate abnormalities in approximately 90% of patients (Fernandes et al., 2013). The prevalence of dysphagia in MS rises with increasing disability; about 17% of individuals with mild disability may develop neurogenic dysphagia, with the percentage escalating to 65% in the most severely affected. Dysphagia in MS is caused by a combination of impairments in several structures including the corticobulbar tracts, cerebellum, brainstem, and lower cranial nerves (Alali et al., 2016). On the other hand, cognitive and affective impairments may also influence the type and severity of symptoms observed. Adults with MS-related dysphagia report reduced scores across all domains of swallowing-related quality of life, including burden of dysphagia, eating duration, food selection, fear related to eating, and social concerns related to swallowing problems (Alali et al., 2018). Abnormalities in the oral, pharyngeal, and even esophageal phases of swallowing have been documented. Rare instances of the anterior operculum syndrome with buccolinguofacial apraxia have been reported in MS. Abnormalities in the oral phase of swallowing are common in MS patients with mild disability, but additional pharyngeal phase abnormalities develop in those with more severe disability. Disturbances in both the sequencing of laryngeal events and function

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CHAPTER 15 Neurogenic Dysphagia of the pharyngeal constrictor muscles are typically present in persons experiencing dysphagia. Pharyngeal sensory impairment may play a role in the development of dysphagia in some patients. If untreated, dysphagia may lead to reduced quality of life, increased risk of weight loss and dehydration, and aspiration pneumonia; therefore dysphagia should be identified and treated at the early stages of the disease (Poorjavad et al., 2010). Steps in the diagnosis of dysphagia in MS include bedside evaluation, questionnaires, and FEES (Giusti and Giambuzzi, 2008). Although treatment approaches are limited, intraluminal PES has been demonstrated to provide sustained benefit in a blinded pilot study of a small number of patients (Restivo et al., 2013a).

Parkinson Disease PD is a neurodegenerative disorder in which symptoms typically emerge between 55 and 65 years of age. The most prominent neuropathology in PD involves the pigmented dopaminergic neurons in the substantia nigra, but neuronal loss in other areas of the nervous system, including the enteric nervous system, has also been documented. Dysphagia was first described in PD by none other than James Parkinson himself in his original description of the illness in 1817. It now is recognized as a frequent component of PD. Results of a meta-analysis indicated that subjective dysphagia is acknowledged by 35% of individuals with PD; studies utilizing objective measures show a much higher prevalence estimate of 82% (Kalf et al., 2012; Takizawa et al., 2016). Sex, age, disease duration, and dementia all seem to contribute to the occurrence of swallowing disturbances (Cereda et al., 2014). Dysphagia in PD may be due to oral, pharyngeal, or esophageal dysfunction. Within the oral phase, difficulty with bolus formation, delayed initiation of swallowing, repeated tongue pumping, and other abnormalities have been demonstrated with modified barium swallow testing. Pharyngeal dysmotility, retention of tablets in the epiglottic vallecula, and impaired relaxation of the cricopharyngeal muscle constitute examples of abnormalities noted in the pharyngeal phase. All of these abnormalities can delay the onset of symptom relief after PD medications are taken and may easily be overlooked because they cannot be assessed visually; diagnosis requires laryngoscopy or videofluorographic examination of swallowing (Sato et al., 2018). Individuals with PD are more likely to swallow during inspiration and also to inhale post swallow, both of which increase the risk of aspiration (Gross et al., 2008). The esophageal phase is the most automatic stage of swallowing and esophageal dysfunction also can trigger dysphagia in PD. Impairment of UES movement is common in PD and can result in esophageal dysphagia (Van Hooren et.al., 2014). Esophageal manometry has demonstrated abnormalities in 61%–73% of PD patients studied; videofluoroscopic studies show a broader range, with some abnormality reported in 5%–86% of individuals (Pfeiffer, 2018). A wide variety of abnormalities of esophageal function have been described, including slowed esophageal transit, both segmental and diffuse esophageal spasm, ineffective or tertiary contractions, and even aperistalsis. Dysfunction of the lower esophageal sphincter may also be present in PD and can produce not only symptoms of reflux but also dysphagia. Aspiration has been noted to be present in 15%–56% of patients with PD and completely silent aspiration in 15%–33% (Pfeiffer, 2003). Even more striking is a study in which vallecular residue, believed to indicate an increased risk of aspiration, was found to be present in 88% of PD patients without clinical dysphagia. Silent aspiration and laryngeal penetration of saliva have been noted to occur in a significant percentage (10.7% and 28.6%, respectively) of individuals with PD who exhibit daily drooling (Rodrigues et al., 2011). In another study by the same group of investigators, a 9.75-fold increased risk of respiratory

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infection was documented in PD patients with daily drooling and silent aspiration or silent laryngeal penetration of food who were followed for 1 year (Nóbrega et al., 2008). However, a cross-sectional study of 119 patients with PD and 32 controls did not support drooling as a hallmark symptom for critical dysphagia in that 39% of patients with critical aspiration had no drooling and 41% of patients with severe drooling had no clinically relevant dysphagia on FEES (Nienstedt et al., 2018). The increased risk of aspiration in individuals with PD is associated with a prolonged swallowing time (Lin et al., 2012). Dysphagia in PD has traditionally been attributed to rigidity and bradykinesia of the involved musculature secondary to basal ganglia dysfunction. However, alpha-synuclein deposition and axonal degeneration have been documented in peripheral motor nerves innervating the pharynx, along with evidence of denervation in pharyngeal muscles (Mu et al., 2013). Hypesthesia of laryngeal structures has also been noted in PD patients, possibly contributing to the risk of aspiration (Rodrigues et al., 2011). Utilizing MEG, diminished cortical activation also has been documented in individuals with PD experiencing dysphagia (Suntrup et al., 2013). Whether dysphagia responds to levodopa or dopamine agonist therapy is controversial. Objective improvement in swallowing, documented by modified barium swallow testing, has been observed in 33%–50% of patients in some but not all studies. It has also been suggested that improvement in motor function with levodopa may make possible the adoption of compensatory swallowing postures (Nóbrega et al., 2014). The effect of deep brain stimulation (DBS) on swallowing is also disputed. Studies assessing the effect of DBS on swallowing using subthalamic nucleus (STN) or globus pallidus internus (GPi) targeting did not identify clinically significant improvement or deterioration. Despite patient reports of improvement in swallowing function, no clinically relevant changes in deglutition were found using FEES or VFS (Silbergleit et al., 2012; Troche et al., 2013). In patients with cricopharyngeal muscle dysfunction, both cricopharyngeal myotomy and botulinum toxin injections have been used successfully. Traditional behavioral swallowing therapy approaches are of benefit to some individuals. Newer techniques—such as expiratory muscle strength training (EMST) and video-assisted swallowing therapy (VAST)—show promise, but surface electrical stimulation (SES) of the neck does not appear to be effective (van Hooren et al., 2014). On rare occasions, PEG tube placement may be necessary.

Other Basal Ganglia Disorders In the PD-plus syndromes—such as progressive supranuclear palsy (PSP), multiple system atrophy, corticobasal degeneration, and dementia with Lewy bodies (DLB)—dysphagia is a frequent problem; in contrast to PD, it often develops relatively early in the course of the illness. The median latency to the development of dysphagia in PD is more than 130 months, whereas it is 67 months in multiple system atrophy, 64 months in corticobasal degeneration, 43 months in DLB, and 42 months in PSP (Muller et al., 2001). In fact, the appearance of dysphagia within 1 year of symptom onset virtually eliminates PD as a diagnostic possibility, although it does not help to distinguish between the various PD-plus syndromes (Muller et al., 2001). In persons with PSP, the presence and severity of dysphagia does not correlate well with the presence and severity of dysarthria, so the decision to evaluate swallowing function should not be based on the presence or absence of speech impairment. Dysphagia can be a prominent problem in patients with Wilson disease and is frequently a component of the clinical picture in chorea-acanthocytosis. Dysphagia in chorea-acanthocytosis is primarily the result of prominent orolingual dyskinesia, which pushes food

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out of the mouth and is pathognomonic of this disorder. A unique basal ganglia process characterized by the presence of subacute encephalopathy, seizures, dysarthria, dysphagia, rigidity, dystonia, and eventual quadriparesis—now labeled biotin thiamine-responsive basal ganglia disease—has been shown to improve promptly and dramatically after biotin and thiamine administration (Algahtani, et al., 2017). Dysphagia may also develop in the setting of spinocerebellar ataxia. Dysphagia is also a well-documented complication of botulinum toxin injections for cervical dystonia, presumably as a consequence of diffusion of the toxin. It should be noted, however, that 11% of patients with cervical dystonia experience dysphagia as part of the disease process itself, and 22% may display abnormalities on objective testing. Whether the dysphagia in individuals with cervical dystonia is mechanical or neurogenic has been the topic of debate. In a study of 25 patients with cervical dystonia, clinical assessment suggested the presence of dysphagia in 36% and electrophysiological evaluation demonstrated abnormalities in 72% (Ertekin et al., 2002). The electrophysiological abnormalities strongly suggested a neurogenic basis for the dysfunction.

Amyotrophic Lateral Sclerosis Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease. It is characterized by progressive loss of motor neurons in the cortex, brainstem, and spinal cord, which results in a clinical picture of progressive weakness that combines features of both upper motor neuron dysfunction with spasticity and hyperreflexia and lower motor neuron dysfunction with atrophy, fasciculations, and hyporeflexia. The mean age of symptom onset is between ages 54 and 58 years. ALS is categorized into two forms. The most common form is sporadic (90%–95%); the remaining 5%–10% are familial ALS (FALS). There is no obvious genetic inheritance in the former group, whereas there is a dominant inheritance pattern in the latter group (Valdmanis and Rouleau, 2018). Although dysphagia eventually develops in most individuals with ALS, bulbar symptoms can be the presenting feature in approximately 25% of patients. Individuals with bulbar onset of symptoms have a fivefold greater risk of developing dysphagia than those with spinal onset (Ruoppolo et al., 2013). A sensation of solid food sticking in the esophagus may provide the initial clue to emerging dysphagia, but abnormalities in the oral phase of swallowing are most often evident in patients with early ALS. Impaired function of the lips and tongue (particularly the posterior portion of the tongue) due to evolving muscle weakness typically appears first, followed next by involvement of jaw and suprahyoid musculature, and finally by weakness of pharyngeal and laryngeal muscles. Lip weakness can result in spillage of food from the mouth; tongue weakness leads to impaired food bolus formation and transfer. Inadequate mastication due to jaw muscle weakness adds to the difficulty with bolus formation, and the eventual development of pharyngeal and laryngeal weakness opens the door for aspiration. Neurophysiological testing in patients with ALS who have dysphagia demonstrates delay in the triggering of the swallowing reflex for voluntarily initiated swallows and its eventual abolishment with relative preservation of spontaneous reflexive swallows until the terminal stages of the disease. Videofluoroscopic studies have demonstrated that reduced pharyngeal constriction is associated with impaired swallowing efficiency in individuals with ALS (Waito et al., 2018b). Although VFS is the most precise means of evaluating dysphagia in individuals with ALS, scales such as the Norris ALS Scale provide an adequate method for deciding on the need for dysphagia treatment. The development of oropharyngeal dysphagia in individuals with ALS has a discernible effect on quality of life and is associated with increased depression and social withdrawal (Paris et al., 2013).

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Spasm of the UES, with hyperreflexia and hypertonicity of the cricopharyngeal muscle, has been reported in ALS patients with bulbar dysfunction, presumably as a consequence of upper motor neuron involvement, and has been considered to be an important cause of aspiration (Ertekin et al., 2001a). This has prompted the employment of cricopharyngeal myotomy and more recently botulinum toxin injection (Restivo et al., 2013b) as a treatment measure in such patients, but these approaches should be limited to those with objectively demonstrated UES spasm. Control of oral secretions can be a difficult problem for patients with ALS. Peripherally acting anticholinergic drugs such as glycopyrrolate are the first line of treatment for this problem. Because beta-adrenergic stimulation increases production of protein and mucus-rich secretions that may thicken saliva and make it especially difficult for patients to handle, administration of beta-blockers such as metoprolol has been proposed to reduce thickness of oral, nasal, and pulmonary secretions. Surgical procedures to reduce the production of saliva (e.g., tympanic neurectomy, submandibular gland resection) have also been employed but have not been extensively studied. Behavioral therapy approaches can be useful in treating mild to moderate dysphagia in ALS. Alterations in food consistency (e.g., thickening liquids), swallowing compensation techniques, and voluntary airway protection maneuvers all provide benefit and can be taught by speech/swallowing therapists. Eventually, however, enteral feeding becomes necessary in many individuals with advanced ALS. Placement of a PEG tube can stabilize weight loss, relieve nutritional deficiency, and improve quality of life for individuals with advanced ALS and severe dysphagia. A radiologically inserted gastrostomy (RIG) has been advocated in patients with respiratory compromise. However, with appropriate precautions, PEG may be equally safe in carefully selected high-risk patients (Talbot et al., 2018). A recent large prospective study of gastrostomy insertion in ALS—comparing RIG, PEG, and per oral radiologically inserted gastrostomy (PIG)— showed no difference in mortality between PEG and RIG, including patients with forced vital capacity (FVC) below 50% (ProGas Study Group, 2015).

Cranial Neuropathies Pathological processes involving the lower cranial nerves can produce dysphagia, usually as a part of a broader clinical picture. Dysphagia can be prominent in the Miller Fisher variant of acute inflammatory demyelinating polyneuropathy (Guillain-Barré syndrome). Response to plasmapheresis is expected in this situation. The pharyngo-cervical-brachial variant of Guillain-Barré syndrome manifests with dysphagia; including weakness of facial muscles, neck flexors, and proximal upper limb muscles; ophthalmoplegia; ataxia; and autonomic dysfunction (heart rate, bladder). Laboratory and electrophysiological investigations are similar to those in evaluating typical Guillain-Barré syndrome. Dysphagia also may be present in herpes zoster infection, where it has been attributed to cranial ganglionic involvement. Examples of other processes in which cranial nerve involvement can result in dysphagia include Charcot-Marie-Tooth disease and primary or metastatic tumors involving the skull base. Severe but reversible dysphagia with significantly prolonged esophageal transit time has been attributed to vincristine therapy. Facial onset sensory and motor neuronopathy (FOSMN) syndrome is a rare, slowly progressive neurodegenerative disorder characterized initially by sensory symptoms involving the face with subsequent development of motor weakness involving bulbar, neck, and upper limb muscles, with resultant dysphagia, dysarthria, and arm weakness. It has been proposed that FOSMN syndrome should be considered to be a variant of ALS (Dalla Bella et al., 2014).

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Brainstem Processes Any process damaging the brainstem’s swallowing centers or lower cranial nerve nuclei can lead to dysphagia. Therefore, in addition to stroke and MS, a number of other processes affecting brainstem function may display dysphagia as part of their clinical picture. Brainstem tumors, both primary and metastatic, may be responsible for dysphagia, as can central pontine myelinolysis, progressive multifocal leukoencephalopathy, and leukoencephalopathy due to cyclosporine toxicity. Brainstem encephalitis produced by organisms such as Listeria and Epstein-Barr virus may also result in dysphagia.

History and examination can provide useful clues to localization and diagnosis (Table 15.1). In fact, it has been reported that a good history will accurately identify the location and cause of dysphagia in 80% of cases (Cook, 2008). Odynophagia, or pain on swallowing, is suggestive of an inflammatory process of the esophageal mucosa and should be distinguished from the usually painless dysphagia. Difficulty initiating swallowing, the need for repeated attempts to succeed at swallowing, the presence of nasal regurgitation during swallowing, and coughing or choking immediately after attempted swallowing all suggest an oropharyngeal source for the dysphagia. A sensation

Cervical Spinal Cord Injury Dysphagia may develop in individuals with cervical spinal cord injury, especially if the injury is associated with respiratory insufficiency. In a study of 51 persons with cervical spinal cord injury and respiratory insufficiency, 21 (41%) suffered from severe dysphagia with aspiration and another 20 (39%) had mild dysphagia (Wolf and Meiners, 2003). Previous studies have reported the incidence of dysphagia following spinal cord injury to range from 16.6% to 60% (Shem et al., 2012). Individuals with higher spinal cord injury were statistically more likely to experience more prominent dysphagia after undergoing therapy, although this difference was not evident on admission. In a retrospective consecutive case series involving 298 patients following acute cervical spinal cord injury, old age, severe paralysis, and the presence of tracheostomy were risk factors for dysphagia (Hayashi et al., 2017). Iruthayarajah and colleagues performed a systematic review and meta-analysis that documented age, injury severity, level of injury, presence of tracheostomy, coughing, voice quality, bronchoscopy need, pneumonia, mechanical ventilation, nasogastric tubes, comorbid injury, and cervical surgery as significant risk factors for dysphagia following spinal cord injury (Iruthayarajah et al., 2018). With treatment and time, most patients demonstrate improvement in their dysphagia. The characteristics of dysphagia in traumatic spinal cord injury suggest an underlying mechanism of neurologic injury to structures and nerves necessary for swallowing. Dysphagia may also develop in the setting of nontraumatic cervical spinal column disease. For example, dysphagia is one of the most frequent symptoms experienced by individuals with diffuse idiopathic skeletal hyperostosis (DISH, Forestier disease).

Other Processes Although rare in developed countries, rabies is encountered more frequently in developing nations. In endemic areas, approximately 10% of affected individuals do not report any prior exposure to animal bite. Dysphagia, typically accompanying phobic spasms in the classic “furious” form of rabies, is a well-recognized feature of the human disease. A hyperactive gag reflex is usually also present in this situation. However, dysphagia may also develop in the “paralytic” form of rabies, which can be more difficult to diagnose because the classically recognized features are often absent. Neurogenic oropharyngeal dysphagia has also been reported as a consequence of severe hypothyroid coma.

Evaluation of Dysphagia Various diagnostic tests ranging from simple bedside analysis to sophisticated radiological, endoscopic, and neurophysiological procedures have been developed to evaluate dysphagia (Box 15.4). Although most are performed by primary care providers or gastroenterologists, it is important for neurologists to be aware of them so that diagnostic tests can be employed when clinical circumstances are appropriate (Box 15.5).

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Diagnostic Tests

Oropharyngeal Clinical examination Cervical auscultation Timed swallowing tests 3-oz water swallow test Modified barium swallow test Pharyngeal videoendoscopy Pharyngeal manometry Videomanofluorometry Electromyographic recording Dysphagia limit Esophageal Endoscopy Esophageal manometry Videofluoroscopy

BOX 15.5

Dysphagia Testing

If Oral Phase Dysfunction Is Suspected Screening tests: Clinical examination Cervical auscultation 3-oz water swallow Primary test: Modified barium swallow If Pharyngeal Phase Dysfunction Is Suspected Screening tests: Clinical examination 3-oz water swallow Timed swallowing Primary test: Modified barium swallow Complementary tests: Pharyngeal videoendoscopy Pharyngeal manometry Electromyography Videomanofluorometry If Esophageal Dysfunction Is Suspected Primary tests: Videofluoroscopy Endoscopy Complementary test: Esophageal manometry

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of food “hanging up” in the area of the xiphoid process implicates esophageal dysfunction, whereas a perception of the bolus “sticking” in the sternal notch may occur as a result of an oropharyngeal process or a lesion anywhere along the course of the esophagus (Fig. 15.1). Therefore the patient’s localization of the site of dysphagia is not always reliable in determining the site of the pathology (Trate et al., 1996). Differentiation between obstructive disease and motor disease can be assessed based on the type of food bolus being held up and the progression of dysphagia. In individuals with motor disorders, dysphagia to solid and liquid occur simultaneously, whereas in patients with mechanical obstruction, dysphagia initially involves solids and later progresses to include liquids (Abdel Jalil et al., 2015). Physical examination may reveal evidence suggesting a cause for dysphagia. Lip and tongue function can easily be assessed during routine neurological examination, and both palatal and gag reflexes can be evaluated. Signs of residual cerebrovascular disease, gait changes of PD, and wasting typical of muscular dystrophies can be elicited during a thorough examination. Hyporeflexia of hypothyroidism; cervical lymphadenopathy of esophageal cancer; and thickened, sclerotic skin lesions of scleroderma are other useful findings that may be evident during general physical examination (Trate et al., 1996). Cervical auscultation is not widely used to evaluate swallowing, but it may be useful to assess coordination between respiration and

TABLE 15.1

Clues to Dysphagia

Clue

Cause of Dysphagia

Difficulty initiating swallowing Repetitive swallowing Retrosternal “hanging-up” sensation Difficulty with solids but not liquids Difficulty with both solids and liquids Regurgitation of undigested food Halitosis

Oropharyngeal dysfunction Oropharyngeal dysfunction Esophageal dysfunction Mechanical obstruction Esophageal dysmotility Zenker diverticulum Zenker diverticulum

swallowing. In the normal situation, swallowing occurs during exhalation, which reduces the risk of aspiration. Conversely, discoordinated swallowing in the midst of inhalation increases the possibility that food might be drawn into the respiratory tract. One of the easiest and potentially most important parts of the physical examination is watching the patient swallow in the office. A standardized 3-oz water swallow test has been advocated as a simple bedside evaluation for oropharyngeal dysphagia. The presence of cough on swallowing during this test has been reported to provide a positive predictive value of 84% with regard to the presence of aspiration and a negative predictive value of 78%. However, the test does not provide any information regarding the specific mechanism of dysphagia. Timed swallowing tests that require repetitive swallowing of specific amounts of water have also been employed to evaluate dysphagia. Individuals with swallowing impairment may display a number of abnormalities including slower swallowing speed ( H) Autosomal dominant parkinsonian-dementia complex with pallidopontonigral degeneration (dementia, dystonia, frontal and pyramidal signs, urinary incontinence) Cerebral amyloid angiopathy with leukoencephalopathy Congenital vertical ocular motor apraxia (rare) Dentatorubral-pallidoluysian atrophy (autosomal dominant, dementia, ataxia, myoclonus, choreoathetosis) Diffuse Lewy body disease (ophthalmoplegia may be global) Dorsal midbrain syndrome Familial Creutzfeldt-Jakob disease (U > D) Familial paralysis of vertical gaze Gerstmann-Sträussler-Scheinker disease (U > D, dysmetria, nystagmus) Guamanian Parkinson disease-dementia complex (Lytico-Bodig disease) HARP syndrome (hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, pallidal degeneration) Hydrocephalus (untreated, decompensated shunt) Joseph disease Kernicterus (U > D) Late-onset cerebellopontomesencephalic degeneration (D > U) Neurovisceral lipidosis; synonyms: DAF syndrome (downgaze palsy-ataxia-foamy macrophages); dystonic lipidosis; Niemann-Pick disease type C (initially loss of downgaze, which may become global, and be associated with ataxia, cognitive changes, sensory neuropathy, and pyramidal findings) Pallidoluysian atrophy (dysarthria, dystonia, bradykinesia) Paraneoplastic disorders Progressive supranuclear palsy (PSP) Stiff person syndrome Subcortical gliosis (U > D) Variant Creutzfeld-Jakob disease (U > D) Vitamin B12 deficiency (U > D) Wilson disease (also slow horizontal saccades) (U > D) Supranuclear (global): Abetalipoproteinemia AIDS encephalopathy Alzheimer disease (pursuit) Cerebral adrenoleukodystrophy Corticobasal ganglionic degeneration Fahr disease (idiopathic striatopallidodentate calcification) Gaucher disease Hexosaminidase A deficiency Huntington disease Joubert syndrome Leigh disease (infantile striatonigral degeneration) Malignant neuroleptic syndrome (personal observation) Methylmalonohomocystinuria Neurosyphilis Opportunistic infections Paraneoplastic disorders Pelizaeus-Merzbacher disease (H > V) Pick disease (impaired saccades) Progressive multifocal leukoencephalopathy Pseudo-PSP, a selective saccadic palsy, associated with progressive ataxia, dysarthria, and dysphagia over several months following aortic/ cardiac surgery under hypothermic circulatory arrest Stiff person syndrome-late Tay-Sachs disease (infantile GM2 gangliosidosis) (V > H) Wernicke encephalopathy Whipple disease (V > H) X-linked dystonia-parkinsonism (Lubag disease)

AIDS, Acquired immunodeficiency syndrome; D, loss of downgaze; EOM, extraocular muscles; global, loss of horizontal and vertical gaze; H, loss of horizontal gaze; HAART, highly active antiretroviral therapy; SMA, spinal muscular atrophy; U, loss of upgaze; V, loss of vertical gaze. @

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findings such as abduction deficits, ataxia, optic disc edema, pathological nystagmus, and saccadic pursuit. Adults who develop isolated esotropia, particularly when they become presbyopic in their early 40s, should have a cycloplegic refraction to detect latent hyperopia, although other acquired causes of adult-onset esotropia should be considered (see Box 18.3). Dissociated vertical deviation (DVD), though not a comitant strabismus, is an asymptomatic congenital anomaly that is usually discovered during the cover test or pupil light reflex testing. While the patient fixates an object, one eye is covered, loses fixation, and rises; the uncovered eye maintains fixation. This congenital ocular motility phenomenon is usually bilateral but frequently asymmetric and often is associated with amblyopia, esotropia, and latent nystagmus (LN). Controversy remains as to whether the number of axons decussating in the chiasm is excessive, as suggested by evoked potential studies. DVD has no other clinical significance.

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Infranuclear Eye Movements

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Fig. 18.15 The Red Glass Test. Diplopia fields for each type of muscle paralysis are shown. By convention, the red glass is placed over the right eye. The charts below each case are displayed as the subject, facing the examiner, indicates the position of the red (red circle) and the white (white circle) images in the nine diagnostic positions of gaze. A, Right lateral rectus palsy. B, Right medial rectus palsy. C, Right inferior rectus palsy. D, Right superior rectus palsy. E, Right superior oblique palsy. F, Right inferior oblique palsy. (Reprinted with permission from Cogan, D.G., 1956. Neurology of the Ocular Muscles, second ed. Charles C Thomas, Springfield, IL. Courtesy Charles C Thomas, Publisher, 1956.)

Extraocular muscles and orbit. Proptosis, eyelid retraction, lid lag (i.e., delayed lowering of the upper lid margin with depression of an eye), conjunctival injection, and periorbital swelling suggest an orbital/ extraocular muscle process, such as an orbital mass lesion, thyroid eye disease (TED), or idiopathic orbital inflammatory syndrome (IOIS, also called orbital pseudotumor). Inflammation, infiltration, or fibrosis of an extraocular muscle often restricts the range of eye movement in the direction opposite that muscle’s field of action (for example, left medial rectus involvement leads to a left abduction defect) and occasionally may cause weakness and impair movement in the direction of action of the muscle. The two most common conditions resulting in diplopia secondary to extraocular muscle disease are TED and IOIS. TED is typically painless except for a foreign body sensation (grittiness) and may present with unilateral or bilateral signs. IOIS is most often unilateral, with subacute painful onset. Classically, TED affects the inferior and medial rectus muscles early, leading to restriction of elevation and abduction of the eye. Both entities may cause vision loss from optic nerve involvement, by compression in TED, or inflammation with IOIS. Chronic progressive external ophthalmoplegia (CPEO) can also cause painless, slowly progressive loss of eye movements (usually without diplopia due to insidious progression and symmetry of the process). Unlike other causes of ophthalmoplegia, classic signs of orbital disease are not present; rather, unilateral or bilateral progressive ptosis is characteristic. Mitochondrial myopathy is the most common etiology of CPEO, either isolated or as part of a syndrome such as Kearns-Sayre.

Fig. 18.16 The Maddox Rod Test. (Unlike in Fig. 18.15, the images are displayed from the patient’s perspective as the patient perceives them.) A, By convention, the right eye is covered by the Maddox rod, which may be adjusted so that the patient sees a red line at right angles to the cylinders in the horizontal or vertical plane as desired (red image seen by the right eye; light source seen by the left eye). B, The Maddox rod is composed of a series of cylinders that diffract a point of light to form a line.

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Fig. 18.18 The Hirschberg method for estimating the amount of ocular deviation. Displacement of the corneal light reflex of the deviating eye varies with the amount of ocular misalignment. One millimeter is equivalent to approximately 7 degrees of ocular deviation, and 1 degree equals approximately 2 prism diopters. A, No deviation (orthotropic). B, Left esotropia. C, Left exotropia.

SR

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Maddox rod 1 cm Left head tilt

Right head tilt L

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R 1 meter Fig. 18.19 A prism with the power of 1 prism diopter (d) can diffract a ray of light 1 cm at 1 m.

B Fig. 18.17 Example of the three-step test in a patient with an acute right superior oblique palsy. A, If a patient has a hypertropia, one of eight muscles may be responsible for the vertical ocular deviation. Identifying the higher eye eliminates four muscles. Step 1: With a right hypertropia, the weak muscle is either one of the two depressors of the right eye (IR or SO) or one of the two elevators of the left eye (IO or SR) (enclosed by solid line). Step 2: If the deviation (or displacement of images) is greater on left gaze, one of the muscles acting in left gaze (enclosed by solid line) must be responsible; in this case either the depressor in the right eye (SO) or the elevator in the left eye (SR). Step 3: If the deviation is greater on right head tilt, the incyclotortors of the right eye (SR and SO) or the excyclotortors of the left eye (IR and IO) (enclosed) must be responsible, in this case, the right SO—that is, the muscle enclosed three times. If the deviation was greater on left head tilt, the left SR would be responsible. IO, Inferior oblique; IR, inferior rectus; SO, superior oblique; SR, superior rectus. B, The Maddox rod test (displayed as in Fig. 18.16, as the subject perceives the images) in a patient with a right SO palsy shows vertical separation of the images that is worse in the direction of action of the weak muscle and demonstrates subjective tilting of the image from the right eye. When the head is tilted toward the left shoulder, the separation disappears; but when the head is tilted to the right shoulder, to the side of the weak muscle, the separation is exacerbated (Bielschowsky third step).

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An orbital CT scan may suffice to identify enlarged extraocular muscles (Fig. 18.22, A) in TED and IOIS; however, orbital magnetic resonance imaging (MRI) with contrast is preferred and should include both axial and coronal images to assess for optic nerve compression; muscle enlargement may be underestimated with axial images alone. Involvement of the tendon of the enlarged extraocular muscle distinguishes IOIS from TED (see Fig. 18.22, B). Serological thyroid function studies, including thyroid-stimulating hormone (TSH), tri-iodothyronine (T3) and thyroxine (T4), and TSH-receptor antibodies should be assessed if TED is suspected. Patients with TED may be serologically hyper-, hypo-, or euthyroid. Antithyroglobulin and antimicrosomal antibodies may be elevated with TED, whereas serum IgG subtyping may be helpful in identifying those patients with IOIS who have IgG4 disease, which can affect up to 50% (Abad et al., 2019; Andrew et al., 2015). Neuromuscular junction. Myasthenia gravis (MG) is the most common disease of the neuromuscular junction. Ocular motor dysfunction can mimic virtually any pupil-sparing abnormal eye movement, from pupil-sparing third nerve palsies to fourth and sixth nerve palsies to brainstem supranuclear gaze palsies to internuclear

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B Fig. 18.20 Primary and Secondary Deviation with Palsy of the Right Lateral Rectus Muscle. A, The right eye is covered with an occluder while the left eye fixates on the object. A small right esotropia (primary deviation) is demonstrated. (The opaque occluder is shown here to be partly transparent so that the reader can observe the position of the covered eye but the patient cannot see through it.) B, The left eye is covered while the paretic right eye fixates on the object. The right eye can fixate on the object despite the weak right lateral rectus muscle because that muscle is overdriven by the central nervous system. The normal left medial rectus muscle is also overdriven (the Hering law of dual innervation), resulting in a large esotropia (secondary deviation). f, fovea.

Causes of Positive (Restrictive) Findings on Testing Forced Ductions

BOX 18.5

Acquired: superior oblique tendinitis, myositis, or injury Brown syndrome Carotid-cavernous or dural shunt fistula Congenital: superior oblique tendon sheath syndrome Duane syndrome Entrapment (blowout fracture) Extraocular muscle fibrosis (congenital, postoperative) Long-standing muscle weakness Orbital infiltration: myositis, lymphoma, metastasis, amyloidosis, cysticercosis, trichinosis Thyroid ophthalmopathy

ophthalmoplegia (INO). Diagnostic confusion often arises when the eye movements of MG mimic another disorder and ptosis is not present to raise suspicion of MG. It is always appropriate to keep MG in the differential diagnosis for any unexplained eye movement abnormality and to have a low threshold for pursuing diagnostic testing. Botulism from Clostridium botulinum neurotoxin blockade also affects neuromuscular junction transmission. The eye movements are like those seen in MG, with variable patterns of ophthalmoplegia. However, unlike the lack of pupillary involvement in MG, tonic pupillary involvement (with slow tonic reaction and redilation to light

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and pupillary light-near dissociation manifested as better reaction to a near stimulus than to a light stimulus) is typical of botulism. A third disorder of the neuromuscular junction is the Lambert-Eaton myasthenic syndrome (LEMS), which is due to presynaptic neuromuscular junction failure (in contrast to MG, which is a postsynaptic disorder). The primary clinical manifestation is skeletal muscle weakness that may improve, rather than fatigue, with repetitive movement. Ptosis is common with LEMS; however, eye movements are affected less often (Young and Leavitt, 2016), and when affected are, rarely, the presenting clinical feature. Historic features such as fatigability with diplopia more common toward the end of the day and/or variability in the pattern of diplopia among horizontal, vertical, and oblique patterns make MG more likely in a patient with diplopia. Signs of MG (Video 18.2) include moment-to-moment or visit-to-visit variability in ocular misalignments, fatigability of eye movements or lids with prolonged upgaze, Cogan lid twitch, orbicularis oculi weakness, ptosis and curtaining or enhanced ptosis, and faster than normal “twitchy” saccades (i.e., lightning saccades). The finding of lid retraction should suggest coexisting TED, especially with proptosis. The incidence of thyroid dysfunction is higher in MG, particularly if seropositive (Lin et al., 2017; Toth et al., 2016). Cogan lid twitch is an excessive twitch of the upper lid upon return of the eyes to central position after 10 seconds of sustained downgaze. The basis for eyelid curtaining is the Hering law of equal (dual) neural innervation to each eyelid: Manually elevating the more ptotic lid results in increased ptosis in the less ptotic or nonptotic eyelid. These signs are not pathognomonic for

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BOX 18.6

A

Diplopia

No diplopia

B Fig. 18.21 Compensatory Head Positions for Diplopia. A, Right lateral rectus palsy. A right esotropia is present in primary gaze; however, by turning the head to the right (in the direction of action of the weak right lateral rectus muscle), the patient can move the eyes into left gaze and maintain both eyes on target (orthotropia), thereby achieving binocular single vision. B, Acute right superior oblique muscle palsy. The right eye extorts (excycloduction) because of the unopposed action of the right inferior oblique muscle. When the patient tilts the head to the left and forward (in the direction of action of the weak muscle), the right eye is passively intorted while the left eye actively intorts to compensate and maintain binocular single vision. The head also tilts forward to compensate for the weak depressor action of the weak right superior oblique.

MG (Kao et al., 1999; Van Stavern et al., 2007); thus confirmatory laboratory testing is important. Although diagnostic testing for MG is covered in more detail in Chapter 108, it is important to note here that the edrophonium test must have an objective endpoint (e.g., ptosis, a tropia, limited ductions), and that the physician must observe an objective change. When forced ductions are positive, indicating a restrictive myopathy, the edrophonium test will be negative and therefore is not indicated. Myasthenic ptosis may be reversed temporarily with application of an ice pack over the affected lid for 1 to 2 minutes (Marinos et al,., 2018; Yamamoto et al., 2017) or after having the patient rest with closed eyes for 30 to 60 minutes. Acetylcholine receptor antibodies are elevated (abnormal) in about 80% of patients with generalized MG but in only 38% to 71% of those with ocular MG (Benatar, 2006; Costa et al., 2004; Padua et al., 2000; Peeler et al., 2015). Anti-MuSK (anti–muscle specific receptor tyrosine kinase) antibodies are rarely associated with chronic ocular MG (Bennett et al., 2006; Hanisch et al., 2006), although ocular manifestations are a common presenting feature in disease that then generalizes (Evoli et al., 2017) and MuSK antibodies are more likely if there is significant bulbar involvement. A decremental response on repetitive electromyographic (EMG) stimulation is highly specific but has a low sensitivity in ocular MG (Benatar, 2006; Costa et al., 2004; Padua et al., 200); single-fiber EMG of the orbicularis oculi has a high sensitivity and specificity (Benatar, 2006; Costa et al., 2004; Padua et al., 2000). A decremental response of the inferior oblique muscle on ocular vestibular evoked myogenic potential (oVEMP) stimulation is a novel and evolving ocular MG diagnostic test (Wirth et al., 2019).

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Extraocular muscle or lid fatigue, suggests myasthenia gravis (MG) Cogan lid twitch, suggests MG Weakness of other muscles (e.g., orbicularis oculi, other facial muscles, neck flexors, bulbar muscles), suggests MG or oculopharyngeal dystrophy Narrowing of the palpebral fissure and retraction of the globe on adduction, associated with an abduction deficit, suggests Duane retraction syndrome Paradoxical elevation of upper lid on attempted adduction or downgaze, and pupil constriction on attempted adduction or downgaze, occurs with aberrant reinnervation of the third cranial nerve, which is nearly always a result of trauma or compression caused by tumor or aneurysm Ptosis with elevation of deep upper lid creases, baggy eyelids, superior sulcal enlargement or deformity, and previous eyelid surgical repair, suggest sagging eye syndrome Miosis accompanying intermittent esotropia with a variable abduction deficit, occurs with spasm of the near reflex (also called convergence spasm) Horner syndrome, ophthalmoplegia, and impaired sensation in the distribution of the first division of the trigeminal nerve occur with superior orbital fissure and anterior cavernous sinus lesions; Horner syndrome with a contralateral superior oblique palsy occurs with a lower midbrain trochlear nucleus lesion Proptosis, suggests an orbital lesion such as thyroid eye disease, inflammatory or infiltrative orbital disease (tumor, orbital pseudotumor, or amyloidosis), or a carotid-cavernous sinus fistula (in which case it may be pulsatile) Ocular bruits, often heard by both patient and doctor, occur with carotidcavernousor dural shunt fistulas Ophthalmoplegia, ataxia, nystagmus, and confusion, suggest Wernicke encephalopathy Facial pain, hearing loss, and ipsilateral lateral rectus weakness, indicate the Gradenigo syndrome Myotonia and retinal pathology in the setting of diplopia and ophthalmoplegia, suggest more widespread disorders such as mitochondrial disease

Conversion to generalized myasthenia will occur in up to 55% of patients presenting with isolated ocular symptoms (Hendricks et al., 2019). Ocular motor cranial nerves. See Chapter 103 for full coverage of the anatomy and clinical lesions of the third (III, oculomotor), fourth (IV, trochlear), and sixth (VI, abducens) cranial nerves. Supplementary comments are included here. Single Versus Multiple Nerves. Differential diagnosis varies substantially between a clinically isolated cranial mononeuropathy and a process involving multiple ocular motor nerves simultaneously. The former, in adults, is often due to microvascular ischemia, trauma, or a focal structural lesion on a single nerve. Unilateral involvement of multiple nerves suggests an orbital apex or cavernous sinus lesion. Bilateral involvement of multiple nerves suggests a leptomeningeal process or Miller Fisher syndrome (triad: ophthalmoplegia, ataxia, and areflexia, associated with GQ1b antibodies). The differential diagnosis of diffuse ophthalmoplegia is broad (Boxes 18.7 and 18.8). Mimics. An examination consistent with weakness of a specific single cranial nerve will typically be due to a lesion of that nerve, although MG can present with weakness identical to a pupil-sparing third, fourth, or sixth nerve palsy. Other mimics of sixth nerve dysfunction include TED (see earlier), divergence insufficiency due to the sagging and heavy-eye syndromes, pseudo–sixth nerve palsy from a midbrain/thalamic lesion, convergence spasm as a component of the spasm of the near triad (see later), and the Duane syndrome. Divergence insufficiency can mimic chronic sixth nerve dysfunction with spread of comitance. Divergence insufficiency presents as

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Causes of Acute Bilateral Ophthalmoplegia*

BOX 18.7

A

B

Fig. 18.22 Extraocular Muscle Imaging in Orbital Conditions. A, Coronal orbital computed tomography (CT) showing enlargement of the extraocular muscles bilaterally, most notable in the bilateral inferior recti, in an individual with painless progressive diplopia from thyroid eye disease. B, Axial orbital CT showing enlargement of the left medial rectus muscle body and the muscle tendon insertion in an individual with painful horizontal diplopia in primary and left gaze from idiopathic orbital inflammation.

binocular horizontal diplopia at distance with full ductions, and at distance greater than near either a comitant eso-deviation of the eyes or an eso-deviation in primary position that becomes smaller in right and left gaze. Though previously thought to have the same localizing value as sixth nerve dysfunction, it is recognized now as a common cause of diplopia, typically in patients over 70 years of age, due to the sagging eye syndrome (Chaudhuri and Demer, 2013). Age-related involution (atrophy) of orbital connective tissue can cause “sagging” of the orbital pulleys (see earlier) and extraocular muscles, particularly affecting the lateral recti. Symmetrical involvement of the orbits causes divergence insufficiency and impaired elevation of both eyes; when it occurs asymmetrically, it causes a small angle hypertropia with excylotorsion of the contralateral eye (opposite to the excyclotorsion seen in the hypertropic eye with superior oblique weakness) and vertical diplopia. A similar process, the heavy-eye syndrome, may occur due to high myopia (Tan and Demer, 2015). Lesions at the level of the thalamus, midbrain, and cerebellum can all cause eso-deviations of the eyes, likely from effects related to the convergence system. Midbrain lesions can cause a pseudo–sixth nerve palsy with limitation of abduction of one eye and a consequent eso-deviation. The Duane syndrome is a congenital disorder of maldevelopment of the sixth cranial nerve (Gunduz et al., 2019). The most common form, type 1, involves impaired abduction associated with retraction

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Basilar meningitis, hypertrophic cranial pachymeningitis, or neoplastic infiltration† Botulism Brainstem encephalitis† Brainstem stroke† Carotid-cavernous or dural shunt fistula† Cavernous sinus thrombosis (febrile, ill patient)† Central herniation syndrome Ciguatera poisoning Diphtheria Fisher syndrome (Miller Fisher syndrome) with or without ataxia Intoxication (sedatives, tricyclics, organophosphates, anticonvulsants— consciousness impaired) Leigh disease (subacute necrotizing encephalomyelitis) Multiple sclerosis Myasthenia Neuroleptic malignant syndrome (personal observation) Orbital pseudotumor† Paraneoplastic encephalomyelitis Pituitary apoplexy† Progressive encephalomyelitis with rigidity and myoclonus, a variant of stiff person syndrome Psychogenic Stiff person syndrome Thallium poisoning Tick paralysis Tolosa-Hunt syndrome† Trauma (impaired consciousness, signs of injury)† Wernicke encephalopathy *All may be unilateral. †Pain may be present.

of the eye and a narrowed palpebral fissure upon attempted abduction. Typically, patients with type 1 Duane syndrome do not have diplopia.

Nuclear See Chapter 21 for a more detailed description of anatomy and clinical conditions of the third (III, oculomotor), fourth (IV, trochlear), and sixth (VI, abducens) cranial nerve nuclei. The abducens nucleus contains two populations of motoneurons: those that innervate the ipsilateral lateral rectus for abduction and those that decussate in the pons and ascend in the contralateral medial longitudinal fasciculus (MLF) to the medial rectus for adduction to allow conjugate horizontal eye movements. A lesion of the abducens nucleus produces paralysis of all ipsilateral versional eye movements. By example, a right abducens nucleus lesion results in right horizontal gaze palsy affecting all eye movements except convergence, as convergence signals do not travel in the MLF. Lesions of the bilateral abducens nucleus result in bilateral horizontal gaze palsies (i.e., loss of all horizontal eye movements, with spared ability to converge). With rare exceptions, lesions of the abducens nucleus that cause an acquired ipsilateral gaze palsy almost always involve the facial nerve fasciculus as it loops around the abducens nucleus and result in an associated facial nerve palsy.

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Causes of Chronic Ophthalmoplegia

Causes of Internuclear Ophthalmoplegia

BOX 18.8

BOX 18.9

Brainstem neoplasm Chronic ataxic neuropathy, ophthalmoplegia, monoclonal protein, cold agglutinins, and disialosyl antibodies (CANOMAD) Chronic basal meningitis (infection, sarcoid, or carcinoma) Chronic ophthalmoplegia with anti-GQ1b antibody Congenital extraocular muscle fibrosis Dysthyroidism Leigh disease Multiple sclerosis Myasthenia gravis Myopathies (e.g., mitochondrial, fiber-type disproportion (see Table 18.3) Nuclear, paranuclear, and supranuclear gaze palsies (see Table 18.3)

Internuclear Internuclear ophthalmoplegia (Video 18.3). Damage to the medial longitudinal fasciculus (MLF) connecting the third and sixth cranial nerve nuclei impairs transmission of neural impulses from the abducens nucleus to the contralateral medial rectus muscle (see Fig. 18.6). This results in an internuclear ophthalmoplegia (INO) manifest as impaired adduction of the eye ipsilateral to the lesion, slowed adducting saccades in that eye, and abducting “nystagmus” upon abduction in the contralesional eye, which is an adaptive response (overshoot dysmetria) because the medial rectus muscle’s weakness causes increased innervation to both itself and the yoked contralateral lateral rectus (the Hering law of dual innervation). Patching the eye with the abducting “nystagmus” can decrease the oscillation, supporting this hypothesis (Zee et al., 1987). Acutely, upward-beating nystagmus and torsional nystagmus (TN) may be present (Choi et al., 2012; Jeong et al., 2011). Convergence may be preserved with an INO, as signals for convergence of the medial rectus muscles are not carried in the MLF. Patients with bilateral INO may be exotropic, designated as the wall-eyed bilateral INO (WEBINO) syndrome, and have slow-abducting saccades because of impaired inhibition of tone in the medial recti. Other clinical features associated with unilateral INO include a partial contralateral ocular tilt reaction (OTR) (Choi et al., 2017 et al., 2017), manifest as a skew deviation with ipsilesional hypertropia (Zwergal et al., 2008), and defective vertical smooth pursuit, OKN, and vertical VORs. A subtle INO is demonstrated by having the patient make repetitive horizontal saccades, which typically discloses slow adduction of the ipsilateral eye and may sometimes be the only sign of an INO. Alternatively, an optokinetic tape may be used to induce repetitive saccades in the direction of action of the suspected weak medial rectus muscle by moving the tape in the opposite direction and observing for slower and adducting saccades of smaller amplitude. INO may occur with a variety of disorders (Box 18.9) affecting the brainstem, although demyelinating lesions in younger patients and ischemic lesions in older patients are most common. INO must be distinguished from the many (primarily peripheral infranuclear) causes of pseudo-INO (see Box 18.9). Rarely, patients with small lesions in the rostral pons or midbrain, remote from the abducens nerve and nucleus, may have a Lutz posterior INO (also called INO of abduction [Kommerell, 1975]). In this condition, abduction is impaired, but the adducting eye has nystagmus. The mechanism is impaired inhibition of the antagonist medial rectus muscle secondary to damage to uncrossed fibers from the PPRF to the oculomotor nucleus, running close to but separate from the MLF. MG can mimic a Lutz posterior INO (Zheng and Lavin, 2018).

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Brainstem (pontine) stroke—unilateral Multiple sclerosis—unilateral or bilateral Intrinsic tumor—primary or metastatic Meningitis (especially tuberculosis, also acquired immunodeficiency syndrome, brucellosis, cystercosis, syphilis) Brainstem encephalitis (infective, inflammatory, lupus, paraneoplastic, sarcoid) Chemotherapy with radiation therapy Drug intoxication: Comatose—anticonvulsants, phenothiazines, tricyclics Awake—lithium Spinocerebellar degeneration Fabry disease (vascular) Herniation (epidural and acute and chronic subdural hemorrhage, cerebral hematoma) Vascular malformations Vasculitis Wernicke encephalopathy Progressive supranuclear palsy Syringobulbia associated with a Chiari malformation Trauma (closed head injury, neck/vertebral artery injury) Hexosaminidase A deficiency Kennedy disease (X-linked recessive progressive spinomuscular atrophy) Maple syrup urine disease Cerebral air embolism Vitamin B12 deficiency Pseudointernuclear ophthalmoplegia Long-standing exotropia Myasthenia Myotonic dystrophy Neuromyotonia of the lateral rectus muscle Partial palsy of cranial nerve III Previous extraocular muscle surgery Thyroid orbitopathy (lateral rectus restriction) Orbital pseudotumor Other infiltrative disorders of extraocular muscle (neoplasm, amyloid, etc.) Miller Fisher syndrome (sometimes may be a true internuclear ophthalmoplegia)

Supranuclear Brainstem

Saccadic gaze palsy A number of congenital and acquired conditions—including degenerative, inflammatory, neoplastic and paraneoplastic, ischemic, metabolic, and hereditary conditions—can cause saccadic gaze palsies with slow saccades (see Table 18.3) (LloydSmith Sequeira et al., 2017). Examination of the different functional classes of eye movements—specifically, saccades, smooth pursuit, and vestibular reflexes—helps to distinguish nuclear, paranuclear, and supranuclear gaze palsies. EBNs in the brainstem are located in the PPRF just rostral to the abducens nucleus (Horn, et al., 1995) for horizontal saccades and in the RIMLF in the midbrain (Horn and Büttner-Ennever, 1998) for vertical and torsional saccades. It follows that a lesion of the PPRF can cause a horizontal saccadic gaze palsy and a lesion in the RIMLF can cause a vertical and torsional saccadic gaze palsy. Thus the clinical hallmark of a supranuclear gaze palsy is D1 F CD @ 2C @ C

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CHAPTER 18 Neuro-Ophthalmology: Ocular Motor System disproportionate involvement of saccades, which classically is manifest as slow saccades with or without limitation of gaze. Eliciting OKN is helpful in identifying saccadic gaze palsies; also, as the quick phases of OKN are saccades and are lost in brainstem supranuclear gaze palsies. Smooth pursuit may be affected, but usually to a lesser extent than saccades. Vestibular eye movements are typically spared. In other words, any limitation in the range of eye movement seen with saccades or smooth pursuit should be overcome with vestibular stimulation. In contrast to supranuclear disorders, nuclear and infranuclear (extraocular muscle, neuromuscular junction, and cranial nerve) processes affect saccades, smooth pursuit, and vestibular reflexes equally. The caveat is that, with acute catastrophic lesions (ischemia or hemorrhage), supranuclear eye movement lesions may affect all classes of eye movements, but the deficits still tend to affect saccades most dramatically. Horizontal. A right PPRF lesion causes impaired conjugate gaze to the right (right eye abduction and left eye adduction). Acutely, gaze may be deviated contralaterally because of unopposed resting innervation from the intact left PPRF. Bilateral PPRF lesions result in absent horizontal gaze (or selective loss of saccades) (Video 18.4) and slowed vertical saccades (Hanson et al., 1986; Pierrot-Deseilligny et al., 1984; Slavin, 1986), as some vertical saccades are programmed in the PPRF and relayed to the midbrain via a juxta-MLF pathway, presumably to coordinate horizontal, vertical, and oblique trajectories as well as head movement. One-and-a-half syndrome. A lesion involving both the PPRF (or the abducens nucleus) and the crossed MLF (with decussated fibers that originated in the contralateral abducens nucleus) on one side of the pons causes the one-and-a-half syndrome (see Fig. 18.6 and Video 18.5). The PPRF lesion causes an ipsilateral horizontal gaze palsy and the MLF lesion causes an ipsilateral INO with impaired ipsilateral adduction (see earlier section on INO). The only horizontal eye movement that remains intact is abduction of the eye contralateral to the lesion; thus “one and a half” of the horizontal eye movements are impaired. Typically an exotropia (outward deviation of the eyes) is present. Also, some patients have a contralateral OTR (Zwergal et al., 2008); those with abducens nucleus, rather than PPRF involvement, have an accompanying facial nerve palsy and may develop oculopalatal myoclonus later, probably because of the proximity of the central tegmental tract to the facial nerve fascicle. MG can cause a pseudo– one-and-a-half syndrome. Vertical. Lesions of the RIMLF result in slowed or absent vertical saccades, especially when bilateral, with or without limitation in vertical gaze range. The RIMLF EBNs for upward saccades are likely caudal, ventral, and medial in the RIMLF and project to the elevator muscles (superior rectus and inferior oblique) bilaterally, with axons crossing within the oculomotor nucleus (Fig. 18.23) and not in the posterior commissure (PC), as previously thought (Bhidayasiri et al., 2000). The RIMLF EBNs for downward saccades are more rostral, dorsal, and lateral in the RIMLF and project only to the ipsilateral depressor muscles (inferior rectus and superior oblique) (see Fig. 18.23). Each RIMLF also projects only ipsilaterally for control of torsional saccades. Given this anatomy, RIMLF lesions might be expected to have a more profound effect on downgaze. Bilateral RIMLF lesions cause either loss of downward saccades or of all vertical saccades. The effects of unilateral lesions are less well understood, as in theory they should cause only mild slowing of downward saccades and loss of torsional quick phases (saccade-like resetting movements seen with torsion VOR testing); however, a wide range of vertical gaze deficits are reported with unilateral RIMLF involvement. Deficits from RIMLF lesions tend to affect the eyes conjugately, as each RIMLF sends signals to vertical

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eye muscles for each eye. However, unilateral (or monocular) vertical gaze palsies are occasionally seen. Two forms of the vertical one-and-a-half syndrome occur with discrete lesions in the upper midbrain. One, which consists of bilateral upgaze palsy associated with monocular paresis of downward movement, can occur with either ipsilateral or contralateral thalamomesencephalic infarction. The other consists of a downgaze palsy associated with monocular elevator paresis that can occur with bilateral mesodiencephalic lesions. A crossed vertical gaze paresis, with supranuclear weakness of elevation of the contralateral eye and weakness of depression of the ipsilateral eye, may occur with a lesion involving the mesodiencephalic junction and medial thalamus. Monocular elevator deficiency, also termed monocular elevator palsy or double elevator palsy, is characterized by limitation of elevation of one eye. The limitation is the same in both adduction and abduction, unlike the Brown superior oblique tendon sheath syndrome, in which the limitation is predominantly in adduction. This can result from a lesion either in supranuclear or infranuclear structures (Gauntt et al., 1995; Jampel and Fells, 1968), such as paretic or restrictive disorders of the extraocular muscles, orbital floor fractures, myasthenia, and fascicular lesions of the oculomotor nerve. When monocular elevator deficiency is congenital or occurs early in life, it may be associated with abnormalities of convergence, amblyopia, a chin-up head position, and ptosis or pseudoptosis (pseudoptosis occurs when a patient with a hypotropic eye fixates with the other eye; the upper lid follows the hypotropic eye and appears ptotic. When the patient fixates with the hypotropic eye, the apparent ptosis disappears. Some patients may have both a true ptosis and a superimposed pseudoptosis). Some congenital cases are supranuclear because of congenital unilateral midbrain lesions; when they are of long standing, inferior rectus restriction and fibrosis prevent reflex elevation of the eye (the Bell phenomenon). In those cases, primary orbital disorders such as myositis, thyroid orbitopathy, orbital floor fractures, and infiltrative disease must be excluded. Corrective surgery is helpful. Acquired supranuclear monocular elevator palsy results in limitation of elevation of one eye on attempted upgaze despite intact downgaze and orthotropia in primary position (unlike patients with monocular elevator deficiency, who have an abnormal head posture). This rare condition occurs with unilateral vascular or neoplastic lesions involving either the ipsilateral or contralateral midbrain. Usually the affected eye can be elevated in response to vestibular stimulation, and ptosis is usually absent. When asymmetrical, the sagging eye syndrome (see earlier section titled “Mimics” [of cranial nerve disorders]) can cause impaired elevation of one eye that cannot be overcome by vestibular stimulation. Acute-onset vertical gaze palsy is due most often to midbrain infarction. The RIMLF is supplied by the thalamic-subthalamic paramedian artery, which originates from the posterior cerebral artery (PCA) at the bifurcation of the basilar artery and the PCAs. A single thalamic-subthalamic paramedian (the artery of Percheron) artery supplies both RIMLF in roughly 20% of people (Lasjaunias et al., 2000), making bilateral RIMLF lesions possible from a single vessel infarct (Matheus and Castillo, 2003). Disorders of vertical gaze, particularly downgaze and combined upgaze and downgaze paresis, may be overlooked in patients with brainstem vascular disease because of impaired consciousness due to concomitant damage to the reticular activating system. The classic cause of chronic progressive vertical saccadic slowing is progressive supranuclear palsy (PSP), a neurodegenerative tauopathy causing rapid deterioration with early falls, akinetic-rigid parkinsonism, and swallowing difficulty. The hallmark feature is slowing of

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Upgaze

Upgaze PC

Aqueduct

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A Downgaze

Downgaze PC

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B Fig. 18.23 Hypothetical Pathways Involved in Controlling Vertical Eye Movements. A, Upward eye movements. Burst neurons for upward saccades are shown projecting from the medial rostral interstitial nucleus of the medial longitudinal fasciculus (RIMLF) to the elevator muscles, superior recti, and inferior obliques bilaterally, with axons crossing within the oculomotor nucleus. B, Burst neurons for downward saccades are shown projecting only to the ipsilateral depressor muscles, the inferior rectus, and the superior oblique. The axons of the burst neurons for upward saccades also project to the interstitial nucleus of Cajal (INC), which plays a role in neural integration for vertical and torsional gaze. From the INC, the axons project dorsally and laterally to cross in the posterior commissure before turning ventrally to the oculomotor and trochlear nerve nuclei. CN III, Third nerve nuclear complex; CN IV, fourth nerve nucleus; IO, inferior oblique subnucleus; IR, inferior rectus subnucleus; PC, posterior commissure; RN, red nucleus; SN, substantia nigra; SO, superior oblique nucleus; SR, superior rectus subnucleus (Redrawn from Bhidayasiri, R., Plant, G.T., Leigh, R.J., 2000. A hypothetical scheme for the brainstem control of vertical gaze. Neurology 54, 1985–1993.)

vertical saccades early in the disease. A common clinical misconception is that downward saccades are impaired more than upward saccades early in the disease (Chen et al., 2010); however, slowing of both downward and upward saccades is common and limitation of upward gaze is more common than that of downward gaze (Chen et al., 2010). Early in the disease course, horizontal saccades are slowed also, but much less than vertical. Late in the disease course, saccades and smooth pursuit may be lost both vertically and horizontally, although VOR still

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Features of Spasm of the Near Reflex (Psychogenic)

BOX 18.10

Near tetrad: Convergence Miosis Accommodation (blur at distance, myopia by retinoscopy) Excyclotorsion (extorsion) Neurasthenic symptoms Blepharoclonus (frequent blink rate) Poor cooperation in other motor tasks Obstructive behavior (e.g., closing eyes, or not responding to commands such as “look to the right” despite being observed to do so during the interview) Other behavioral changes (e.g., tunnel vision) May disappear with rapid saccades Full range of eye movement: With pursuit of own hand With one eye covered Doll’s eyes with fixation Ice-cold calorics: Normal response Bizarre behavioral response Normal optokinetic nystagmus if patient encouraged or distracted (e.g., count stripes) Demeanor: Affective disorder Tinted glasses or sunglasses

(Eggers et al., 2015). The delayed progression of this syndrome remains unexplained but may represent a form of decelerated apoptosis. Dorsal midbrain syndrome. The features of the dorsal midbrain syndrome (the Parinaud syndrome) (Video 18.6) include a supranuclear saccadic upgaze palsy, convergence-retraction “nystagmus” (often elicited by attempted upgaze), lid retraction (Collier sign), and pupillary light-near dissociation (pupillary constriction upon viewing a near target but not with direct light testing). Pineal region tumors, ischemic stroke, hemorrhage, and decompensated hydrocephalus are common etiologies. The EBNs for vertical saccades also project to the INC, which plays a major role in neural integration for vertical and torsional gaze (Bhidayasiri et al., 2000). From the INC, the pathways project dorsally and laterally to cross in the PC before turning ventrally to the oculomotor and trochlear nerve nuclei (see Fig. 18.23). The axons to the elevator muscles travel more dorsally and thus are more susceptible to extrinsic compression, as often occurs with the dorsal midbrain syndrome. Convergence-retraction nystagmus is not a true nystagmus as it lacks slow phases or drifts (see section titled “Nystagmus,” later), but a rapid dysmetric horizontal eye movement induced by attempted upward saccades. This is assessed clinically by having the patient look at an OKN tape moving downward in an attempt to induce upward saccades. Rapid convergence with synchronous retraction of both globes caused by simultaneous cocontraction of the extraocular muscles is followed by a slow divergent movement. Less commonly, if lateral rectus innervation is dominant, a rapid divergent movement occurs initially. The pupillary light-near dissociation occurs because the light reflex pathways are more superficial. In contrast, intrinsic midbrain lesions cause impairment of convergence and accommodation (the near reflex) while sparing the light reflex. Vergence deficits Disorders of vergence include convergence insufficiency, convergence spasm, and divergence insufficiency. Convergence insufficiency is most commonly seen clinically as a benign, often self-limited condition in children or as an acquired deficit after

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traumatic head injury or with parkinsonian disorders. Occasionally it is seen as an isolated phenomenon in adults without neurological illness. Convergence is very dependent on effort, so repeated examination to ensure maximum effort is important. Symptoms include words running together when reading; frank binocular horizontal diplopia at near; and vague symptoms such as eyestrain, headache, and burning eyes that are often associated with asthenopia. Examination signs of convergence insufficiency include a reduced near point of convergence (inability to convergence the eyes to within a few centimeters of the nose), an exophoria with near fixation larger than any exophoria with distance fixation, and low convergence amplitudes (inability to fuse an image at near with base-out prisms placed in front of one eye). Orthoptic exercises (pencil push-ups) (Rucker and Phillips, 2018), reading glasses with base-in prisms, and myopic correction are useful in management. Central disruption of fusion, or posttraumatic fusion deficiency, can occur after moderate head injury and causes intractable diplopia despite the patient’s ability to fuse intermittently and, even briefly, achieve stereopsis. The diplopia fluctuates and varies between crossed, uncrossed, and vertical. Versions and ductions may be full, but vergence amplitudes are greatly reduced. Prism therapy or surgery is ineffective, but an eye patch or centrally frosted lens may provide symptomatic relief. The location of injury is presumed to be in the midbrain. Also, central disruption of fusion is reported with brainstem tumors, stroke, following removal of long-standing cataracts, uncorrected aphakia, and neurosurgical procedures. This condition must be distinguished from bilateral fourth cranial nerve palsies, when diplopia is constant and associated with cyclodiplopia and excyclotropia (>10 degrees) and also from psychogenic disorders of vergence. Convergence spasm, or spasm of the near reflex, is a disorder characterized by intermittent episodes of convergence, miosis, and accommodation. It may mimic bilateral (and occasionally unilateral) abducens paresis. The patient may complain of double or blurred vision and is esotropic, particularly at distance; however, prominent miosis is the clue, as is variability in the exam over time (i.e., one moment there appears to be an abduction defect and the next moment it is gone). Spasm of the near reflex is reported in patients with organic disorders but is more commonly psychogenic, either in patients with conversion reactions or in anxious patients in whom the “spasm” is a manifestation of misdirected effort. The differential diagnosis is that of esotropia (see Box 18.3). Miosis on gaze testing generally establishes the diagnosis but can be difficult to discern. Accommodative esotropia and latent hyperopia must be excluded by obtaining a cycloplegic refraction. Patients with psychogenic spasm of the near reflex often have associated somatic complaints and obstructionist behavior such as blepharoclonus on lateral gaze and poor cooperation in performing motor tasks such as smiling, opening the mouth, and protruding the tongue (features of neurasthenia and asthenopia) (Box 18.10). Management should focus on identifying the source of the psychopathology and may require psychiatric evaluation. Strategies such as the use of cycloplegia (homatropine eye drops) to prevent accommodative spasm, thus inhibiting the near triad, may be helpful. Divergence insufficiency is characterized by esotropia that is either comitant or reduced in lateral gaze and uncrossed horizontal diplopia at distance in the absence of other neurological symptoms or signs. The esotropia may be intermittent or constant, but the patients can fuse at near. Versions and ductions are full, and saccadic velocities, if measured quantitatively, appear normal. The origin of divergence insufficiency is unclear, but it may result from a break in fusion in an individual with a congenital esophoria usually coming on later in life; it also occurs in patients with midline cerebellar disease. The condition is easily treated with base-out prisms for the distance correction

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Eye position during head tilt

Normal ocular counter-rolling reflex

Ocular tilt reaction Fig. 18.24 A, Normal ocular counter-rolling phenomenon during head tilt. B, Ocular tilt reaction consists of spontaneous skew deviation, cyclotorsion of both eyes (upper poles rotated toward lower eye), paradoxical head tilting, and displacement of the subjective visual vertical toward the side of the lower eye. (From Lavin, P.J.M., Donahue, S.P., 2013. Disorders of supranuclear control of ocular motility. In: Yanoff, M., Duker, J.S. [Eds.], Ophthalmology, fourth ed. Elsevier.)

and rarely requires extraocular muscle surgery. Divergence insufficiency in the elderly occurs with the sagging eye syndrome (see earlier); it is recognized by the associated signs of involutional changes such as ptosis and/or elevated upper lid creases, superior sulcus enlargement, deformity, or baggy eyelids; it is differentiated from divergence insufficiency of neurogenic origin by the absence of nystagmus, saccadic dysmetria, and ataxia. Divergence paralysis, a controversial entity that may be difficult to distinguish from divergence insufficiency, usually occurs in the context of a severe head injury or other cause of raised intracranial pressure. Such patients have horizontal diplopia at distance; however, quantitatively, in contrast to divergence insufficiency, abducting saccades are slow. Patients with bilateral palsies of the sixth cranial nerve who recover gradually may go through a phase in which the esotropia becomes comitant with full ductions, mimicking divergence paralysis. Divergence paralysis can also occur with Miller Fisher syndrome, Chiari malformations, pontine tumors, and excessive sedation from drugs. Ocular tilt reaction and skew deviation In normal circumstances, a synkinetic movement, ocular counter-rolling, allows people to maintain horizontal orientation of the environment while tilting the head to either side (Fig. 18.24, A). When the head is tilted to the left, the left eye rises and intorts as the right eye falls and extorts within the range of the ocular tilt reflex (approximately 10 degrees from the vertical). The initial transient dynamic (phasic) counter-rolling response results from stimulation of the semicircular canals, whereas the sustained (tonic) response is mediated by the otolith organs and holds the eyes in their new position. Lesions of these pathways result in an inappropriate OTR and skew deviation.

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The OTR consists of spontaneous skew deviation, cyclotorsion of both eyes (the upper poles rotated toward the lower eye), paradoxical head tilting (see Fig. 18.24, B), and displacement of the subjective visual vertical, all toward the side of the lower eye. A tonic (sustained) OTR occurs with a prenuclear (i.e., supranuclear) lesion causing imbalance in the otolithic (gravireceptive) pathways to the ocular motor system anywhere along the pathway from the ipsilateral utricle, vestibular nerve, nuclei, or the contralateral MLF, contralateral INC, to the medial thalamus. A phasic (paroxysmal) OTR occurs with a lesion, such as a cavernoma, in the region of the INC, and may respond to baclofen or carbamazepine (Rodriguez et al., 2009). An OTR can be induced by sound in patients with perilymph fistulas of the vestibular end organ (the Tullio phenomenon). A partial OTR in which there is no head tilt or there is merely ocular torsion, can occur with lesions of the cerebellar nodulus and uvula. This is attributed to an increase in the tonic resting activity of secondary otolithic neurons in the ipsilesional vestibular nucleus because of loss of inhibition from the injured nodulus. A contralateral OTR occurs in individuals with INO and those with the one-and-a-half syndrome (Zwergal et al., 2008). A variant of the OTR, characterized by the alternating tonic conjugate ocular torsion that accompanies congenital ocular motor apraxia (COMA), occurs in Joubert syndrome. The eyes rotate, cycling every 10 to 15 seconds, with torsional amplitudes of 30 to 45 degrees in each direction. Affected individuals may have an intermittent skew deviation with intermittent head tilting. Neuroimaging demonstrates superior cerebellar hypoplasia, with elongation of the superior cerebellar peduncles producing a molar tooth sign (Papanagnu et al., 2014). Skew deviation is a vertical divergence of the ocular axes caused by a prenuclear asymmetry of ascending utricular input to the cranial nerve nuclei serving vertical eye movements. Lesions causing skew are typically in the brainstem or cerebellum, involving the vertical vestibulo-ocular pathways; occasionally they occur peripherally in the vestibular nerve or end organ. Skew deviation is particularly common with vascular lesions of the pons or lateral medulla (Wallenberg syndrome). A skew deviation is usually but not always comitant; when incomitant, it may mimic a partial third cranial nerve or a fourth cranial nerve palsy. Dieterich and Brandt demonstrated ocular torsion of one or both eyes associated with subjective tilting of the visual vertical toward the lower eye in most patients with skew deviations (Dieterich and Brandt, 1993). With lesions caudal to the lower pons, the ipsilateral eye is lower (ipsiversive skew); but with lesions rostral to the midpontine level, the contralateral eye is lower (contraversive skew). Ocular torsion may be present without a vertical deviation and, in either situation, can be detected by blind spot mapping, indirect ophthalmoscopy, fundus photography, double Maddox rod test, or settings of the visual vertical. Lateropulsion Saccadic lateropulsion is characterized by hypermetric (overshoot) saccades (Fig. 18.25, B) to the side of the lesion (ipsipulsion) and hypometric (undershoot) saccades (see Fig. 18.25, C) to the opposite side. In darkness or with the eyelids closed, the patient may have conjugate deviation toward the side of the lesion (ipsipulsion). Saccadic lateropulsion occurs with lesions of the lateral medulla (most commonly ischemic) involving cerebellar inflow (inferior cerebellar peduncle). Saccadic lateropulsion with a bias away from the side of the lesion (contrapulsion) may occur with lesions involving the region of the superior cerebellar peduncle (outflow tract) and adjacent cerebellum (superior cerebellar artery territory). Pulsion of vertical saccades with a parabolic trajectory occurs in patients with lateral medullary injury: both upward and downward saccades deviate toward the side of the lesion with corrective oblique saccades; whereas

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Fig. 18.25 Oculographic Diagrams of Waveforms in Various Nonnystagmus Oscillations. A, Spontaneous ocular flutter in primary position. B, Overshoot dysmetria (hypermetria). C, Undershoot dysmetria (hypometria). D, Flutter dysmetria exacerbated by refixation of 1–10 degrees.

in those with lesions involving cerebellar outflow, vertical saccades deviate away from the side of the injury. Cerebellum. Several eye movement abnormalities or combinations thereof strongly suggest a cerebellar localization. Some of these are mentioned in the earlier discussion, such as impaired smooth pursuit, eso-deviations and divergence weakness, and skew deviations. Cerebellar forms of nystagmus are covered later, in the section titled “Nystagmus.” The cerebellum coordinates the ocular motor system to drive the eyes smoothly and accurately and is supplied richly by afferent fibers conveying ocular information (e.g., velocity, position, neural integration) from the vestibular system, the afferent visual system, the PPRF, and the MRF. The dorsal vermis and fastigial nuclei determine the accuracy of saccades by modulating saccadic amplitude; also, they adjust the innervation to each eye selectively to ensure precise conjugate movements. Lesions of the dorsal vermis and fastigial nuclei result in saccadic dysmetria (often, overshoot dysmetria that is greater centripetally), macrosaccadic oscillations (MSO) (see the section titled “Saccadic Intrusions,” further on), and disorders of vergence (see the section titled “Vergence deficits”). Selective cerebellar lesions have differential effects on eye movements. Bilateral lesions of the fastigial and globose (interpositus) nuclei cause hypermetria of externally triggered saccades but do not affect internally triggered saccades. Bilateral lesions of the posterior vermis (lobules VI and VII) cause hypometric horizontal and vertical saccades and impaired pursuit. Unilateral lesions of the posterior vermis cause hypometric ipsilateral and hypermetric contralateral saccades, whereas unilateral lesions of the caudal fastigial nucleus cause hypermetric ipsilateral and hypometric contralateral saccades.

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The flocculus, part of the vestibulocerebellum, is responsible for matching the saccadic pulse and step appropriately and for stabilizing images on the fovea. It adjusts the output of the NI and participates in long-term adaptive processing to ensure that eye movements remain appropriate to the stimulus. For example, the amplitude (gain) and even the direction of the slow phases of the VOR are adjusted by the flocculus. Lesions of the flocculus result in gaze-holding deficits such as gaze-evoked, rebound, and downbeat nystagmus (see the section titled “Nystagmus,” later). Floccular lesions also impair smooth pursuit, cancelation (suppression) of the VOR by the pursuit system during combined head and eye tracking, and the ability to suppress nystagmus (and vertigo) by fixation. The nodulus, also part of the vestibulocerebellum, influences vestibular eye movements and vestibular optokinetic interaction. Lesions of the nodulus in monkeys and humans produce periodic alternating nystagmus (PAN) (see the section titled “Nystagmus,” later). A specific form of skew deviation, called alternating skew deviation on lateral gaze, in which the hypertropia changes sides (i.e., right hyper on right gaze, left hyper on left gaze), often results from lesions affecting the cerebellar pathways or cervicomedullary junction. This is probably the result of asymmetrical vestibular input to the yoked superior oblique and contralateral inferior rectus muscles (see Table 18.2) because of increased central otolithic tone for downgaze. Skew deviation that alternates between up- and downgaze can occur with spinocerebellar degeneration. Congenital superior oblique overaction causes an A-pattern exotropia (eyes diverge on downgaze) and an abducting hypertropia on lateral gaze; often it is associated with disorders of the posterior fossa, such as hydrocephalus, meningomyelocele, and Chiari II malformations. Congenital inferior oblique overaction causes a V-pattern esotropia (eyes converge or cross on downgaze) and is otherwise benign. Bilateral fourth cranial nerve palsies may mimic gaze-dependent alternating skew, in which the adducting eye is hypertropic; however, diplopia is worse on downgaze, with significant excyclotorsion and a V-pattern esotropia. Cerebellar lesions can impact torsional eye movements. Pathological rapid torsional eye deviation during voluntary saccades may occur with large lesions involving the midline cerebellum, deep cerebellar nuclei, and dorsolateral medulla. The amplitudes of these torsional saccades (“blips”) are larger for ipsilesional (hypermetric) than for contralesional (hypometric) horizontal saccades. Eye movement recordings using a scleral search coil (see the section titled “Recording of Eye Movements,” further on) demonstrated that the blips are followed by an exponentially slow torsional drift toward the initial torsional eye position. These blips may be a form of torsional saccadic dysmetria.

Cortex

Horizontal gaze deviations Transient gaze deviation, usually of the head and eyes, occurs in about 20% of patients with acute hemisphere stroke and other insults. Because of gaze paresis to the hemiplegic side (i.e., paralyses of gaze and limbs are on the same side), the eyes are deviated toward the side of the lesion (ipsiversive gaze deviation), which may be seen on imaging studies performed at presentation. With stroke, right-sided lesions are more common but smaller; consequently, patients with left-sided lesions (gaze deviation to the left) have a worse prognosis. Ipsiversive gaze deviation occurs more often when the inferior parietal lobule (IPL) or circuits between the FEF and the IPL or their projections to the brainstem (superior colliculus or PPRF) are involved; the FEF usually are spared. After about 5 days, the intact hemisphere, which contains neurons for bilateral gaze, takes over. Thereafter, subtle abnormalities such as prolonged saccadic latencies and impaired saccadic suppression can be detected only by quantitative oculography. Bilateral lesions of the D1 F CD @ 2C @ C

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frontomesencephalic pathways cause loss of horizontal saccades in both directions and impair vertical saccades (particularly upward) but spare pursuit, VORs, and the slow phases of OKN. Conjugate eye deviation to the “wrong” side—that is, away from the lesion and toward the hemiplegia (contraversive gaze deviation)—may occur with supratentorial lesions, particularly thalamic lesions, such as hemorrhage, and (rarely) large perisylvian or lobar hemorrhage. The mechanism is unclear, but possibilities include the following: 1. An irritative or seizure focus causing “contraversive ocular deviation” is unlikely, because neither clinical nor electrical seizure activity is reported in these patients. 2. Because eye movements are represented bilaterally in each frontal lobe, it is conceivable that the center for ipsilateral gaze alone may be damaged, resulting in contraversive ocular deviation. 3. An irritative lesion of the intralaminar thalamic neurons, which discharge for contralateral saccades, could theoretically cause contraversive ocular deviation. 4. Damage to the contralateral inhibitory center could be responsible also. Postictal “paralytic” conjugate ocular deviation occurs after adversive seizures as part of a Todd paresis. Spasticity of conjugate gaze (lateral deviation of both eyes away from the lesion) during forced eyelid closure can occur in patients with large, deep parietotemporal lesions; eye movements are otherwise normal except for ipsilateral saccadic pursuit. Psychogenic ocular deviation can occur in patients feigning unconsciousness; the eyes are directed toward the ground irrespective of which way the patient is turned. Ocular motor apraxia Ocular motor apraxia (OMA) is the inability to perform voluntary eye movements, including saccades and smooth pursuit, while spontaneous saccades and reflexive eye movements (vestibular and OKN fast and slow phases) are preserved. Individuals with OMA often utilize head thrusting or blinking behaviors to initiate eye movements. OMA represents a type of supranuclear gaze palsy that can be congenital or acquired and that is distinct etiologically, mechanistically, and on examination from brainstem supranuclear saccadic gaze palsies. Acquired forms generally localize to either bifrontal or biparietal lesions and occur with illness such as posterior cortical atrophy, corticobasal degeneration, and others (see Table 18.3). OMA is a component of the triad of the Balint syndrome, which also includes simultanagnosia (ability to see components of a visual scene but not the cohesive scene) and optic ataxia (impaired visually guided limb movements). Spasm of fixation, a term introduced by Gordon Holmes in 1930, describes patients who have difficulty shifting visual attention because of impaired initiation of voluntary saccades when looking at a fixation target but are capable of normal initiation of saccades in the absence of such a target or when it is removed. Their saccades have a prolonged latency and may be hypometric in the presence of a central visual target; however, blinks or combined eye and head movements may sometimes facilitate normal saccades. Holmes stressed that fixation was an active process and attributed spasm of fixation to “exaggerated” fixation; evidence from other studies supports this concept. The lesions that cause spasm of fixation may be bihemispheric and interrupt indirect FEF projections via the caudate nucleus and substantia nigra reticularis to the superior colliculus. Normally, during saccades to auditory, visual, and remembered targets, neurons in the FEFs discharge via these pathways and disinhibit the superior colliculus to allow the saccades and disengage fixation. Interruption of these and perhaps other pathways might contribute to spasm of fixation by maintaining tonic inhibitory suppression of saccades by the SC (Leigh and Zee, 2015). Congenital ocular motor apraxia is more common in boys than in girls and is characterized by impaired voluntary horizontal pursuit and

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saccadic movements but preservation of vertical eye movements; reflex saccades may be retained partly. Because random eye movements also are absent in many of these children, the term apraxia is strictly incorrect; congenital saccadic palsy or congenital gaze palsy is more accurate, but the term COMA is now established in the literature. By 4 to 8 months of age, the child develops a thrusting head movement strategy, often with prominent blinking, to overcome the eye movement deficit. Because the VOR prevents a change in direction of gaze on head turning, the child closes the eyes to reduce the degree of reflex eye movement (the gain of the VOR falls with the eyes closed) while thrusting the head beyond the range of the VOR arc to bring the eyes in line with the target. Then, with the eyes open, the child slowly straightens the head while the contralateral VOR maintains fixation. Some patients may use dynamic head thrusts to facilitate saccadic eye movements or reflexively to induce fast phases of vestibular nystagmus. Because children with COMA cannot easily refixate or pursue new targets, particularly in the first 6 months of life, before they develop the head-thrusting strategy, they are sometimes misdiagnosed as being blind. After 6 months of age, children with COMA present because of the head thrusts. The diagnosis of COMA can be confirmed by demonstrating the inability to make saccades; this is most easily done by spinning the infant. In normal infants, the eyes tonically deviate in the same direction as head movement; persistent absence of reflex saccades (fast phases in the opposite direction) after 2 to 3 weeks of age is abnormal and indicates saccadic palsy. As children with COMA reach school age, pursuit and voluntary saccades improve variably. However, the condition does not resolve completely and can be detected in adulthood. COMA may be associated with structural abnormalities (Box 18.11) and occasionally strabismus, psychomotor developmental delay (particularly reading and expressive language ability), clumsiness, and gait disturbances. COMA may be familial. Congenital vertical ocular motor apraxia is rare and must be differentiated from metabolic and degenerative disorders that cause progressive neurological dysfunction (e.g., neurovisceral lipidosis) and from stable disorders such as birth injury, perinatal hypoxia, and Leber congenital amaurosis. Early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH), an autosomal recessive disorder described in Japanese families, presents in childhood and is associated with progressive ataxia with marked cerebellar atrophy on imaging, horizontal and vertical OMA, a peripheral neuropathy with early areflexia and late distal wasting and weakness, and hypoalbuminemia. Some patients have foot deformities, kyphoscoliosis, choreiform movements, facial grimacing, and exaggerated blinking (perhaps to initiate saccades). When the condition is advanced, external ophthalmoplegia can mask the saccadic failure. This disorder is associated with hypercholesterolemia and mimics Friedreich ataxia; patients with EAOH have OMA, chorea, and intention tremor but not extensor plantar responses or cardiomyopathy. Leg edema correlates with the degree of albumen; the pseudohypercholesterolemia resolves with replacement of albumen. EAOH is likely a variant of autosomal recessive ataxia with ocular motor apraxia (AOA), described next. Both disorders have missense mutations in the aprataxin (APTX) gene. Ataxia with ocular motor apraxia, an autosomal recessive disorder described in Portuguese families, presents in early childhood and is associated with cerebellar ataxia, horizontal and vertical OMA, and very early areflexia that later progresses to a full-blown axonal neuropathy. Some patients have pes cavus, scoliosis, dystonia, and optic atrophy. In advanced cases, external ophthalmoplegia can mask the saccadic failure, as in EAOH. AOA resembles ataxia telangiectasia but without the telangiectasia, developmental delay, and immune dysfunction. It is very similar to ataxia with ocular motor apraxia type 1 (AOA1) syndrome.

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Disorders Associated with Ocular Motor Apraxia

BOX 18.11

Aicardi syndrome Aplasia or hypoplasia of the corpus callosum Aplasia or hypoplasia of the cerebellar vermis (up to 53% of patients) Ataxia with “ocular motor” apraxia type I syndrome Ataxia telangiectasia Autosomal recessive AOA associated with axonal peripheral neuropathy, areflexia, and pes cavus (may be the same as EOAH) Bardet-Biedl syndrome Bilateral cerebral cortical lesions Birth injuries (see perinatal/postnatal disorders) Carbohydrate-deficient glycoprotein syndrome type Ia Carotid fibromuscular hypoplasia Cockayne syndrome COMA (occasionally may be familial) Congenital vertical ocular motor apraxia (rare) Cornelia de Lange syndrome Dandy-Walker malformation EOAH (may be the same disorder as AOA) GM1 gangliosidosis Hydrocephalus Infantile Gaucher disease Infantile Refsum disease Joubert syndrome Krabbe leukodystrophy Leber congenital amaurosis Megalocephaly Microcephaly Microphthalmos Neurovisceral lipidosis (e.g., Niemann-Pick type C) Occipital porencephalic cysts Pelizaeus-Merzbacher disease Perinatal and postnatal disorders (hypoxia, meningitis, PV leukomalacia, athetoid cerebral palsy, perinatal septicemia and anemia, herpes encephalitis, epilepsy) Propionic acidemia Succinic semialdehyde dehydrogenase deficiency Wieacker syndrome AOA, Ataxia with ocular motor apraxia; COMA, congenital ocular motor apraxia; EOAH, early-onset ataxia with ocular motor apraxia and hypoalbuminemia; PV, periventricular.

Ataxia with ocular motor apraxia type 1, a late-onset autosomal recessive neurodegenerative form with progressive ataxia and peripheral neuropathy, can mimic ataxia telangiectasia but without the extraneurological features (Criscuolo et al., 2004). It is associated with mutations of the APTX gene. Ataxia with ocular apraxia type 2 (AOA2), a juvenile-onset autosomal recessive disorder, is a slowly progressive cerebellar ataxia characterized by cerebellar atrophy and a sensorimotor neuropathy. Almost all patients have elevated serum alpha-fetoprotein levels, but OMA is observed in only 47% of patients (Asaka et al., 2006). Thus the disease name, AOA2, could be misleading. The responsible gene (SETX) maps to chromosome 9q34.

Treatment of Diplopia Patching (occlusive) therapy is used to eliminate one image, mainly during the acute phase of diplopia. In children younger than age 6, each eye should be patched alternately to prevent developmental amblyopia. Such young patients should be under the care of an

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experienced ophthalmologist, with regular follow-up evaluations. Adults may wear the patch over whichever eye is more comfortable, although some clinicians feel that alternating the patch reduces the incidence of contractures. An excellent method of patching utilizes spectacles. If the patient does not wear glasses, an inexpensive pair of plano (nonprescription plain lenses) glasses or sunglasses can be used. Options include clip-on occluders that can be switched from lens to lens or placement of frosted plastic tape on one lens. The use of tape also allows the option of partial occlusion, which can be very useful in selected cases. For example, if fusion can be obtained at distance but diplopia occurs with reading, occlusion of the lower portion of a bifocal lens often works well. Prisms are helpful in eliminating double vision if the deviation is not too great. A reasonable range of binocular single vision may be achieved with prisms provided that the individual’s expectations are not too high and there is no significant cyclodeviation. Botulinum toxin injections into selected eye muscles is used with mixed success in patients with both comitant and incomitant strabismus. It may be helpful in patients with acute abducens palsies, particularly if they are bilateral and traumatic in origin. This treatment should be performed only by an ophthalmologist experienced in orbital injections. The main drawbacks are the variability and transience of effect and complications. The most common untoward effects are ptosis, dry-eye problems, and worsening diplopia. As a rule, the beneficial effects wear off in 3 to 4 months. Extraocular muscle surgery can correct long-standing strabismus (comitant or noncomitant). Generally a period of at least 6 months of stable ocular alignment measures is required for consideration of surgery. Finally, orthoptic exercises are of use in patients with convergence insufficiency.

DISORDERS OF EYE MOVEMENTS—ABNORMAL SPONTANEOUS MOVEMENTS AND OSCILLATIONS Approach to History and Examination The main forms of abnormal spontaneous eye movements include nystagmus, which may be congenital or acquired, and saccadic intrusions. Often, congenital nystagmus is asymptomatic and rarely causes oscillopsia (a subjective sense of visual motion). The physician should determine whether the nystagmus was present since birth or is acquired and whether there is a family history or a history of amblyopia or lazy eye. A list of current medications should be reviewed. For any spontaneous abnormal eye movement, the presence or absence of visual impairment (i.e., reduced visual quality, blurred vision, oscillopsia) should be queried and symptoms such as headache, diplopia, vertigo, or other neurological abnormalities must be taken into account. Examination should include assessment of visual acuity, confrontation visual fields, ocular motility, pupillary reflexes, observation for ocular albinism, and ophthalmoscopy. Ophthalmoscopy may be used to detect subtle nystagmus not apparent to the naked eye. Clinical features that must be determined are listed in Box 18.12.

Examine All Classes of Eye Movements Fixation and stability of gaze holding should be checked. This is done by having the individual look at a target and observing for spontaneous eye movements such as drift, microtremor, nystagmus, opsoclonus, ocular myokymia, ocular myoclonus, or saccadic intrusions. If spontaneous primary-position nystagmus is present, the effects of changes in the direction of gaze and convergence on the nystagmus should be determined. Pursuit movements provide an opportunity to

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Clinical Features to Look for in Patients with Nystagmus

Causes of Monocular Oscillopsia and/or Nystagmus

BOX 18.12

BOX 18.13

Are there signs of ocular albinism? Is there a spontaneous head tilt or turn? Is the nystagmus present in primary position or only with eccentric gaze (gaze-evoked nystagmus)? Is the nystagmus binocular and conjugate or is it dissociated? Is the waveform pendular or jerk? If jerk, what is the direction of the fast phase? Is there a latent component (i.e., an increase in nystagmus intensity when one eye is covered)? Is there a torsional component? Is there spontaneous alteration of direction, as with periodic alternating nystagmus? This entity, for which recognition requires observation over time, must be distinguished from rebound nystagmus. Is there a null zone (a direction of gaze in which the nystagmus is minimal or absent)? Determine whether convergence damps the nystagmus or changes its direction. Is the nystagmus altered (accentuated or suppressed) by head positioning or posture or by head shaking (as in spasmus nutans)? Do the following provocative maneuvers—elimination of visual fixation, supine positioning, head shaking, hyperventilation, mastoid vibration— unmask or modify the appearance of nystagmus? What is the effect of optokinetic stimulation? In infantile nystagmus syndrome, the response is paradoxical—that is, the fast phase is in the direction of the slow-moving target. Are there associated rhythmic movements of other muscle groups (e.g., face, tongue, ears, neck, palate [as in oculopalatal myoclonus/tremor], limbs)?

Acquired monocular blindness (nystagmus in blind eye) Alternating hemiplegia of childhood Amblyopia Brainstem infarction (thalamus and upper midbrain) Ictal nystagmus Internuclear and pseudointernuclear ophthalmoplegia Multiple sclerosis Nystagmus with monocular ophthalmoplegia Nystagmus with one eye absent Pseudonystagmus (lid fasciculations) Spasmus nutans Superior oblique myokymia

helpful with congenital nystagmus, wherein the fast phase may be absent or the direction paradoxical—that is, in the direction of the slowly moving tape or drum.

Clinical Disorders Nystagmus

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observe for gaze-evoked nystagmus (GEN). Gaze shifts with saccades offer an opportunity to determine if saccadic intrusions are provoked by these movements. Changes in the amplitude, frequency, or even direction of nystagmus may be elicited by convergence and may have diagnostic and therapeutic implications. OKN testing is particularly

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Nystagmus is an involuntary biphasic rhythmic ocular oscillation in which one or both phases are slow (Fig. 18.26). The slow phase of nystagmus is the pathological component responsible for the initiation and generation of the nystagmus. With pendular nystagmus, only back-to-back slow phases are present, whereas with jerk forms of nystagmus, the fast (saccadic) phase is a corrective movement bringing the fovea back toward the target. Often, nystagmus interferes with vision by blurring the object of regard (poor foveation), or making the environment appear to oscillate (oscillopsia), or both. For clinical purposes, nystagmus may be divided into pendular and jerk forms. Nystagmus may result from dysfunction of the vestibular end organ, vestibular nerve, brainstem, cerebellum, or cerebral centers for ocular pursuit. Pendular nystagmus (see Fig. 18.26, A) is central (brainstem or cerebellum) in origin, whereas jerk nystagmus may be either central or peripheral. Either form may have horizontal, vertical, or torsional components. Disconjugate (dissociated) nystagmus occurs when the ocular oscillations are out of phase (in different directions) in each eye. It is seen with brainstem lesions (see following discussion of pendular vergence nystagmus), and spasmus nutans. Monocular nystagmus is also disconjugate and may be associated with amblyopia and other forms of vision loss (Box 18.13). Jerk nystagmus is named conventionally by the direction of the fast phase and is divided into three types (increasing, decreasing, or linear velocity) on the basis of the shape of the slow-phase tracing on oculographic recordings (see Fig. 18.26). Jerk nystagmus with a linear (constant velocity) slow phase (see Fig. 18.26, B) is caused by vestibular dysfunction, either peripheral or central, resulting in an imbalance in vestibular input to the brainstem gaze centers. When the slow phase has a decreasing velocity exponential (see Fig. 18.26, C), the brainstem NI that holds the eyes in eccentric gaze positions is at fault and is said to be “leaky.” The integrator is unable to maintain a constant output to the gaze center to hold the eyes in an eccentric position, resulting in gaze-paretic nystagmus. An increasing velocity exponential slow phase (see Fig. 18.26, D) is central in origin and is the usual form of congenital nystagmus (now termed infantile nystagmus syndrome [INS]), although it is not pathognomonic, as it is also reported in forms of acquired nystagmus (Bakaeva et al., 2018; Zee et al., 1980).

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Localizing Value of Nystagmus Syndromes and Nonnystagmus Ocular Oscillations

TABLE 18.4

Nystagmus Syndrome

Localization

Downbeat nystagmus

Bilateral cervicomedullary junction (flocculus) Floor of the fourth ventricle Cervicomedullary junction (nodulus) Bilateral pontomesencephalic junction Bilateral pontomedullary junction Cerebellar vermis Medial medulla, syringomyelia, syringobulbia, tobacco inhalation Paramedian pons Deep cerebellar (fastigial) nuclei Mesodiencephalic junction, chiasm, disorders that disrupt central vision Unilateral mesodiencephalic lesions: upper poles of the eyes jerk toward side of the lesion, and vertical component is always disjunctive (eyes oscillate in opposite directions, with the intorting eye rising and the extorting eye falling) Lateral medullary lesions: upper poles of the eyes jerk away from the side of lesion; but the vertical component may be either conjugate, usually upward, or disjunctive Middle cerebellar peduncle Cerebellum Cerebellopontine angle, AICA territory stroke Central vestibular system Medulla

Periodic alternating nystagmus (PAN) Alternating windmill nystagmus (a variant of PAN) Upbeat nystagmus Bow-tie nystagmus (a variant of upbeat nystagmus) Pendular nystagmus Seesaw nystagmus (SSN): Hemi-jerk SSN

Alternating hemi-SSN with direction of vertical pursuit Rebound nystagmus Bruns nystagmus Torsional nystagmus, jerk Torsional nystagmus, pendular Atypical infantile nystagmus syndrome: Asymmetric horizontal Vertical (pendular, downbeat, or upbeat) Nonnystagmus Ocular Oscillations Convergence-retraction “nystagmus” Opsoclonus Ocular flutter Ocular dysmetria Ocular myoclonus (oculopalatal) Ocular bobbing Square-wave jerks Square-wave pulses

Ocular albinism Retina: congenital cone dysfunction, congenital stationary night blindness Localization Dorsal midbrain Cerebellar fastigial nuclei or brainstem Deep cerebellum nuclei or brainstem Cerebellum (dorsal vermis and fastigial nuclei) Guillain-Mollaret triangle (central tegmental tract in the pons) Pons Superior colliculus or its inputs, cerebellum Cerebellar outflow tracts (may be associated with rubral tremor)

AICA, Anteroinferior cerebellar artery.

A helpful approach in understanding the various mechanisms of nystagmus is to consider the mechanisms by which a visual target is maintained on the fovea: (1) stabilization of fixation, including via visual feedback mechanisms by which the visual system suppresses unwanted saccades and detects retinal drifts followed by programming of corrective eye movements; (2) VORs, by which eye position is maintained despite small head and body movements; and (3) NIs, which largely serve to maintain the eyes in a desired eccentric gaze position by counteracting the elastic pull of orbital tissues that draws the eyes back toward the center (Leigh and Zee, 2015). Table 18.4 summarizes the localizing value of nystagmus syndromes and nonnystagmus ocular oscillations.

Acquired Nystagmus.

Impaired fixational mechanisms. Nystagmus in blindness. Large-amplitude (“searching”) pendular nystagmus is usually associated with poor vision because of afferent disorders such as optic neuropathy, which can be unilateral, and retinal disorders. Pendular waveforms are common with optic nerve causes of vision loss, whereas jerk nystagmus is more often seen with retinal causes of vision loss. The Heimann-Bielschowsky phenomenon is a rare form of monocular vertical or occasionally oblique pendular oscillation, with a frequency of 1 to 5 Hz, that occurs

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in an amblyopic eye or after acquired monocular vision loss, as with cataract (Nguyen and Borruat, 2019). In the latter situation, it may be reversible after successful treatment of the underlying condition or with gabapentin (Rahman et al., 2006). Monocular nystagmus may be pendular or jerk and may be horizontal, vertical, or oblique. Oculographic recordings may reveal small-amplitude oscillations in the fellow eye. Monocular nystagmus may occur with amblyopia, blindness, and in several other conditions (see Box 18.13). Superior oblique myokymia (SOM) may be mistaken for a monocular torsional or vertical nystagmus. Acquired pendular nystagmus. Acquired pendular nystagmus (APN) may have horizontal, vertical, and torsional components, although one is usually dominant. The most common cause of APN is multiple sclerosis (MS), followed by brainstem vascular disease. Other disorders of myelin—including Cockayne syndrome, PelizaeusMerzbacher disease, peroxisomal disorders, disorders associated with toluene abuse, as well as spinocerebellar disease, hypoxic encephalopathy, and Whipple disease—can cause pendular nystagmus. Pendular nystagmus likely results from disruption of normal feedback from cerebellar nuclei to the NIs (Das et al., 2000). This is in keeping with the predominance of paramedian pontine lesions on MRI in patients with horizontal pendular nystagmus and with the

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predominance of medullary lesions in those with torsional pendular nystagmus (Lopez et al., 1996). The rhythmic pendular oscillations may be the result of deafferentation of the inferior olive by lesions involving the central tegmental tracts, medial vestibular nuclei, or paramedian tracts, causing instability in the system. Disruption of prenuclear ocular motor pathways necessary for orthotropia (and conjugacy) may be a factor as well. A similar mechanism may be responsible for oculopalatal myoclonus (discussed later in this section). In demyelinating diseases, APN most often is horizontal and/or elliptical in trajectory, with a frequency of 3 to 5 Hz (Gresty et al., 1982). MS patients frequently have optic neuropathy that usually is worse in the eye with the larger oscillations. The oscillations of each eye may be so different that the nystagmus may appear monocular clinically (Leigh and Zee, 2015). Elliptical APN with a larger vertical component and superimposed or interposed upbeat nystagmus is characteristic of Pelizaeus-Merzbacher disease. This nystagmus can be difficult to discern with the naked eye. It is seen more easily with an ophthalmoscope, but oculography using scleral search coils may be necessary to detect it. Oculopalatal myoclonus (Video 18.7), also called oculopalatal tremor, is a pure vertical or vertical-torsional pendular oscillation with a frequency of 1 to 3 Hz, usually associated with similar oscillations of the soft palate (palatal tremor) and sometimes other muscles of branchial origin. The classic presentation is delayed development of the nystagmus and palatal tremor, often with one beginning prior to the other, that occurs weeks or months after brainstem infarction or hemorrhage of a brainstem cavernoma. Typically the location of the original insult is the pons, involving the central tegmental tract. Following a latency of months, hypertrophic degeneration of the inferior olives, which can be seen on MRI as increased T2 signal, ensues and the oculopalatal tremor begins. Dissociated nystagmus is predictive of unilateral inferior olivary changes on MRI, with the MRI changes being on the side of the eye with larger-amplitude oscillations (Kim, et al., 2007). The association of a facial nerve palsy with the one-and-a-half syndrome may predict the development of oculopalatal myoclonus, probably because of the proximity of the central tegmental tract to the facial nerve. Also, oculopalatal myoclonus can have an insidious onset in the absence of an original vascular insult in association with progressive ataxia, a condition called progressive ataxia with palatal tremor (PAPT) (Samuel et al., 2004). Cyclovergent nystagmus (i.e., disconjugate TN in which the upper poles of the eyes oscillate in opposite directions) was detected by scleral search coil oculography in a patient with progressive ataxia and palatal myoclonus. On rare occasions, cyclovergent nystagmus may be observed clinically. PAPT is attributed to superficial siderosis, adult-onset Alexander disease, and mitochondrial disease (Nicastro et al., 2016). Dysfunction of the cerebellar nuclei or their connections (GuillainMollaret triangle) and disruption of retinal error signals relayed to the inferior olive may be responsible for oculopalatal myoclonus, which is confined to the muscles of branchial origin. The current hypothesis relates to the development of new soma-to-soma electrical coupling via gap junctions (connexins) in inferior olivary neurons that in a healthy normal state fire only dysychronously via dendrite-to-dendrite connections (Shaikh et al., 2010, 2017). Pendular vergence nystagmus, previously called convergent-divergent nystagmus, a very rare variant of APN, is disconjugate and occurs in patients with MS, brainstem stroke, Chiari malformations, cerebral Whipple disease as oculomasticatory myorhythmia (OMM), occasionally oculopalatal myoclonus, and pseudo-Whipple disease (anti-Ma2– associated encephalitis). OMM, to date, is pathognomonic of Whipple disease. It consists of continuous rhythmic jaw contractions

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synchronous with dissociated pendular vergence oscillations present in primary position. It may be associated with supranuclear vertical gaze palsy, altered mentation, somnolence, mild uveitis, or retinopathy. With pendular vergence nystagmus, the eyes oscillate, mainly horizontally, in opposite directions simultaneously, although they sometimes form circular, elliptical, or oblique trajectories, depending on the phase relationship of the horizontal, vertical, and torsional vectors responsible for the oscillations. Convergence-evoked nystagmus is an unusual ocular oscillation that is usually pendular and is induced by voluntary convergence. The movements may be conjugate or dissociated. This condition may be congenital or acquired, as in patients with MS. A jerk form occurs with Chiari type I malformations. Convergence-evoked vertical nystagmus (upbeat more common than downbeat) also occurs. Convergenceevoked nystagmus should be distinguished from voluntary nystagmus and from convergence retraction nystagmus (see later section titled “Saccadic Intrusions” for the former and, earlier, “Dorsal midbrain syndrome” for the latter). See-saw nystagmus (SSN) is a spectacular ocular oscillation in which one eye rises and intorts as the other eye falls and extorts. The waveform is pendular (see later section titled “Vestibular nystagmus” for discussion of a jerk form of see-saw). The oscillations usually become faster and smaller on upgaze but slower and larger on downgaze; they may cease in darkness. Disordered control of the normal ocular counter-rolling reflex may be responsible. Bitemporal hemianopia, caused by acquired chiasmal defects or impaired central vision, plays a significant role in generating SSN. Disruption of retinal error signals necessary for VOR adaptation, normally conveyed to the inferior olive by the chiasmal crossing fibers, results in an unstable visuovestibular environment. Fixation and pursuit feedback accentuate this instability, causing synchronous oscillations of floccular Purkinje cells, which relay to the nodulus, resulting in SSN. This mechanism also may be the basis for the ocular oscillations of oculopalatal myoclonus. The observations of SSN and INS in achiasmatic humans and achiasmatic Belgian sheepdogs support this hypothesis (Dell’Osso and Daroff, 1998). Significantly, the onset of both SSN and oculopalatal myoclonus may be delayed after CNS lesions. SSN occurs with lesions in the region of the mesodiencephalic junction, particularly the zona incerta and the INC. Congenital SSN may be associated with a superimposed horizontal pendular nystagmus; some patients with congenital SSN may be achiasmatic or have septo-optic dysplasia. Reverse congenital SSN is a rare condition in which the rising eye extorts as the falling eye intorts. Acquired SSN may be associated with suprasellar tumors, Joubert syndrome, and Leigh disease (particularly the jerk form described further on in the section “Vestibular nystagmus”). Acquired pendular SSN may be accompanied by a bitemporal hemianopia from trauma, an expanding lesion in the third ventricular region, or severe loss of central vision due to disorders such as choroiditis, cone-rod dystrophy, whole-brain radiation, intrathecal methotrexate, and vitreous hemorrhage. Transient (latent) SSN may occur for a few seconds after a blink, perhaps because of loss of fixation, in patients with chiasmal region lesions. If SSN damps with convergence, base-out prisms may be helpful. Baclofen also may be beneficial in SSN. APN is severely disabling due to the incessant to-and-fro foveal drift it creates, which is typically accompanied by constant oscillopsia. APN in demyelinating disease tends to respond fairly well to treatment with gabapentin or memantine (Thurtell et al., 2010) (Table 18.5), though APN with oculopalatal myoclonus often is refractory to treatment. Clonazepam and valproic acid may also be helpful, as can chronically patching the eye with larger oscillations if they are dissociated. Palatal

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TABLE 18.5

Nystagmus Syndrome

Treatment

Infantile nystagmus syndrome

Prisms Contact lenses Extraocular muscle surgery Kestenbaum-Anderson procedure Tenotomy and reattachment procedure (experimental) Acetazolamide 250–1000 mg bid (Thurtell et al., 2010a) Brinzolamide 1% eye drops, 1 drop OU bid (Aygit et al., 2018; Dell’osso et al., 2011; Hertle et al., 2015) Memantine (Sherry et al., 2006) Gabapentin 300–600 mg qid (Sherry et al., 2006) Gene therapy (experimental) when the nystagmus is associated with retinal disorders (Leigh and Zee, 2015) Trihexyphenidyl 5–20 mg tid, benztropine, clonazepam 0.5–1 mg bid, gabapentin 300 mg qid, isoniazid, memantine 10 mg qid† (Starck et al., 2010; Thurtell et al., 2010b), valproate, diethylpropion hydrochloride, tenotomy followed by memantine, hand held muscle massager (vibrator) held to the head (Beh et al., 2014) Base-in prisms Base-out prisms (if nystagmus damps with convergence) Base-down prisms over both eyes if intensity of nystagmus diminishes in upgaze Contact lenses (personal observation) Extraocular muscle surgery realignment (Donahue, personal communication, and observation) Baclofen 5 mg tid, chlorzoxazone 500 mg tid (Feil et al., 2013), betahistine, clonazepam 0.5–1 mg bid, gabapentin, scopolamine, 4-AMP 5–10 mg tid (dalfampridine, the sustained-release form of 4-AMP at 10 mg bid may be more effective than 4-AMP [Claassen et al., 2013]), 3,4-diaminopyridine 10–20 mg bid Brinzolamide 1% eye drops, 1 drop OU bid (personal observation)

Acquired pendular nystagmus

Convergence-evoked horizontal Downbeat nystagmus

Periodic alternating nystagmus: Congenital Acquired Upbeat nystagmus Oculopalatal myoclonus

Seesaw nystagmus (SSN) Hemi-SSN Ictal nystagmus Episodic nystagmus: Episodic ataxia-1 Episodic ataxia-2 Oculomasticatory myorhythmia Torsional nystagmus Nonnystagmus Ocular Oscillations Opsoclonus Superior oblique myokymia Ocular neuromyotonia Microflutter Square-wave jerks and square-wave oscillations

Dextroamphetamine, baclofen 5–10 mg tid (occasionally), 5-HT Baclofen 5–10 mg tid, phenytoin, memantine 5–10 mg qid Base-up prisms over both eyes if intensity of nystagmus diminishes in downgaze Baclofen 5–10 mg tid, gabapentin, 4-AMP 5–10 mg tid-qid, memantine 10 mg qid (Thurtell et al., 2010b), thiamine Chronically patch one eye Baclofen, carbamazepine, cerulein, clonazepam, gabapentin 300 mg qid, memantine 10 mg qid, scopolamine, trihexyphenidyl 5–20 mg tid, valproate Baclofen, clonazepam 0.5–1 mg bid, gabapentin, memantine 10 mg qid (Huppert et al., 2011), base-out prisms Memantine (Thurtell et al., 2010b) AEDs Acetazolamide 125–1000 mg bid Acetazolamide 125–1000 mg bid, 4-AMP 5–10 mg tid, dalfampridine 10 mg bid Antibiotics for Whipple disease; consider gabapentin or memantine Gabapentin 300 mg qid, memantine (Thurtell et al., 2010b) Treatment Treat underlying condition when possible, ACTH, thiamine, clonazepam, gabapentin, ondansetron, steroids; if paraneoplastic, protein A immunoabsorption Carbamazepine, gabapentin, oxcarbazepine, other AEDs, topical beta-blockers, memantine, base-down prism over the affected eye, muscle/tendon surgery, microvascular decompression Carbamazepine, oxcarbazepine (Whitted and Lavin, personal observation) Propranolol, verapamil Valproate, amphetamines, barbiturates, diazepam, clonazepam, memantine (Rosini et al., 2013; Serra et al., 2008)

*Treat underlying cause when possible. †Memantine is reported to exacerbate multiple sclerosis (Villoslada et al., 2009). ACTH, Adrenocorticotropic hormone; AEDs, antiepileptic drugs; 4-AMP, 4-aminopyridine; 5-HT, 5-hydroxytryptamine.

tremor may respond to botulinum injections. Palatal tremor should be distinguished from pulsations of the uvula that are synchronous with the systolic pulse (Muller sign) in patients with aortic regurgitation (Williams and Steinberg, 2006). Vestibular nystagmus. Vestibular nystagmus results from damage to the labyrinth, vestibular nerve, vestibular nuclei, or their

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connections in the brainstem or cerebellum. Vestibular nystagmus may be divided into central and peripheral forms based on the associated features outlined in Chapter 22. Vestibular nystagmus is jerk nystagmus that tends to follow Alexander’s law, with increasing amplitude and frequency in the direction of the fast phases of the nystagmus.

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Causes of Downbeat

BOX 18.14

Nystagmus

Congenital (rare) Transiently in normal neonates Idiopathic (common) Craniocervical junction abnormalities: Basilar invagination (e.g., Paget disease) Chiari malformations Dolichoectasia of the vertebrobasilar arterial system Foramen magnum tumors Syringobulbia Cerebellar disorders: Alcoholic cerebellar degeneration (chronic usage) Anoxic cerebellar degeneration Anti–glutamic acid decarboxylase antibodies (anti-GAD65 antibodies) Cerebellar degeneration following human T-lymphotropic virus types I and II Episodic ataxia Familial spinocerebellar degeneration, particularly SCA-6, and with multiple system atrophy Heat stroke–induced cerebellar degeneration Paraneoplastic cerebellar degeneration Metabolic disorders (drugs, toxins, and deficiencies): Alcohol intoxication Amiodarone Anticonvulsants Lithium Magnesium depletion Opioids Toluene abuse Vitamin B12 deficiency Wernicke encephalopathy (as a chronic, persistent late-stage finding) Other: Benign paroxysmal positional vertigo: positional downbeat nystagmus with an anterior canal lesion Brainstem encephalitis Cardiogenic vertigo Cephalic tetanus Finger extensor weakness and downbeat nystagmus motor neuron disease (FEWDON-MND) Hydrocephalus Leukodystrophy Multiple sclerosis Small-amplitude downbeat nystagmus in carriers of blue-cone monochromatism Syncope Vertebrobasilar ischemia

Peripheral vestibular nystagmus. Peripheral vestibular nystagmus (see Chapter 22), caused by dysfunction of the vestibular end organ or nerve, has a linear slow phase (see Fig. 18.26, B), whereas with central lesions, the slow phase may be variable. Nystagmus in specific patterns induced by provocative maneuvers such as elimination of visual fixation, head shaking, hyperventilation, or supine positioning, often is the key to establishing a peripheral localization. Peripheral vestibular nystagmus is usually associated with vertigo, nausea, vomiting, perspiration, diarrhea, hearing loss, and tinnitus. These symptoms, as opposed to oscillopsia, are typically the reason the individual seeks medical attention. With central vestibular nystagmus, symptoms such as nausea are less severe, but other neurological features @

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may be present, such as headache, ataxia, diplopia, and pyramidal tract signs. Downbeat nystagmus (Video 18.8). Downbeat nystagmus is the most common form of acquired primary positional nystagmus; it is a spontaneous downward-beating jerk nystagmus (i.e., slow drifts of the eyes upward, followed by fast-resetting downward movements) present in primary position and is attributed to either (1) interruption of the posterior semicircular canal projections, which are responsible for the downward VOR, causing upward drift of the eyes with corrective downward saccades; (2) impaired cerebellar inhibition of the vestibular circuits for upward eye movements, resulting in uninhibited upward drifting of the eyes, with corrective downward saccades; or (3) dysfunction of pursuit pathways. The amplitude of the oscillations increases significantly when the eyes are deviated laterally and slightly downward (Daroff sign, “side-pocket” nystagmus), particularly when the oscillations are subtle in primary gaze. Downbeat nystagmus may be precipitated or worsened by horizontal or vertical head shaking or with changes in posture (positional downbeat nystagmus), particularly the head-hanging position (Choi et al., 2015), although the latter may also signify benign paroxysmal positional vertigo (Oh et al., 2019). Development of downbeat nystagmus after horizontal head shaking, called perverted nystagmus, is a definite sign of CNS disease and is suggested to be due to enhanced activity in central anterior semicircular canal pathways (Choi et al., 2016). Downbeat nystagmus results from either damage to the commissural fibers between the vestibular nuclei in the floor of the fourth ventricle or bilateral damage to the vestibulocerebellum (flocculus, paraflocculus, nodulus, and uvula) that disinhibits the VOR in pitch. Rarely it is due to a brainstem lesion, typically involving a group of neurons called the paramedian tracts (Nakamagoe et al., 2013). It frequently occurs with structural lesions at the craniocervical junction; MRI of the foramen magnum region (in the sagittal plane) is the imaging investigation of choice. A wide variety of other pathologies can also cause downbeat nystagmus, and a large percentage of cases are idiopathic (Box 18.14). In some cases of unexplained downbeat nystagmus, the cause is a radiographically occult infarction; however, lesions that cause downbeat nystagmus are bilateral. The treatment of downbeat nystagmus involves correction of the underlying cause when possible. When downbeat nystagmus damps on convergence, it may be treated successfully with baseout prisms, reducing the oscillopsia and improving visual acuity. Medications including clonazepam, chlorzoxazone, and 4-aminopyridine may help as well (see Table 18.5); 4-aminopyridine is more effective in downbeat nystagmus associated with cerebellar atrophy rather than structural lesions (Huppert et al., 2011), and the sustained-release form (dalfampyridine) may be more effective (Claassen et al., 2013). Upbeat nystagmus. Upbeat nystagmus is a spontaneous jerk nystagmus with the fast phase upward while the eyes are in primary position (Video 18.9). It is attributed to interruption of the anterior semicircular canal projections, which are responsible for the upward VOR, resulting in downward drift of the eyes with corrective upward saccades. The amplitude and intensity of the nystagmus usually increase on upgaze. This finding strongly suggests bilateral paramedian lesions of the brainstem, usually at the pontomedullary (or, less often pontomesencephalic) junction, affecting perihypoglossal nuclei in the lower medulla that project to the cerebellum. Upbeat nystagmus is most common with Wernicke encephalopathy (WE) and MS. Upbeat nystagmus that converts to downbeat nystagmus on examination may specifically suggest WE; conversion to a chronic persistent downbeat nystagmus may occur over time after resolution of the acute phase

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CHAPTER 18 Neuro-Ophthalmology: Ocular Motor System of WE (Kattah et al., 2018). Upbeat nystagmus may also be seen with intoxication from anticonvulsants, organophosphates, lithium, nicotine, or thallium (author’s personal observation, PL). Rarely, upbeat nystagmus may be congenital. In infants, upbeat nystagmus may be a sign of anterior visual pathway disease, such as Leber congenital amaurosis, optic nerve hypoplasia, aniridia, or cataracts. Small-amplitude upbeat nystagmus may be seen in individuals who are carriers of blue-cone monochromatism, whereas affected individuals may have intermittent pendular oblique nystagmus. If the intensity of upbeat nystagmus diminishes in downgaze, base-up prisms over both eyes may improve the oscillopsia. Medications such as memantine may also be helpful (see Table 18.5). A comprehensive list of causes of upbeat nystagmus can be found elsewhere (Leigh and Zee, 2015). A variant of upbeat nystagmus, so-called bow-tie nystagmus, is reported with posterior fossa medial medullary stroke (Choi et al., 2004) and is characterized by oblique upward fast phases alternating to the left or right because of the changing direction of each horizontal component (Leigh and Zee, 2015). Torsional and jerk see-saw nystagmus. In torsional nystagmus (TN), the eye oscillates in a pure rotary plane. TN may be present in primary position or with either head positioning or gaze deviation. It usually results from lesions in the central vestibular pathways. Pure TN occurs with central vestibular dysfunction only, whereas mixed torsional-horizontal nystagmus is common with peripheral vestibular disease. In patients with lesions of the middle cerebellar peduncle, TN with a jerk waveform—like jerk see-saw nystagmus—may be evoked by vertical pursuit eye movement and during fixation suppression of the vertical VOR. The direction of the fast phase changes with pursuit direction; it usually is toward the side of the lesion on downward pursuit and away from the side of the lesion on upward pursuit (FitzGibbon et al., 1996). When the waveform of TN is pendular (i.e., torsional pendular nystagmus), the lesion is usually in the medulla. Skew deviation frequently coexists with TN. Gabapentin may help (see Table 18.5). A jerk waveform hemi-SSN (see earlier section titled “Acquired pendular nystagmus” for pendular forms of SSN) occurs with unilateral mesodiencephalic lesions, presumably because of selective unilateral inactivation of the torsional eye-velocity integrator in the INC; during the fast (jerk) phases, the upper poles of the eyes rotate toward the side of the lesion. In hemi-jerk SSN caused by lateral medullary lesions, the fast phases jerk away from the side of the lesion. In both situations, the torsional component is always conjugate. With mesodiencephalic lesions, the vertical component is always disjunctive (the eyes oscillate in opposite directions, with the intorting eye rising and the extorting eye falling), but with medullary lesions it may be either conjugate (usually upward) or disjunctive. Other features of brainstem dysfunction may be necessary to localize the lesion. Periodic alternating nystagmus. PAN is a horizontal jerk nystagmus in which the fast phase beats in one direction and then damps or stops for a few seconds before changing direction to the opposite side; the cycle repeats every 30 to 180 seconds. During the short transition period, vertical nystagmus or square-wave jerks (SWJs) may occur. PAN localizes to the cerebellar nodulus and uvula. PAN may occur with any lesion affecting this location, including Chiari malformations, infarction, encephalitis, and Creutzfeldt-Jacob disease. When PAN is congenital, it may be associated with albinism. In one series of patients with congenital PAN, none had pure vertical oscillations, even during the transition period (Gradstein et al., 1997). Although not all patients with acquired PAN have vertical nystagmus during the transition period, its presence may distinguish acquired from congenital PAN (personal observation); this finding does not obviate further evaluation when appropriate. Transient episodes of

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PAN were provoked by attacks of Meniere disease in a patient with a hypoplastic cerebellum and an enlarged cisterna magna (Chiu and Hain, 2002). Episodic PAN can be a manifestation of a seizure (see later discussion of eye movements in seizure and coma). A variant of PAN called “alternating windmill nystagmus,” consisting of oscillations in both the horizontal and vertical planes, 90 degrees out of phase, occurred in a blind patient (Leigh and Zee, 2015). Lesions of the cerebellar nodulus cause loss of γ-aminobutyric acid (GABA)–mediated inhibition from the Purkinje cells to the vestibular nuclei, impairing the velocity storage mechanism. It is likely that overcompensation in feedback loops causes cyclical firing between reciprocally connected inhibitory neurons and generates the unusual oscillations of acquired PAN. Affected patients have hyperactive vestibular responses and poor vestibular fixation suppression, attributed to involvement of the nodulus and uvula (Leigh and Zee, 2015). Treatment of PAN should be directed at correcting the cause, such as a Chiari malformation, when possible. Baclofen, a GABAB agonist, replaces the missing inhibition and is usually effective in stopping the nystagmus completely in the acquired form and occasionally in the congenital form. Dextroamphetamine is a second option (see Table 18.5).

Nystagmus in eccentric gaze Gaze-evoked nystagmus. GEN may also be called directionchanging nystagmus or gaze-paretic nystagmus. GEN is an appropriate term to use when there is uncertainty as to whether the nystagmus is physiological or pathological. The term gaze-paretic nystagmus implies pathology. Gaze-paretic nystagmus, the most common type of nystagmus, is usually symmetrical and evoked by eccentric gaze to either side but is absent in the primary position (Video 18.10). Frequently it is present on eccentric vertical gaze, especially upward with upward-beating nystagmus on upgaze. It may be asymmetric with asymmetric CNS disease. With myasthenia, fatigue of gaze maintenance with drifts of the eyes toward primary position and resetting saccades may mimic the appearance of gaze-paretic nystagmus. The latter has a jerk waveform, with the fast phase in the direction of gaze (i.e., right beating in right gaze). Oculographic recordings show a decreasing exponential slow phase (see Fig. 18.26, C). Gaze-paretic nystagmus results from dysfunction of the NIs and is commonly caused by alcohol or drug intoxication as from anticonvulsants or tranquilizers. When it is caused by structural disease, it tends to be asymmetric. Bruns nystagmus occurs in patients with large cerebellopontine angle tumors. The nystagmus is bilateral but asymmetrical, with a jerk waveform. It is characterized by large-amplitude low-frequency fast phases on gaze toward the side of the lesion but small-amplitude high-frequency fast phases on gaze to the opposite side. The ipsilateral large-amplitude (coarse) nystagmus has an exponentially decreasing velocity slow phase attributed to compression of the brainstem NI, which includes the ipsilateral medial vestibular nucleus. The contralateral small-amplitude high-frequency nystagmus has a linear slow phase attributed to ipsilateral vestibular dysfunction (see Fig. 18.26). Occasionally a stroke in the territory of the anteroinferior cerebellar artery can cause Bruns nystagmus (personal observation). Physiological (endpoint) nystagmus is a jerk nystagmus observed on extreme lateral or, rarely, upward gaze. If the bridge of the nose obstructs the view of the adducting eye, it may be disconjugate because the amplitude is greater in the abducting eye. A torsional component is sometimes seen. Physiological nystagmus is distinguished from pathological nystagmus by its symmetry on right and left gaze and by the absence of other neurological features. It is not present when the angle of gaze is less than 30 degrees from primary position. Oculographic recordings demonstrate a linear slow phase (see Fig. 18.26, B) and may detect transient small-amplitude rebound nystagmus.

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Rebound nystagmus is a horizontal GEN in which the direction of the fast phase reverses with sustained lateral gaze or beats transiently in the opposite direction when the eyes return to primary position. The latter is occasionally a physiological finding. Rebound nystagmus is caused by dysfunction of the cerebellum or the perihypoglossal nuclei in the medulla. Occasionally rebound nystagmus may be torsional. Cerebellar dysfunction can cause a form of GEN in which the fast phase beats toward primary position (i.e., centripetally) and the slow phase drifts peripherally toward an eccentric target. Centripetal nystagmus is like rebound nystagmus and may result from overcompensation by the cerebellar nodulus and uvula to adjust for a directional bias by temporarily moving the null zone during eccentric gaze. Centripetal nystagmus in both the horizontal and vertical planes may be associated with Creutzfeldt-Jakob disease. Congenital Nystagmus. The three distinct nystagmus syndromes seen in infancy and childhood were renamed by the Classification of Eye Movement Abnormalities and Strabismus (CEMAS) Working Group, sponsored by the National Eye Institute (Hertle, National Eye Institute Sponsored Classification of Eye Movement Abnormalities and Strabismus Working Group, 2002). The first of these syndromes, previously known as congenital nystagmus, is now called infantile nystagmus syndrome; the second, fusion maldevelopment nystagmus syndrome (FMNS), includes the latent form and manifest latent nystagmus (MLN); and the third, spasmus nutans syndrome (SNS), remains unchanged. Infantile nystagmus syndrome (congenital). INS is usually present from birth but may not be noticed for the first few weeks or occasionally even years of life. It may be accompanied by severe visual impairment but is not the result of poor vision. Disorders that, through genetic association, are responsible for poor vision in patients with INS include those designated by the mnemonic of A’s— achiasma, achromatopsia, albinism (both ocular and oculocutaneous forms), amaurotic idiocy of Leber (Leber congenital amaurosis), aniridia, aplasia (usually hypoplasia) of the fovea, and aplasia (usually hypoplasia) of the optic nerve—and congenital cataracts and congenital stationary night blindness. Paradoxical pupil constriction in darkness, particularly in patients with poor vision, suggests an associated retinal or optic nerve disorder. High myopia (uncommon early in life) in infants with INS suggests congenital stationary night blindness, and high hyperopia suggests Leber congenital amaurosis; such retinal disorders can be confirmed by electroretinography. INS may be familial and is inherited in an autosomal recessive X-linked dominant or recessive pattern. Genetic defects identified in some families include a dominant form of INS linked to chromosomal region 6p12, an X-linked form of INS with incomplete penetrance among female carriers associated with a defect on the long arm of the X chromosome, a deletion in the OA1 gene (ocular albinism) in a family with X-linked INS associated with macular hypoplasia and ocular albinism, and three mutations in the OA1 gene in families with hereditary nystagmus and ocular albinism (Faugere et al., 2003). For a review of the molecular genetics of INS see Self and Lotery (2007). INS appears horizontal in most patients and may be either pendular or jerk in primary position. Pendular nystagmus often becomes jerk on lateral gaze. The horizontal oscillations may be accentuated during vertical tracking. Oculography with three-dimensional scleral search coils demonstrates that many patients with INS have a torsional component phase locked with the horizontal component. Individuals with INS often have good vision unless an associated afferent defect is present (see earlier discussion). In INS, the nystagmus damps with convergence; latent superimposition (an increase in nystagmus amplitude occurring when one eye is covered) may be present. A null zone wherein the nystagmus intensity is minimal may be found; if this zone

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is to one side, the affected individual turns the head to improve vision. Often the head “oscillates” as well. Both features—damping of nystagmus with convergence and a null zone—can be used in therapy by changing the direction of gaze with prisms or extraocular muscle surgery to improve head posture and visual acuity. Oculographic recordings usually demonstrate either a sinusoidal (see Fig. 18.26, A) or a slow phase with an increasing exponential waveform (see Fig. 18.26, D). However, in the first few months of life, the waveform of INS may be more variable, evolving into the more classic pattern as the child grows older. Outside the null zone, the nystagmus follows Alexander’s law and increases in intensity (amplitude × frequency) on lateral gaze. Thus patients with INS or FMNS may induce an esotropia intentionally to suppress the nystagmus in the adducting eye. This strategy is called the nystagmus blockage syndrome. Patients with INS do not experience oscillopsia (an illusory oscillation of the environment) unless a head injury, decompensated strabismus, or retinal degeneration causes a decline in vision, ocular motor function, or both. Prisms or strabismus surgery may correct such late-onset oscillopsia. Up to 50% of patients with INS have strabismus (Brodsky and Fray, 1997). Rarely in INS, the nystagmus is in the vertical plane, or circumductory where the eyes move conjugately in a circular or cycloid pattern. In patients with retinal disorders such as achromatopsia, albinism, congenital cone dysfunction, or congenital stationary night blindness, INS can have an asymmetrical horizontal or vertical waveform that varies among pendular, downbeat, and upbeat. Occasionally INS may be unilateral, occur later in the teens or adult life, or become symptomatic if changes in the internal or external environment alter foveation stability and duration, causing oscillopsia. Less common patterns of INS such as periodic alternating, upbeat, downbeat, and SSN are discussed later.

Fusional maldevelopment syndrome (FMNS) (latent). FMNS includes both LN and MLN. LN occurs with monocular fixation: that is, when one eye is covered. The slow phase is directed toward the covered eye. The amplitude of the oscillations increases on abduction of the fixating eye. With MLN, the oscillations are present with both eyes open, but only one eye is fixating; vision in the other is ignored or suppressed because of strabismus or amblyopia. The nystagmus waveform has a linear (decreasing velocity) slow phase (see Fig. 18.26, B), which differs from that of true INS. Some patients with LN can suppress it at will. The pathogenesis of LN may be related to impaired development of binocular vision mechanisms. Under monocular viewing conditions, rhesus monkeys deprived of binocular vision early in life have poor nasal-to-temporal optokinetic responses. The pretectal nucleus of the optic tract (NOT) is necessary for generation of slow-phase eye movements in response to horizontal full-field visual motion. In normal monkeys, the NOT on each side is driven binocularly and responds well to visual stimuli presented to either eye. In monkeys with LN, each NOT is driven mainly by the contralateral eye. Thus, in the altered monkeys, when only one eye is viewing, one optic tract nucleus is stimulated, causing an imbalance between each NOT. This imbalance is believed to be responsible for LN. Of interest, under monocular viewing conditions, patients with congenital esotropia have poor temporal-to-nasal pursuit, and some have LN or MLN. Indeed, in esotropic patients, LN may be unmasked in dim light or by shining a bright light at the dominant eye, as when pupil reflexes are being tested. Spasmus nutans syndrome. SNS is a transient high-frequency, low-amplitude pendular nystagmus with onset between the ages of 6 and 12 months that lasts approximately 2 years but occasionally can continue for as long as 5 years. The direction of the oscillations may be

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BOX 18.16 SWJs

MSWJs

MSO

SP

DSP 5 degrees 200 msec

Fig. 18.27 Simulated eye movement recordings of square-wave jerks (SWJs), macro–square wave jerks or square-wave pulses (MSWJs), macrosaccadic oscillations (MSOs), a saccadic pulse (SP), and a double saccadic pulse (DSP).

BOX 18.15

Oscillations

Saccadic Intrusions and

Square-wave jerks and square-wave oscillations Flutter (voluntary, involuntary) Flutter dysmetria Microsaccadic flutter (variant of voluntary flutter?) Opsoclonus Macro–square wave jerks (now designated square-wave pulses) Ocular bobbing, reverse and inverse bobbing, dipping, and reverse dipping Superior oblique myokymia Convergence-retraction nystagmus Abduction nystagmus with internuclear ophthalmoplegia Tic-like ocular myoclonic jerks (eye tics)

horizontal, vertical, or torsional; the oscillations are often disconjugate, asymmetrical (usually greater in the abducting eye if seen in lateral gaze), even monocular, and variable. SNS may be associated with torticollis and head titubation; these three features constitute the spasmus nutans triad. The titubation has a lower frequency than that of the nystagmus and thus is not compensatory. Patients can improve their vision by vigorously shaking the head, presumably to stimulate the VOR and suppress or override the ocular oscillations. Some patients may have esotropia. Clinically, spasmus nutans is distinguished from INS and FMNS by its intermittency, high frequency, vertical component, and dysconjugacy (Leigh and Zee, 2015). Although spasmus nutans is a benign and transient disorder, it must be distinguished from acquired nystagmus caused by structural lesions involving the anterior visual pathways in approximately 2% of patients. In the latter situation, a careful ophthalmological examination reveals abnormalities such as impaired vision, a relative afferent pupillary defect, or optic atrophy. Also, retinal disorders may masquerade as spasmus nutans; paradoxical pupil constriction in darkness

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Square-Wave Jerks

Normal subjects ( torsional Vertical, torsional Horizontal > torsional

VN, ischemia VN, ischemia VN, VP, ischemia

Labyrinth

AC, HC, PC, utricle, saccule

Horizontal > torsional

EH, labyrinthitis

Nystagmus, head-thrust test Nystagmus Nystagmus, head-thrust test, auditory findings Nystagmus, auditory findings

AC, Anterior canal; BPPV, benign paroxysmal positional vertigo; EH, endolymphatic hydrops; HC, horizontal canal; PC, posterior canal; SCD, superior canal dehiscence; VN, vestibular neuritis; VP, vestibular paroxysmia.

HISTORY OF PRESENT ILLNESS The history and physical examination provide the most important information when evaluating patients complaining of dizziness (Colledge et al., 1996; Lawson et al., 1999). Often, patients have difficulty describing the exact symptom experienced (Kerber, 2017), so the onus is on the clinician to elicit pertinent information. The first step is to define the symptom. No clinician should ever be satisfied to record the complaint simply as “dizziness.” For patients unable to provide a more detailed description of the symptom, the physician can ask the patient to place their symptom into one of the following categories: movement of the environment (vertigo), lightheadedness, or strictly imbalance without an abnormal head sensation. However, caution must be taken in placing too much emphasis on the type of dizziness because patient descriptions about dizziness can be unreliable, inconsistent, and overlap (NewmanToker et al., 2007; Kerber, 2017). Most dizziness patients report more than one type of dizziness, and specific types of dizziness symptoms have a stronger correlation with each other than they do with disease-based constructs (Kerber, 2017). Therefore other details about the symptom (e.g., timing, triggers) need to be considered as well. Table 22.2 displays the key distinguishing features of common causes of dizziness. One key point is that any type of dizziness may worsen with position changes, but some disorders such as BPPV only occur after position change.

PHYSICAL EXAMINATION General Medical Examination A brief general medical examination is important. Identifying orthostatic drops in blood pressure can be diagnostic in the correct clinical setting. Orthostatic hypotension is probably the most common general medical cause of dizziness among patients referred to neurologists. Identifying an irregular heart rhythm may also be pertinent. Other general examination measures to consider in individual patients include a visual assessment (adequate vision is important for balance) and a musculoskeletal inspection (significant arthritis can impair gait).

General Neurological Examination The general neurological examination is very important in patients complaining of dizziness, because dizziness can be the earliest symptom of a neurodegenerative disorder (de Lau et al., 2006) and can also be an important symptom of stroke, tumor, demyelination, or other pathologies of the nervous system. One should ensure that the patient

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has full ocular ductions. A posterior fossa mass can impair facial sensation and the corneal reflex on one side. Assessing facial strength and symmetry is important because of the close anatomical relationship between the seventh and eighth cranial nerves. The lower cranial nerves should also be closely inspected by observing palatal elevation, tongue protrusion, and trapezius and sternocleidomastoid strength. The general motor examination determines strength in each muscle group and also assesses bulk and tone. Increased tone or cogwheel rigidity could be the main finding in a patient with an early neurodegenerative disorder. The peripheral sensory examination is important because a peripheral neuropathy can cause a nonspecific dizziness or imbalance. Temperature, pain, vibration, and proprioception should be assessed. Reflexes should be tested for their presence and symmetry. One must take into consideration the normal decrease in vibratory sensation and absence of ankle jerks that can occur in elderly patients. Coordination is an important part of the neurological examination in patients with dizziness because disorders characterized by ataxia can present with the principal symptom of dizziness. Observing the patient’s ability to perform the finger-nose-finger test, the heel-knee-shin test, and rapid alternating movements adequately assesses extremity coordination (Schmitz-Hubsch et al., 2006).

Neuro-Otological Examination When the general neurological examination is not revealing, the neuro-otological exam can be the critical element. The neuro-otological examination is a specialty examination expanding upon certain aspects of the general neurological examination and also includes an audio-vestibular assessment.

Ocular Motor The first step in assessing ocular motor function is to search for spontaneous involuntary movements of the eyes. The examiner asks the patient to look straight ahead while observing for nystagmus or saccadic intrusions. Nystagmus is characterized by a slow- and fast-phase component and is classified as spontaneous, gaze-evoked, or positional. The direction of nystagmus is conventionally described by the direction of the fast phase, which is the direction it appears to be “beating” toward. Recording whether the nystagmus is vertical, horizontal, torsional, or a mixture of these provides important localizing information. Spontaneous nystagmus can have either a peripheral or central pattern. Although central lesions can mimic a “peripheral” pattern of nystagmus (Lee and Cho, 2004; NewmanToker et al., 2008), unusual circumstances are required for peripheral

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TABLE 22.2

Distinguishing Among Common Peripheral and Central Vertigo Syndromes

Cause

History of Vertigo

Duration of Vertigo

Associated Symptoms

Peripheral Vestibular neuritis

Single prolonged episode

Days to weeks

Nausea, imbalance

Positionally triggered episodes May be triggered by salty foods

24 h; TIA, < 24 h

Brainstem, cerebellar

MS

Subacute onset

Minutes to weeks

Neurodegenerative disorders

May be spontaneous or positionally triggered

Minutes to hours

Unilateral visual loss, diplopia, incoordination, ataxia Ataxia

Migraine

Seconds to days Onset usually associated with typical migraine triggers Acute-subacute onset; usu- Hours ally triggered by stress, exercise, or excitement

Spontaneous “central” nystagmus; gaze-evoked nystagmus; focal neurological signs; negative head-thrust test; skew deviation “Central” types or rarely “peripheral” types of spontaneous or positional nystagmus; usually other focal neurological signs “Central” types of spontaneous or positional nystagmus; gaze-evoked nystagmus; impaired smooth pursuit; cerebellar, extrapyramidal and frontal signs Normal interictal examination; ictal examination may show “peripheral” or “central” types of spontaneous or positional nystagmus “Central” types of spontaneous or positional nystagmus Ictal, or even interictal, gaze-evoked nystagmus; ataxia; gait disorders

BPPV Meniere disease

Vestibular paroxysmia Perilymph fistula

Central Stroke/TIA

Familial ataxia syndromes

Headache, visual aura, photo-/phonophobia Ataxia

Physical Examination “Peripheral” nystagmus, positive head-thrust test, imbalance Characteristic positionally triggered burst of nystagmus

Usually normal

BPPV, Benign paroxysmal positional vertigo; MS, multiple sclerosis; TIA, transient ischemic attack.

lesions to cause “central” patterns of nystagmus. The peripheral pattern of spontaneous nystagmus is unidirectional: that is, the eyes beat only to one side (Video 22.1). Peripheral spontaneous nystagmus never changes direction. It is usually a horizontal greater than torsional pattern because of the physiology of the asymmetry in firing rates within the peripheral vestibular system whereby the vertical canals cancel each other out. The prominent horizontal component results from the unopposed horizontal canal asymmetry. Other characteristics of peripheral spontaneous nystagmus are suppression with visual fixation, increase in velocity with gaze in the direction of the fast phase, and decrease with gaze in the direction opposite of the fast phase. Some patients are able to suppress this nystagmus so well at the bedside, or have partially recovered from the initiating event, that spontaneous nystagmus may only appear by removing visual fixation. Several simple bedside techniques can be used to remove the patient’s ability to fixate. Frenzel glasses are designed to remove visual fixation by using +30 diopter lenses. An ophthalmoscope can be used to block fixation. While the fundus of one eye is being viewed, the patient is asked to cover the other eye. Probably the simplest technique involves holding a blank sheet of paper close to the patient’s face (so as to block visual fixation) and observing for spontaneous nystagmus from the side. Saccadic intrusions are spontaneous, involuntary saccadic movements of the eyes, without the rhythmic fast and slow phases characteristic of nystagmus. Saccades are fast movements of the eyes normally under voluntary control and used to shift gaze from one object to another. Square-wave jerks and saccadic oscillations are the most common types of saccadic intrusions. Square-wave jerks refer to

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small-amplitude, involuntary saccades that take the eyes off a target, followed after a normal intersaccadic delay (around 200 msec) by a corrective saccade to bring the eyes back to the target. Square-wave jerks can be seen in neurological disorders such as cerebellar ataxia, Huntington disease (HD), or progressive supranuclear palsy (PSP), but they also occur in normal individuals. If the square-wave jerks are persistent or of large amplitude (macro-square wave jerks), pathology is more likely. Saccadic oscillations refer to back-to-back saccadic movements without the intersaccadic interval characteristic of square-wave jerks, so their appearance is that of an oscillation. When a burst occurs only in the horizontal plane, the term ocular flutter is used (Video 22.2). When vertical and/or torsional components are present, the term opsoclonus (or so-called dancing eyes) is used. The eyes make constant random conjugate saccades of unequal amplitude in all directions. Ocular flutter and opsoclonus are pathological findings typically seen in several different types of CNS diseases involving brainstem–cerebellar pathways. Paraneoplastic disorders should be considered in patients presenting with ocular flutter or opsoclonus.

Gaze Testing The patient should be asked to look to the left, right, up, and down; the examiner looks for gaze-evoked nystagmus in each position (Video 22.3). A few beats of unsustained nystagmus with gaze greater than 30 degrees is called end-gaze nystagmus and variably occurs in normal subjects. Gazeevoked downbeating nystagmus (Video 22.4), vertical nystagmus that increases on lateral gaze, localizes to the craniocervical junction and midline

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cerebellum. Gaze testing may also trigger saccadic oscillations (see Videos 22.3 and 22.4).

Smooth Pursuit Smooth pursuit refers to the voluntary movement of the eyes used to track a target moving at a low velocity. It functions to keep the moving object on the fovea to maximize vision. Though characteristically a very smooth movement at low frequency and velocity testing, smooth pursuit inevitably breaks down when tested at high frequencies and velocities. Though smooth pursuit often becomes impaired with advanced age, a longitudinal study of healthy elderly individuals found no significant decline in smooth pursuit over 9 years of evaluation (Kerber et al., 2006). Patients with impaired smooth pursuit require frequent small saccades to keep up with the target; thus the term saccadic pursuit is used to describe this finding. Abnormalities of smooth pursuit occur as the result of disorders throughout the CNS and with tranquilizing medicines, alcohol, inadequate concentration or vision, and fatigue. However, in a cognitively intact individual presenting with dizziness or imbalance symptoms, bilaterally impaired smooth pursuit is highly localizing to the cerebellum. Patients with early or mild cerebellar degenerative disorders may have markedly impaired smooth pursuit with mild or minimal truncal ataxia as the only findings.

Saccades Saccades are fast eye movements (velocity of this eye movement can be as high as 600 degrees per second) used to quickly bring an object onto the fovea. Saccades are generated by the burst neurons of the pons (horizontal movements) and midbrain (vertical movements). Lesions or degeneration of these regions leads to slowing of saccades, which can also occur with lesions of the ocular motor neurons or extraocular muscles. Severe slowing can be readily appreciated at the bedside by instructing the patient to look back and forth from one object to another. The examiner observes both the velocity of the saccade and the accuracy. Overshooting saccades (missing the target and then needing to correct) indicates a lesion of the cerebellum (Video 22.5). Undershooting saccades are less specific and often occur in normal subjects.

Optokinetic Nystagmus and Fixation Suppression of the Vestibulo-Ocular Reflex Optokinetic nystagmus (OKN) and fixation suppression of the VOR suppression can also be tested at the bedside. OKN is a combination of fast (saccadic) and slow (smooth pursuit) movements of eyes and can be observed in normal individuals when, for example, watching a moving train. OKN is maximally stimulated with both foveal and parafoveal stimulation, so the proper laboratory technique for measuring OKN uses a full-field stimulus by having the patient sit stationary while a large rotating pattern moves around them. This test can be approximated at the bedside by moving a striped cloth in front of the patient, though this technique only stimulates the fovea. Patients with disorders causing severe slowing of saccades will not be able to generate OKN, so their eyes will become pinned to one side. VOR suppression can be tested at the bedside using a swivel chair. The patient sits in the chair and extends his or her arm in the “thumbs-up” position out in front. The patient is instructed to focus on the thumb and to allow the extended arm to move with the body so the visual target of the thumb remains directly in front of the patient. The chair is then rotated from side to side. The patient’s eyes should remain locked on the thumb, demonstrating the ability to suppress the VOR stimulated by rotation of the chair. Nystagmus will be observed during the rotation movements in patients with impairment of VOR suppression, which is analogous to impairment of

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smooth pursuit. Both OKN and VOR suppression can also be helpful when examining patients having difficulty following the instructions for smooth pursuit or saccade testing.

Vestibular Nerve Examination Often omitted as part of the cranial nerve examination in general neurology texts, important localizing information can be obtained about the functioning of the vestibular nerve at the bedside. A unilateral or bilateral vestibulopathy can be identified using the head-thrust test (Halmagyi et al., 2008) (Fig. 22.3 and Video 22.6). To perform the head-thrust test, the physician stands directly in front of the patient, who is seated on the examination table. The patient’s head is held in the examiner’s hands, and the patient is instructed to focus on the examiner’s nose. The head is then quickly moved about 5–10 degrees to one side. In patients with normal vestibular function, the VOR results in movement of the eyes in the direction opposite the head movement. Therefore the patient’s eyes remain on the examiner’s nose after the sudden movement. The test is repeated in the opposite direction. If the examiner observes a corrective saccade bringing the patient’s eyes back to the examiner’s nose after the head thrust, impairment of the VOR in the direction of the head movement is identified. Rotating the head slowly back and forth (the doll’s eye test) also induces compensatory eye movements, but both the visual and vestibular systems are activated by this low-velocity test, so a patient with complete vestibular function loss and normal visual pursuit will have normal-appearing compensatory eye movements on the doll’s eye test. This slow rotation of the head, however, is helpful in a comatose patient who is not able to generate voluntary visual tracking eye movements. Slowly rotating the head can also be a helpful test in patients with impairment of the smooth-pursuit system, because smooth movements of the eyes during slow rotation of the head indicates an intact VOR, whereas continued saccadic movements during slow rotation indicates an accompanying deficit of the VOR (Migliaccio et al., 2004).

Positional Testing Positional testing can help identify peripheral or central causes of vertigo. The most common positional vertigo, BPPV, is caused by free-floating calcium carbonate debris, usually in the posterior semicircular canal, occasionally in the horizontal canal, or rarely in the anterior canal. The characteristic burst of upbeat torsional nystagmus is triggered in patients with BPPV by a rapid change from the sitting-up position to supine head-hanging left or head-hanging right (the Dix–Hallpike test; Video 22.7). When present, the nystagmus is usually only triggered in one of these positions. A burst of nystagmus in the opposite direction (downbeat torsional) occurs when the patient resumes the sitting position since the debris moves in the opposite direction. A repositioning maneuver can be used to move the debris out of the canal. The modified Epley maneuver (Fig. 22.4 and Video 22.8) is more than 80% effective in treating patients with posterior canal BPPV, compared with 10% effectiveness of a sham procedure (Hilton, 2014). The key feature of this maneuver is the roll across in the plane of the posterior canal so that the debris rotates around the posterior canal and out into the utricle. Once the debris enters the utricle, it no longer disrupts semicircular canal function. Recurrences are common, however (see Videos 22.7 and 22.8). If the debris is in the horizontal canal, direction-changing horizontal nystagmus is seen. Patients are tested for HC-BPPV by turning the head to each side while lying in the supine position. The nystagmus can be either paroxysmal geotropic (beating toward the ground) or persistent apogeotropic nystagmus (beating away from the ground). In the case of geotropic nystagmus, the debris is in the posterior segment (or “long arm”) of the horizontal canal, whereas the debris is in

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20°

Eyes remain fixed on target

Line of sight Fixed target

A

20°

Line of sight moves with head movement

Line of sight

Quick saccade back to target

Fixed target

B

Fig. 22.3 Head-Thrust Test. The head-thrust test is a test of vestibular function that can be easily done during the bedside examination. This maneuver tests the vestibulo-ocular reflex (VOR). The patient sits in front of the examiner and the examiner holds the patient’s head steady in the midline. The patient is instructed to maintain gaze on the nose of the examiner. The examiner then quickly turns the patient’s head about 10–15 degrees to one side and observes the ability of the patient to keep the eyes locked on the examiner’s nose. If the patient’s eyes stay locked on the examiner’s nose (i.e., no corrective saccade) (A), then the peripheral vestibular system is assumed to be intact. If, however, the patient’s eyes move with the head (B) and then the patient makes a voluntary eye movement back to the examiner’s nose (i.e., corrective saccade), then this indicates a lesion of the peripheral vestibular system and not the central nervous system (CNS). Thus, when a patient presents with the acute vestibular syndrome, the test result shown in A would suggest a CNS lesion (because the VOR is intact), whereas the test result in B suggests a peripheral vestibular lesion on the right side (because the VOR is not intact). (From Edlow, J.A., Newman-Toker, D.E., Savitz, S.I., 2008. Diagnosis and initial management of cerebellar infarction. Lancet Neurology 7, 951–964.)

the anterior segment (or “short arm”) when apogeotropic nystagmus is triggered. When geotropic nystagmus is triggered, the side with the stronger nystagmus is the involved side. However, when apogeotropic nystagmus is observed, the involved side is generally opposite the side of the stronger nystagmus. With the geotropic variant, class I evidence supports treatment with the barbecue maneuver or the Gufoni maneuver (Kim et al., 2012a). Another maneuver for HC-BPPV is the “forced prolonged position” (Vannucchi et al., 1997). In cases of the apogeotropic variant of HC-BPPV, a variation of the Gufoni maneuver or a head-shaking maneuver can effectively treat the condition, though

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patients may require a second maneuver to clear the debris from the long arm of the horizontal canal (the same maneuver to treat geotropic HC-BPPV; Kim et al., 2012b). Positional testing can also trigger central types of nystagmus (usually persistent downbeating), which may be the most prominent examination finding in patients with disorders like Chiari malformation or cerebellar ataxia (Kattah and Gujrati, 2005; Kerber et al., 2005a). Central positional nystagmus can also mimic the nystagmus of HC-BPPV. Positional nystagmus may also be prominent in patients with migraine-associated dizziness (von Brevern et al., 2005).

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A

PSC D

E

C

B

E Utricle

A

C

D

Fig. 22.4 Treatment Maneuver For Benign Paroxysmal Positional Vertigo Affecting the Right Ear. Procedure can be reversed for treating the left ear. Drawing of labyrinth in the center shows position of the debris as it moves around the posterior semicircular canal (PSC) and into the utricle. A, Patient is seated upright with head facing examiner, who is standing on the right. B, Patient is then rapidly moved to head-hanging right position (Dix–Hallpike test). This position is maintained until nystagmus ceases. Examiner moves to the head of the table, repositioning hands as shown. C, Patient’s head is rotated quickly to the left, with right ear upward. This position is maintained for 30 seconds. D, Patient rolls onto the left side while examiner rapidly rotates the head leftward until the nose is directed toward the floor. This position is then held for 30 seconds. E, Patient is then rapidly lifted into the sitting position, now facing left. The entire sequence should be repeated until no nystagmus can be elicited. Following the maneuver, the patient is instructed to avoid head-hanging positions to prevent the debris from re-entering the posterior canal. (From Baloh, R.W., 1998. Dizziness, Hearing Loss, and Tinnitus. F.A. Davis Company, Philadelphia, Figure 69, p. 166.)

Fistula Testing

Auditory Examination

In patients reporting sound- or pressure-induced dizziness, a defect of the bony capsule of the labyrinth can be tested for by pressing and releasing the tragus (small flap of cartilage that can be used to occlude the external ear canal) and observing the eyes for brief associated deviations. Pneumatoscopy (introducing air into the external auditory canal through an otoscope) or Valsalva against pitched nostrils or closed glottis can also trigger associated eye movements. The direction of the triggered nystagmus helps identify the location of the fistula.

The bedside examination of the auditory system begins with otoscopy. The tympanic membrane is normally translucent; changes in color indicate middle ear disease or tympanosclerosis, a semicircular crescent or horseshoe-shaped white plaque within the tympanic membrane. Tympanosclerosis is rarely associated with hearing loss but is an important clue to past infections. The area just superior to the lateral process of the malleus should be carefully inspected for evidence of a retraction pocket or cholesteatoma. Findings on otoscopy are usually not associated with causes of dizziness because the visualized abnormalities typically do not involve the inner ear. Finger rubs at different intensities and distances from the ear are a rapid, reliable, and valid screening test for hearing loss in the frequency range of speech (Torres-Russotto et al., 2009). If a patient can hear a faint finger rub stimulus at a distance of 70 cm (approximately one arm’s length) from one ear, then a hearing loss on that side—defined by a gold-standard audiogram threshold of greater than 25 dB at 1000, 2000, and 4000 Hz—is highly unlikely. On the other hand, if a patient cannot hear a strong finger rub stimulus at 70 cm, hearing loss on that side is highly likely. The whisper test can also be used to assess hearing at the bedside (Bagai et al., 2006). For this test, the examiner stands

Gait Casual gait is examined for initiation, heel strike, stride length, and base width. Patients are then observed during tandem walking and while standing in the Romberg position (with eyes open and closed). A decreased heel strike, stride length, flexed posture, and decreased arm swing suggest Parkinson disease. A wide-based gait with inability to tandem walk is characteristic of truncal ataxia. Patients with acute vestibular loss will veer toward the side of the affected ear for several days after the event. Patients with peripheral neuropathy or bilateral vestibulopathy may be unable to stand in the Romberg position with eyes closed.

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behind the patient to prevent lip reading and occludes and masks the nontest ear, using a finger to rub and close the external auditory canal. The examiner then whispers a set of three to six random numbers and letters. Overall, the patient is considered to have passed the screening test if they repeat at least 50% of the letters and numbers correctly. The Weber and Rinne tests are commonly used bedside tuning fork tests. To perform these, a tuning fork (256 Hz or 512 Hz) is gently struck on a hard rubber pad, the elbow, or the knee about two-thirds of the way along the tine. To conduct the Weber test, the base of the vibrating fork is placed on the vertex (top or crown of the head), bridge of the nose, upper incisors, or forehead. The patient is asked if the sound is heard and whether it is heard in the middle of the head or in both ears equally, toward the left, or toward the right. In a patient with normal hearing, the tone is heard centrally. In asymmetrical or a unilateral hearing impairment, the tone lateralizes to one side. Lateralization indicates an element of conductive impairment in the ear in which the sound localizes, a sensorineural impairment in the contralateral ear, or both. The Rinne test compares the patient’s hearing by air conduction with that by bone conduction. The fork is first held against the mastoid process until the sound fades. It is then placed 1 inch from the ear. Normal subjects can hear the fork about twice as long by air as by bone conduction. If bone is greater than air conduction, a conductive hearing loss is suggested.

SPECIFIC DISORDERS CAUSING VERTIGO Peripheral Vestibular Disorders Peripheral vestibular disorders are important for neurologists to understand because they are common, readily identified at the bedside, and often missed by frontline physicians (see Table 22.2).

Acute Unilateral Vestibulopathy (Vestibular Neuritis) A common presentation to the ED or outpatient clinic is the rapid onset of severe vertigo, nausea, vomiting, and imbalance. The symptoms gradually resolve over days to weeks, but about 20% of patients report some dizziness even 12 months later (Shupak, 2008). The typical etiology of this disorder is vestibular neuritis, which is presumed to be viral because the course is generally benign and self-limited, similar to Bell palsy. Small histopathological studies support the etiology of a viral cause. However, ischemia or demyelination can also cause an acute unilateral vestibulopathy. The key to identifying an acute unilateral vestibulopathy is recognizing the peripheral vestibular pattern of nystagmus and identifying a positive head-thrust test in the setting of a rapid onset of vertigo without other neurological symptoms. The course of vestibular neuritis is self-limited, and the mainstay of treatment is symptomatic. A course of corticosteroids might improve recovery of the caloric response but symptomatic and functional outcomes were not clinically different (Fishman et al., 2011). Vestibular physical therapy—delivered with in person sessions or even home training—can help patients compensate for the vestibular lesion (Hillier et al., 2011).

Benign Paroxysmal Positional Vertigo BPPV has a lifetime cumulative incidence of nearly 10% (von Brevern, 2005). Patients typically experience brief episodes of vertigo when getting in and out of bed, turning in bed, bending down and straightening up, or extending the head back to look up. As noted earlier, the condition is caused when calcium carbonate debris dislodged from the otoconial membrane inadvertently enters a semicircular canal. The debris can be free-floating within the affected canal (canalithiasis) or stuck against the cupula (cupulolithiasis). Though the positional attacks are the hallmark feature, some BPPV patients also report constant mild

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unsteadiness (Von Brevern, 2015). The gold standard test is the DixHallpike test with the positive finding being the hallmark triggered and transient upbeat-torsional nystagmus. Repositioning maneuvers are highly effective in removing the debris from the canal, though recurrence is common (see Fig. 22.4; Fife et al., 2008). Once the debris is out of the canal, patients are instructed to avoid extreme head positions to prevent the debris from re-entering the canal. Patients can also be taught to perform a repositioning maneuver, should they have a recurrence of the positional vertigo.

Meniere Disease Meniere disease is characterized by recurrent attacks of vertigo associated with auditory symptoms (hearing loss, tinnitus, aural fullness) during attacks. Over time, progressive hearing loss develops. Attacks are variable in duration, most lasting longer than 20 minutes, and are associated with severe nausea and vomiting. The course of the disorder is also highly variable. For some patients, the attacks are infrequent and decrease over time, but for others they can become debilitating. Occasionally, auditory symptoms are not appreciated by the patients or identified by interictal audiograms early in the disorder, but inevitably patients with Meniere disease develop these features, usually within the first year. Thus the term vestibular Meniere disease, previously used for patients with recurrent episodes of vertigo but no hearing loss, is no longer used. Though usually a disorder involving only one ear, Meniere disease becomes bilateral in about one-third of patients. Endolymphatic hydrops, or expansion of the endolymph relative to the perilymph, is regarded as the etiology, though the underlying cause is unclear. In addition, the characteristic histopathological changes of endolymphatic hydrops have been identified in temporal bone specimens of patients with no clinical history of Meniere disease (Merchant et al., 2005). Some patients with well-documented Meniere disease experience abrupt episodes of falling to the ground, without loss of consciousness or associated neurological symptoms. Patients often report the sensation of being pushed or thrown to the ground. The falls are hard and often result in fractures or other injuries. These episodes have been called otolithic catastrophes of Tumarkin because of the suspicion that they represent acute stimulation of the otoliths. The bedside interictal examination of patients with Meniere disease may identify asymmetrical hearing, but the head-thrust test is usually normal. Treatment is initially directed toward an aggressive low-salt diet and diuretics, though the evidence for these treatments is poor. Intratympanic gentamicin injections can be effective and are minimally invasive. Sectioning of the vestibular nerve and destruction of the labyrinth are other procedures (Minor et al., 2004). Autoimmune inner-ear disease presents as a fulminate variant of Meniere disease. Another variant is so-called delayed endolymphatic hydrops. Patients with this disorder report recurrent episodes of severe vertigo without auditory symptoms developing years after a severe unilateral hearing loss caused by a viral or bacterial infection.

Vestibular Paroxysmia Vestibular paroxysmia is characterized by brief (seconds to minutes) episodes of vertigo, occurring suddenly without any apparent trigger (Strupp, 2016). The disorder may be analogous to hemifacial spasm and trigeminal neuralgia, which are felt to be due to spontaneous discharges from a partially damaged nerve. In patients with vestibular paroxysmia, unilateral dysfunction can sometimes be identified on vestibular or auditory testing. Like the analogous disorders, it is conceivable that a normal vessel could be compressing the cranial nerve, and surgical removal of the vessel might seem to be a treatment option. However, many asymptomatic subjects have a normal vessel lying on the eighth nerve (usually the anterior inferior cerebellar artery), and

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most vestibular paroxysmia patients have a favorable course with conservative or medication management (Strupp, 2016), so the decision to operate in this delicate region is rarely indicated. Medications associated with a reduction in episodes include carbamazepine, oxcarbazepine, and gabapentin (Strupp, 2016).

Vestibular Fistulae Superior canal dehiscence was first described in 1998 (Minor et al., 1998). As the name implies, dehiscence of the bone overlying the superior canal results in a fistula between the superior canal and the middle cranial fossa. Normally the semicircular canals are enclosed by the rigid bony capsule, so these vestibular structures are unaffected by sound pressure changes. The oval and round windows direct the forces associated with sound waves into the cochlea and along the spiral basilar membrane. A break in the bony capsule of the semicircular canals can redirect some of the sound or pressure to the semicircular canals, causing vestibular activation, a phenomenon known as Tullio phenomenon. Prior to the discovery of SCD, fistulas were known to occur with rupture of the oval or round window or erosion into the horizontal semicircular canal from chronic infection. Pressure changes generated by increasing intracranial pressure (ICP; Valsalva against closed glottis) or increasing middle ear pressure (Valsalva against pinched nostrils or compression of the tragus) triggers brief nystagmus in the plane of the affected canal. Surgically repairing the defect can be attempted if the patient is debilitated by the symptoms, but most patients do well with conservative management (Ward, 2017). A study looking at long-term outcome after SCD surgical treatment had a low follow-up rate (43%; 93/218) but reported trends in improved audio-vestibular symptoms that were greatest for autophony, pulsatile tinnitus, audible body sounds, and sensitivity to loud sounds, and least for dizziness (Alkhafaii, 2017). Patients with SCD may have hypersensitivity to bone-conducted sound and bone-conduction thresholds on the audiogram lower than the normal 0 dB hearing levels, even though air conduction thresholds remain normal (Minor, 2005).

Other Peripheral Disorders There are many other peripheral vestibular causes of vertigo, but most are uncommon. Vertigo often follows a blow to the head, even without a corresponding temporal bone fracture. This so-called labyrinthine concussion results from the susceptibility of the delicate structures of the inner ear to blunt trauma. Vestibular ototoxicity, usually from gentamicin, can cause a vestibulopathy that is usually bilateral but rarely can be unilateral (Waterston and Halmagyi, 1998). A bilateral vestibulopathy can also occur from an immune-mediated disorder (e.g., autoimmune inner-ear disease, Cogan syndrome), infectious process (e.g., meningitis, syphilitic labyrinthitis), structural lesion (bilateral acoustic neuroma), or a genetic disorder (e.g., neurodegenerative or isolated vestibular). The bilateral vestibular loss often goes unrecognized because the vestibular symptoms can be overshadowed by auditory or other symptoms. Although the most prominent vestibular symptoms of bilateral vestibulopathy are oscillopsia and imbalance, some nonspecific dizziness and vertigo attacks may occur as well. Vestibular schwannomas typically present with slowly progressive unilateral hearing loss, but rarely vertigo can occur. Because the tumor growth is slow, the vestibulopathy is compensated by the CNS. Finally, any disorder affecting the skull base, such as sarcoidosis, lymphoma, bacterial and fungal infections, or carcinomatous meningitis, can cause either unilateral or bilateral peripheral vestibular symptoms.

Central Nervous System Disorders The key to the diagnosis of CNS disorders in patients presenting with dizziness is the presence of other focal neurological symptoms or identifying central ocular motor abnormalities or ataxia. Because central

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disorders can mimic peripheral vestibular disorders, the most effective approach in patients with isolated dizziness is first to rule out common peripheral causes.

Brainstem or Cerebellar Ischemia/Infarction Ischemia affecting vestibular pathways within the brainstem or cerebellum often causes vertigo. Brainstem ischemia is normally accompanied by other neurological signs and symptoms, because motor and sensory pathways are in close proximity to vestibular pathways. Vertigo is the most common symptom with Wallenberg syndrome, infarction in the lateral medulla in the territory of the posterior inferior cerebellar artery (PICA), but other neurological symptoms and signs (e.g., diplopia, facial numbness, Horner syndrome) are typically present. Ischemia of the cerebellum can cause vertigo as the most prominent or only symptom, and a common dilemma is whether the patient with acute-onset vertigo needs a magnetic resonance imaging (MRA) scan to rule out cerebellar infarction. Computed tomography (CT) scans of the posterior fossa are not a sensitive test for acute ischemic stroke (Chalela et al., 2007). Abnormal ocular motor findings in patients with brainstem or cerebellar strokes include (1) spontaneous nystagmus that is purely vertical or torsional, (2) direction-changing gaze-evoked nystagmus (patient looks to the left and has left-beating nystagmus, looks to the right, and has right-beating nystagmus), (3) impairment of smooth pursuit, and (4) overshooting saccades. Central causes of nystagmus can sometimes closely mimic the peripheral vestibular pattern of spontaneous nystagmus (Lee et al., 2006b; Kerber, 2015; Newman-Toker et al., 2008). In these cases, a negative head-thrust test (i.e., no corrective saccade) or a skew deviation could be the key indicators of a central rather than a peripheral vestibular lesion (Newman-Toker et al., 2013a, 2013b). Cardiovascular risk factors are also independent predictors of stroke in dizziness patients (Kerber, 2015) and therefore should be considered in evaluation and management plans.

Multiple Sclerosis Dizziness is a common symptom in patients with multiple sclerosis (MS). Vertigo is the initial symptom in about 5% of patients with MS. A typical MS attack has a gradual onset, reaching its peak within a few days. Milder spontaneous episodes of vertigo, not characteristic of a new attack, and positional vertigo lasting seconds are also common in MS patients. Nearly all varieties of central spontaneous and positional nystagmus occur with MS, and occasionally patients show typical peripheral vestibular nystagmus when the lesion affects the root entry zone of the vestibular nerve. MRI of the brain identifies white matter lesions in about 95% of MS patients, although similar lesions are sometimes seen in patients without the clinical criteria for the diagnosis of MS.

Posterior Fossa Structural Abnormalities Any structural lesion of the posterior fossa can cause dizziness. With the Chiari malformation, the brainstem and cerebellum are elongated downward into the cervical canal, causing pressure on both the caudal midline cerebellum and the cervicomedullary junction. The most common neurological symptom is a slowly progressive unsteadiness of gait, which patients often describe as dizziness. Vertigo and hearing loss are uncommon, occurring in about 10% of patients. Ocular motor abnormalities (e.g., spontaneous or positional downbeat nystagmus, impaired smooth pursuit) are particularly common with Chiari malformations. Dysphagia, hoarseness, and dysarthria can result from stretching of the lower cranial nerves, and obstructive hydrocephalus can result from occlusion of the basilar cisterns. MRI is the procedure of choice for identifying Chiari malformations; midline sagittal sections clearly show the level of the cerebellar tonsils. The most common

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CNS tumors in the posterior fossa are gliomas in adults and medulloblastoma in children. Ocular motor dysfunction (impaired smooth pursuit, overshooting saccades), impaired coordination, or other central findings occur in these patients. An early finding of patients with cerebellar tumors can be central positional nystagmus. Vascular malformations (arteriovenous malformations [AVMs], cavernous hemangiomas) can similarly cause dizziness but generally are asymptomatic until bleeding occurs.

Neurodegenerative Disorders Patients with neurodegenerative disorders (e.g., Parkinson disease, other parkinsonian syndromes, or progressive ataxia) can present with the main complaint of dizziness (de Lau et al., 2006). However, dizziness in these patients is usually better clarified as imbalance. Positional downbeat nystagmus occurs in patients with spinocerebellar ataxia type 6 (SCA6) and other progressive ataxia disorders (Kattah and Gujrati, 2005; Kerber et al., 2005a).

Epilepsy Vestibular symptoms are common with focal seizures, particularly those originating from the temporal and parietal lobes. The key to differentiating vertigo with seizures from other causes of vertigo is that seizures are almost invariably associated with an altered level of consciousness. Episodic vertigo as an isolated manifestation of a focal seizure is a rarity if it occurs at all.

Vertigo in Inherited Disorders The clinical evaluation of patients presenting with dizziness has traditionally hinged on the history of present illness and examination. However, with the recent rapid advances in molecular biology, it has become apparent that many causes of vertigo have a strong genetic component. Because of this, obtaining a complete family history is very important, particularly in patients without a specific diagnosis for their dizziness. Since the symptoms of these familial disorders are often not debilitating and can be highly variable, simply asking the patient about a family history at the time of the appointment may not be adequate. The patient should be instructed to specifically interview other family members regarding the occurrence of these symptoms.

Migraine Migraine is a heterogeneous genetic disorder characterized by headaches in addition to many other neurological symptoms. Several rare monogenetic subtypes have been identified. Linkage analysis has identified a number of chromosomal loci in common forms of migraine, but no specific genes have been found. Dizziness has long been known to occur among patients with migraine headaches, and BRV is usually a migraine equivalent because no other signs or symptoms develop over time, the neurological examination remains normal, and a family or personal history of migraine headaches is common, as are typical migraine triggers. Interestingly, some patients with BRV also report auditory symptoms similar to patients with Meniere disease, and a mild hearing loss may also be seen on the audiogram (Battista, 2004). The key distinguishing factor between migraine and Meniere disease is the lack of progressive unilateral hearing loss in patients with migraine. Other types of dizziness are common in patients with migraine as well, including nonspecific dizziness and positional vertigo (von Brevern et al., 2005). The cause of vertigo in migraine patients is not yet known, but the diagnosis of migraine should be entertained in any patient with chronic recurrent attacks of dizziness of unknown cause. Longstanding motion sensitivity including carsickness, sensitivities to other types of stimuli, and a clear family history of migraine help support the diagnosis. Also, some patients have a typical migraine visual aura or

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other focal neurological symptoms associated with headache. Though the diagnosis of migraine-associated dizziness remains one of exclusion, little else can cause recurrent episodes without any other symptoms over a long period of time. In a genome-wide linkage scan of BRV patients (20 families), linkage to chromosome 22q12 was found, but genetic heterogeneity was evident (Lee et al., 2006a). Testing linkage using a broader phenotype of BRV and migraine headaches weakened the linkage signal. Thus no evidence exists at this time that migraine is allelic with BRV, even though migraine has a high prevalence in BRV patients.

Familial Bilateral Vestibulopathy Familial bilateral vestibulopathy (FBV) patients typically have brief attacks of vertigo followed by progressive loss of peripheral vestibular function leading to imbalance and oscillopsia, usually by the fifth decade. The recurrent attacks of vertigo may somehow cause damage to vestibular structures, leading to progressive vestibular loss. Quantitative rotational testing shows gains greater than 2 standard deviations below the normal mean for both sinusoidal and step changes in angular velocity. Caloric testing is insensitive for identifying bilateral vestibulopathy because of the wide range of normal caloric responses. The bedside head-thrust test may show bilateral corrective saccades when vestibulopathy is severe. As the vestibulopathy becomes more severe, attacks of vertigo become less frequent and eventually cease. Despite the high prevalence of familial hearing loss and enormous progress in identifying the genetic basis of deafness, to date no gene mutations that lead to isolated bilateral vestibulopathy in humans have been identified (Jen, 2011; Strupp, 2017). Only a few FBV families have been described (Brantberg, 2003; Jen et al., 2004b). Given the high prevalence and genetic diversity of familial hearing loss, it seems reasonable to suspect that bilateral vestibulopathy would have a similar prevalence and genetic diversity. The huge disparity in knowledge about genetic deafness and genetic vestibulopathy might stem from our inadequacy to identify vestibulopathy rather than the rareness of the disorder. It is much more straightforward for healthcare providers to identify the symptoms of hearing loss than the symptoms of vestibular loss. Adequate laboratory testing for hearing loss is also much more readily available than it is for vestibular loss. Increased knowledge and use of the bedside head-thrust test, however, has the potential to substantially enhance the identification of bilateral vestibular loss.

Familial Hearing Loss and Vertigo Familial progressive vestibular-cochlear dysfunction was first identified in 1988. Linkage to chromosome 14q12–13 was later found, and the disorder was designated DFNA9 (DFNA = deafness, familial, nonsyndromic, type A [autosomal dominant]; Manolis et al., 1996). Using an organ-specific approach, mutations within COCH were found to cause DFNA9 (Robertson et al., 1998). This disorder of progressive hearing loss is unique because no other autosomal dominant genetic hearing loss syndromes have vertigo as a common symptom. Progressive hearing loss is the most prominent symptom of DFNA9. Vertigo occurs in about 50% of DFNA9 patients. When present, vertigo may be spontaneous in onset or positionally triggered (Lemaire et al., 2003). Age of onset is variable, with some patients developing symptoms in the second to third decade and others developing symptoms later. Vertigo attacks last minutes to hours and can be accompanied by worsening of hearing, aural fullness, or tinnitus, thus closely mimicking Meniere syndrome. Vertigo episodes can precede or accompany onset of hearing loss. In addition to severe progressive hearing loss, eventually DFNA9 patients develop progressive loss of vestibular function and corresponding symptoms of imbalance and oscillopsia. Because some patients have attacks closely resembling Meniere syndrome, the

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COCH gene was screened for mutations in idiopathic Meniere disease patients, but none were found. No studies report the use of effective treatments for vertigo attacks, but like FBV patients, these attacks generally only last a few years and then become less frequent, presumably due to loss of vestibular function. Of the many autosomal dominant genes that cause hearing loss, DFNA11 is the only other one associated with vestibulopathy. Enlarged vestibular aqueduct (EVA) syndrome, designated DFNB4 (DFNB = deafness, familial, nonsyndromic, type B [autosomal recessive]), is characterized by early-onset hearing loss with enlargement of the vestibular aqueduct best seen on temporal bone CT. Normally, the vestibular aqueduct is less than 1.5 mm in diameter, but in EVA it is much larger. The mechanism leading to hearing loss and vertigo is unclear. The vestibular aqueduct contains the endolymphatic duct, which connects the medial wall of the vestibule to the endolymphatic sac and is an important structure in the exchange of endolymph. Enlargement may cause increased transmission of ICPs to the innerear structures. However, the Valsalva maneuver—which increases ICP—does not trigger symptoms in EVA patients. Vertigo attacks last 15 minutes to 3 hours and are not associated with changes in hearing. Vertigo attacks may begin at the onset of hearing loss (early childhood) or years later and can be triggered by blows to the head or vigorous spinning (Oh et al., 2001a). Quantitative vestibular testing may be normal in EVA patients or reveal mild to moderate loss of vestibular function. Enlargement of the vestibular aqueduct has also been observed in Pendred syndrome (PS), branchio-oto-renal syndrome, CHARGE (coloboma of the eye, heart defects, atresia choanae, retardation of growth or development, genitourinary anomalies, and ear abnormalities or hearing impairment), Waardenburg syndrome, and distal renal tubular acidosis with deafness. EVA syndrome is allelic to PS, which is characterized by developmental abnormalities of the cochlea in combination with thyroid dysfunction and goiter.

medications are common causes of nonspecific dizziness. Bothersome lightheadedness can be a direct effect of the medication itself or the result of lowering of the patient’s blood pressure. Ataxia can be caused by antiepileptic medications and is usually reversible once the medication is decreased or stopped. Patients with peripheral neuropathy causing dizziness report significant worsening of their balance in poor lighting and also the sensation that they are walking on cushions. Drops in blood pressure can be caused by dehydration, vasovagal attacks, or as part of an autonomic neuropathy. Patients with panic attacks can present with nonspecific dizziness, but their spells are invariably accompanied by other symptoms such as sense of fear or doom, palpitations, sweating, shortness of breath, or paresthesias. Persistent postural perceptual dizziness (PPPD) is a new label for a form of chronic dizziness manifested by sensations of postural instability and sensitivity to self and surround motion that is often associated with migraine, panic attacks, and generalized anxiety (Popkirov, 2018). Other medical conditions such as cardiac arrhythmias or metabolic disturbances can also cause nonspecific dizziness. In the elderly, confluent white matter hyperintensities have a strong association with dizziness and balance problems. Presumably the result of small vessel arteriosclerosis, decreased cerebral perfusion (Marstrand et al., 2002) has been identified in these patients even when blood pressure taken at the arm is normal. Patients with dizziness related to white matter hyperintensities on MRI usually feel better sitting or lying down and typically have impairment of tandem gait. Since many elderly patients are taking blood pressure medications, at least a trial of lowering or discontinuing these medications is warranted.

Familial Ataxia Syndromes

Acute Severe Vertigo

Vestibular symptoms and signs are common with several of the hereditary ataxia syndromes including SCA types 1, 2, 3, 6, and 7, Friedreich ataxia, Refsum disease, and EA types 2, 3, 4, and 5. In most of these disorders, the symptoms are slowly progressive, with the cerebellar ataxia and incoordination overshadowing the vestibular symptoms. Head movement-induced oscillopsia commonly occurs because the patient is unable to suppress the VOR with fixation. Attacks of vertigo may occur in up to half of patients with SCA6 (Takahashi et al., 2004), many of which are positionally triggered (Jen et al., 1998). Persistent downbeating nystagmus is often seen with the Dix-Hallpike test; the positional vertigo and nystagmus can even be the initial symptom in these patients. Most of the EA syndromes have onset before the age of 20 (Jen et al., 2004a). The attacks are characterized by extreme incoordination, leading to severe difficulty walking during attacks. Vertigo can occur as part of these attacks, and migraine headaches are common in these patients as well. In fact EA2, SCA6, and familial hemiplegic migraine type 1 are all caused by mutations with the same gene, CACNA1A. An additional feature of EA2 and EA4 is the eventual development of interictal nystagmus and progressive ataxia. Patients with EA2 may experience reduced attacks with acetazolamide or 4-aminopyridine (Zesiewicz, 2018).

The patient presenting with new-onset severe vertigo probably has an acute unilateral vestibulopathy caused by vestibular neuritis; however, stroke should also be a concern. In the absence of focal neurological symptoms or signs on the general evaluation, attention should focus on the neuro-otological evaluation. If no spontaneous nystagmus or gaze nystagmus is observed, a technique to block visual fixation should be applied. The direction of the nystagmus should be noted and the effect of gaze assessed. If a peripheral vestibular pattern of nystagmus is identified, a positive head-thrust test in the direction opposite the fast phase of nystagmus suggests a lesion of the vestibular nerve. Vestibular neuritis is presumed to be the most common cause of this presentation but there is no mechanism to confirm a viral/postviral etiology. A central vestibular lesion (e.g., ischemic stroke) becomes a serious concern if there are “red flags” such as other central signs or symptoms, direction-changing nystagmus, vertical nystagmus, a negative headthrust test (i.e., no corrective saccade after the head-thrust test to the direction opposite the fast phase of spontaneous nystagmus), a skew deviation, or substantial stroke risk factors (Kerber, 2015; NewmanToker, 2013a; Newman-Toker, 2013b). Vertebral artery dissection can lead to an acute vertigo presentation, but the most common symptom is severe, sudden-onset occipital or neck pain, with additional neurological signs and symptoms (Arnold et al., 2006). If hearing loss accompanies the episode, either labyrinthitis or an ischemic lesion via the anterior inferior cerebellar artery are possible. When hearing loss and facial weakness accompany the acute onset of vertigo, one should closely inspect the outer ear for vesicles characteristic of herpes zoster (Ramsay Hunt syndrome). An acoustic neuroma is a slow-growing tumor, so only rarely is it associated with acute-onset vertigo. Migraine

COMMON CAUSES OF NONSPECIFIC DIZZINESS Patients with nonspecific dizziness are probably referred to neurologists more frequently than patients with true vertigo. These patients are usually bothered by lightheadedness (wooziness), presyncope, imbalance, motion sensitivity, or anxiety. Side effects or toxicity from

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COMMON PRESENTATIONS OF VERTIGO Patients present with symptoms rather than specific diagnoses. The most common presentations of vertigo are the following.

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can mimic vestibular neuritis, though the diagnosis of migraine-associated vertigo hinges on recurrent episodes and lack of progressive auditory symptoms.

Recurrent Attacks of Vertigo In patients with recurrent attacks of vertigo, the key diagnostic information lies in the details of the attacks. Meniere disease is the likely cause in patients with recurrent vertigo lasting longer than 20 minutes and associated with unilateral auditory symptoms. If the Meniere-like attacks present in a fulminate fashion, the diagnosis of autoimmune inner-ear disease should be considered. Transient ischemic attacks (TIAs) should be suspected in patients having brief episodes of vertigo, particularly when vascular risk factors are present and other neurological symptoms are reported (Josephson et al., 2008). Case series of patients with rotational vertebral artery syndrome demonstrate that the inner ear and possibly central vestibular pathways have high energy requirements and are therefore susceptible to levels of ischemia tolerated by other parts of the brain (Choi et al., 2005). Crescendo TIAs can be the harbinger of impending stroke or basilar artery occlusion. As with acute severe vertigo, accompanying auditory symptoms do not exclude the possibility of an ischemic disorder. Migraine and the migraine equivalent, BRV, are characterized by a history of similar symptoms, a normal examination, family or personal history of migraine headaches and/or BRV, other migraine characteristics, and typical triggers. Attacks are otherwise highly variable, lasting anywhere from seconds to days. If the attacks are consistently seconds in duration, the diagnosis of vestibular paroxysmia should be considered (Strupp, 2016). MS may be the cause when patients have recurrent episodes of vertigo and a history of other attacks of neurological symptoms, particularly when fixed deficits such as an afferent pupillary defect or internuclear ophthalmoplegia are identified on the examination.

Recurrent Positional Vertigo Positional vertigo is defined by the symptom being triggered, not simply worsened, by certain positional changes. Physicians often confuse vestibular neuritis with BPPV because vestibular neuritis patients can often settle into a relatively comfortable position and then experience dramatic worsening with movement. The patient complaining of recurrent episodes of vertigo triggered by certain head movements likely has BPPV, but this is not the only possibility. BPPV can be identified and treated at the bedside, so positional testing should be performed in any patient with this complaint. Positional testing can also uncover the other causes of positionally triggered dizziness (Bertholon et al., 2002). The history strongly suggests the diagnosis of BPPV when the positional vertigo is brief (30%) indicates an imbalance in the

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vestibular system but is nonlocalizing, occurring with both peripheral and central lesions. Rotational testing. For rotational testing, the patient sits in a motorized chair that rotates under the control of a computer, and the patient’s head and body move in unison with the chair. The chair is in a dark room, so visual fixation is removed. Eye movements induced by the vestibular system stimulating movements of the patient’s head and body within the chair are recorded using ENG or VNG. The computer precisely controls the velocity and frequency of rotations so that the VOR can be measured at multiple frequencies in a single session. Sinusoidal and step (impulse) changes in angular velocity are routinely used (Fig. 22.6). In clinical testing, generally only rotations about the vertical axis are used, which maximally stimulates the horizontal canals. Off-vertical rotation can be used to measure the function of the vertical semicircular canals and otoliths, but typically this is only done in research studies. For sinusoidal rotations, results are reported as gain (peak slow-component eye velocity divided by

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peak chair velocity) and phase (timing between the peak velocity of eye and head) at different frequencies. Because both inner ears are stimulated at the typically low velocities and frequencies used, rotational testing is most effective at determining a bilateral peripheral vestibular hypofunction that leads to a decreased gain and increased phase. Unilateral vestibular hypofunction can be suggested by a normal gain with increased phase on standard testing or a decreased unilateral gain with shortened time constant on impulse (rapid movement) testing. Normal rotational testing results in gains around 0.5 at low-frequency rotation (0.05 Hz), with gains approaching 1.0 at higher-frequency rotations (>1 Hz). Even patients with partial loss of bilateral vestibular function may have gains in the normal range at the higher-frequency rotations, probably owing to the contribution of additional sensory systems (Jen et al., 2005; Wiest et al., 2001). The main disadvantage of rotational chair testing is the expense associated with setting it up. As a result, this vestibular test is typically only available at large academic centers. Because of this, portable devices using either passive (examiner-generated) head rotations or active (patient-generated) head turns have been developed, but the quality of evidence to support the use of these tests is low (Fife et al., 2000). Rotational chair testing can also be used to measure the patient’s ability to suppress the VOR and a combined measure of both OKN and rotational testing (visual VOR). Quantitative head-thrust testing. New devices that enable quantitative measurement of the vestibular-ocular reflex as elicited by the head-thrust test have been developed (Halmagyi, 2017). The devices consist of goggles that contain a video camera to measure eye movement velocity and an accelerometer to measure head movement velocity. Because of its ability to determine eye and head velocity, the device-based head-thrust test is mainly focused on measuring the VOR gain to each side rather than on the presence or absence of corrective saccades, which are the focus of the non—device-based head-thrust test. The quantitative measure of the head-thrust test is an advantage of the device because corrective saccades can be imperceptible, so-called covert saccades. The head-thrust test uses much higher acceleration than caloric testing to elicit eye movements via the vestibular system so that a direct comparison of the results of these tests is not entirely appropriate. However, one comparison found that a clinically significant abnormal device-based head-thrust test result is unlikely to occur in subjects with only a mild caloric asymmetry (Mahringer and Rambold, 2014). For acute peripheral lesions, the VOR gain is typically substantially reduced on the affected side (side opposite the fast phase of nystagmus; gain ∼0.2–0.4) and normal to mildly reduced to the unaffected side (Choi, 2018). Acute lesions of the central vestibular system are typically normal to mildly reduced bilaterally when the lesion is in the distribution of the PICA. However, the VOR gains can closely mimic peripheral disorders when the lesion is in the distribution of the anterior inferior cerebellar artery. Posturography. Posturography is a method for quantifying balance. This testing consists of measuring sway while standing on a stable platform and also with tilt or linear displacement of the platform, both with eyes open and eyes closed, and also with movement of the visual surround. Posturography is not a diagnostic test and is of little use for localizing a lesion. It can be helpful for following the course of a patient and may serve as a quantitative measure of the response to therapy or in research studies. Posturography may be useful for identifying people at risk for falling, though whether it is better at this than a careful clinical assessment is unclear (Piirtola and Era, 2006). Posturography may be helpful in identifying patients with factitious balance disorders (Gianoli et al., 2000).

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Vestibular evoked myogenic potentials. It has long been known that the sacculus, which during the course of its evolution functioned as an organ of hearing and still does in primitive vertebrates, can be stimulated by loud sounds. As a result of this stimulation, a signal travels via the inferior trunk of the vestibular nerve to cranial nerve VIII and into the brainstem. From there, inhibitory postsynaptic potentials travel to the ipsilateral sternocleidomastoid muscle (SCM), essentially allowing the individual to reflexively turn toward the sound. To generate this vestibular evoked myogenic potential (VEMP) response, intense clicks of about 95–100 dB above normal hearing level (NHL) are required (Fife, 2017). The response is measured from an activated ipsilateral SCM. Tonic contraction of the muscle is required to demonstrate the inhibitory response. The amplitude of the response and also the threshold needed to generate it are measured. Because the absolute amplitudes vary greatly from patient to patient, the more reliable abnormality is detecting a side-to-side difference in an individual. In addition, responses are unreliable in subjects older than 60 years and in patients with middle ear abnormalities. Abnormal VEMP responses can be detected in most disorders affecting the peripheral vestibular system, but this test may help identify disorders that selectively affect the inferior vestibular nerve or SCD (Fife, 2017). Because caloric and rotational testing mainly stimulate the horizontal semicircular canal (which sends afferent responses via the superior vestibular nerve), the rare disorder affecting only the inferior vestibular nerve will not be identified with these tests. In patients with SCD, VEMP testing leads to increased amplitudes and lowered thresholds due to the low-impedance pathway created by the third window.

Hearing Loss and Tinnitus Auditory Testing

Audiological assessment is the basis for quantifying auditory impairment. Most neurologists rely on bedside assessments of hearing. In defining an auditory abnormality, tuning forks are no substitute for a complete audiological battery. Audiological testing is most reliable in defining peripheral or cochlear auditory disturbances and often may provide useful information, based on subtests, to diagnose retrocochlear disorders such as an acoustic neuroma. Tests for central auditory dysfunction are more difficult and poorly understood. Detailed descriptions of audiological tests, both peripheral and central, are provided in standard texts (Katz et al., 2009). The basic audiological evaluation establishes the degree and configuration of hearing loss, assesses ability to discriminate a speech signal, and provides some insight into the type of loss and possible cause. The test battery consists of pure-tone air- and bone-conduction thresholds, speech thresholds, speech discrimination testing, and immittance measures. Pure-tone testing. Pure-tone air-conduction thresholds provide a measure of hearing sensitivity as a function of frequency and intensity. When a hearing loss is present, the pure-tone air-conduction test indicates reduced hearing sensitivity. Pure tones are defined by their frequency (pitch) and intensity (loudness). NHLs for pure tones are defined by international standards. Brief-duration pure tones at selected frequencies are presented through earphones (air conduction) or a bone-conduction oscillator on the mastoid bone (bone conduction). The audiogram indicates the lowest intensity at which a person can hear at a given frequency and displays the degree (in decibels) and configuration (sensitivity loss as a function of frequency) of a hearing loss. Thresholds in audiology are usually defined as the lowest-intensity signal a person can detect approximately 50% of the time during a given number of presentations. Bone-conduction tests are intended to be a direct measure of inner-ear sensitivity. Pure-tone

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Fig. 22.7 Audiograms Illustrating Four Characteristic Patterns of Sensorineural Hearing Loss. A, Notched pattern of noise-induced hearing loss. B, Downward-sloping pattern of presbycusis. C, Low-frequency trough of the Meniere syndrome. D, Pattern of congenital hearing loss. (From Baloh, R.W., 1998. Dizziness, Hearing Loss, and Tinnitus. F.A. Davis Company, Philadelphia, Figure 39, p. 95.)

bone-conduction thresholds are obtained when a stimulus is presented by bone conduction. Comparison of air- and bone-conduction thresholds establishes the type of hearing loss. Conductive loss results from disorders in the outer or middle ear. The audiogram of patients with SCD may also have an air/bone gap, even though there is no abnormality of the outer or middle ear. This exception results from the third window created by the dehiscence, which increases bone conduction. Sensorineural loss is associated with disorders of the cochlear and eighth cranial nerves. Mixed loss is a conductive and sensorineural loss coexisting in the same ear. Typical audiogram pure-tone patterns seen in patients with four common causes of sensorineural hearing loss are shown in Fig. 22.7. Speech testing. The speech reception threshold (SRT) is the lowest-intensity level at which the listener can identify or understand two-syllable spoken words 50% of the time. This test provides a check on the validity of the pure-tone test, as it should agree (±5 dB) with an average of the two best pure-tone thresholds in the speech range (500–2000 Hz). Once the SRT is determined, the audiologist measures speech discrimination ability by presenting a standardized list of 50 phonetically balanced monosyllabic words at volume levels approximately 35–40 dB above SRT. The speech discrimination score is reported as the percentage of words the subject can correctly repeat back to the audiologist. Pure tone, SRT, and speech discrimination testing comprise the major routine measures of hearing. Considering these tests together can also provide localizing information. In patients with retrocochlear lesions, speech discrimination can be severely reduced even when

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pure-tone levels are normal or near normal, whereas in patients with cochlear lesions, discrimination tends to be proportional to the magnitude of hearing loss. Middle ear testing. Immittance measures assess the status of the middle ear and confirm information obtained in other tests of the battery. The basic immittance battery consists of tympanometry, static immittance, and acoustic reflex thresholds. Data from the tympanogram permit determination of the static compliance of the middle ear system. A result of “type A tympanogram” means that mobility of the tympanic membrane and middle ear structures is within normal limits. Acoustic reflex testing. Acoustic reflex measures the contraction of the stapedius muscle (innervated by the seventh cranial nerve) in response to a loud sound. The afferent limb of the reflex arch is through the auditory portion of the eighth cranial nerve, and the efferent portion of the reflex arch is through the seventh cranial nerve. The stapedius muscle normally contracts on both sides when an adequate sound is presented in one ear. As a result of contraction of the stapedius muscle, the tympanic membrane tightens or stiffens, thereby increasing the impedance or resistance of the eardrum to acoustic energy and resulting in a slight attenuation of sound transmitted through the middle ear system. In a normal subject, the acoustic reflex occurs in response to a pure tone between 70 and 100 dB above hearing level or when a white noise stimulus is presented at 65 dB above hearing level. Patients with conductive hearing loss due to middle ear pathology do not have reflexes because the lesion prevents a change in compliance with

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stapedius muscle contraction. With cochlear lesions, the acoustic reflex may be present at sensation levels less than 60 dB above the auditory pure-tone threshold, which is a form of abnormal loudness growth or recruitment. Cochlear hearing losses must be moderate or severe before the acoustic reflex is lost. In contrast, patients with retrocochlear or eighth cranial nerve lesions often have abnormal acoustic reflexes with normal hearing. The reflex may be absent or exhibit an elevated threshold or abnormal decay. Reflex decay is present if the amplitude of the reflex decreases to half its original size within 10 seconds of stimulation at 1000 Hz, 10 dB above reflex threshold. Observation of the pattern of acoustic reflex testing, along with hearing evaluation, permits inferences to support the presence of a cochlear, conductive, or retrocochlear lesion of the seventh or eighth cranial nerves. Evoked potentials. Brainstem auditory evoked potentials are also known as brainstem auditory evoked responses or auditory brainstem responses. These physiological measures can be used to evaluate the auditory pathways from the ear to the upper brainstem. In addition, ABR threshold testing, although not a test of hearing sensitivity, may be used to determine behavioral threshold sensitivity in infants or uncooperative patients. The most consistent and reproducible potentials are a series of five submicrovolt waves that occur within 10 msec of an auditory stimulus. These potentials are recorded by averaging 1000–2000 responses from click stimuli by use of a computer system and amplifying the response. The anatomical correlates of the five reliable potentials have been only roughly approximated. Wave I of the brainstem auditory evoked potential is a manifestation of the APs of the eighth cranial nerve and is generated in the distal portion of the nerve adjacent to the cochlea. Wave II may be generated by the eighth cranial nerve or cochlear nuclei. Wave III is thought to be generated at the level of the superior olive, and waves IV and V are generated in the rostral pons or in the midbrain near the inferior colliculus. The complex anatomy of the central auditory pathway, with multiple crossing of fibers from the level of the cochlear nuclei to the inferior colliculus, makes the interpretation of central disturbances in the evoked responses difficult. Abnormal interwave latencies (I–III or I–V) are seen with retrocochlear lesions (cerebellopontine angle tumors) and can even be seen when only mild or no hearing loss is detected on pure-tone audiometry. However, compared with brain MRI with gadolinium, the sensitivity of the ABR test is low, particularly with small tumors (Cueva, 2004). The least specific finding is the absence of all waves. This occurs in some patients with acoustic neuroma and in some with cerebellopontine angle meningiomas. Such patients often have marked hearing deficits with poor discrimination, suggesting retrocochlear disease. The absence of all waves should not occur unless a severe hearing loss exists. Other tests. Electrocochleography is a method of recording the stimulus-related electrical potentials associated with the inner ear and auditory nerve, including the cochlear microphonic, summating potential (SP), and compound AP of the auditory nerve. The amplitude of the SP and compound AP is measured; an increased SP/AP ratio suggests increased endolymphatic pressure. This test is sometimes used in an attempt to distinguish Meniere disease from other causes of dizziness and hearing loss but lacks a rigorous analysis of its usefulness when there is clinical uncertainty.

MANAGEMENT OF PATIENTS WITH VERTIGO Treatments of Specific Disorders BPPV can be diagnosed and treated at the bedside, requiring no further treatment. Once repositioning is confirmed to be successful (see Fig. 22.4), patients are instructed to avoid head-hanging positions such

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as those used by dentists and hairdressers. These positions can cause the particles to reaccumulate in the posterior semicircular canals. For patients with HC-BPPV, the “barbeque” rotation, Gufoni maneuver, or forced prolonged position can be used (Fife et al., 2008; Kim et al., 2012a; Tirelli and Russolo, 2004; Vannucchi et al., 1997). The management of patients with vestibular neuritis is primarily symptomatic. Prolonged use of sedating medications to treat symptoms is not recommended, because it can slow down the vestibular compensation process. Randomized controlled trials have found that vestibular physical therapy improves outcomes in patients with unilateral vestibulopathy, though very few of these studies were specifically performed in a vestibular neuritis population (Hillier and McDonnell, 2011). A course of corticosteroids may improve recovery of the caloric response, but studies have not revealed evidence of symptomatic and functional improvements compared with placebo (Fishman et al., 2011; Ismail, 2019). The early treatment of Meniere disease continues to be a low-salt diet and diuretics, though the evidence to support these interventions is weak (Minor et al., 2004). Minimally invasive intratympanic gentamicin injections can be used for patients with debilitating symptoms. Surgical ablation of the labyrinth and sectioning of the vestibular nerve are other options. Patients with vestibular paroxysmia may benefit from carbamazepine, oxcarbamazepine, or gabapentin (Strupp, 2017). The third window in patients with SCD can be surgically repaired but is only recommended in patients debilitated by the symptoms (Ward, 2017). Patients identified as having an infarction in the posterior fossa should be closely monitored, as herniation or recurrent stroke can occur. Patients with acute infarction presentations should be considered for tissue plasminogen activator (tPA) eligibility. Stenting of a symptomatic (i.e., TIA or nonsevere stroke) stenosis of the basilar artery or an intracranial vertebral artery has been shown to be substantially inferior to medical management (Chimowitz et al., 2011). Patients identified with demyelinating lesions may be candidates for disease-modifying treatments even after presenting with a clinically isolated syndrome. Patients with EA are typically highly responsive to treatment with acetazolamide or 4-aminopyridine, and there is anecdotal evidence of benefit of the use of acetazolamide in patients with BRV, a migraine equivalent. Patients with migraine-associated dizziness should first attempt to identify and eliminate triggers of their symptoms and also obtain adequate sleep and cardiovascular exercise. If these general measures are not adequate in controlling symptoms, a migraine prophylactic medication could be tried but clinical trials are lacking. Small trials of triptan medications in patients with migrainous vertigo suggest safety of these medicines but no significant benefit (Neuhauser et al., 2003). A phase II/III trial of rizatriptan for acute vestibular migraine has an estimated completion date of June 2019 (NCT02447991).

Symptomatic Treatment of Vertigo The commonly used antivertiginous drugs and their dosages are listed in Table 22.3 (Huppert et al., 2011). It is often difficult to predict which drugs or combinations of drugs will be most effective in individual patients, and large trials are lacking. In addition, the mechanisms of these medications are not specific to the vestibular system, so side effects are common. Anticholinergic or antihistamine drugs are usually effective in treating patients with mild to moderate vertigo, and sedation is minimal. If the patient is particularly bothered by nausea, the antiemetics prochlorperazine and metoclopramide can be effective and combined with other antivertiginous medications. For severe vertigo, sedation is often desirable, and drugs such as promethazine and diazepam are particularly useful, though prolonged use is not recommended.

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Medical Therapy for Symptomatic Vertigo*

MANAGEMENT OF PATIENTS WITH HEARING LOSS AND TINNITUS

Class

Dosage†

Antihistamines Meclizine Dimenhydrinate Promethazine

25 mg PO q 4–6 h 50 mg PO or IM q 4–6 h, or 100 mg suppository q 8 h 25–50 mg PO or IM or as a suppository q 4–6 h

Hearing aids continue to become more effective and better designed for patient comfort and acceptance, although cost remains the major limiting factor in their more widespread use. Cochlear implants have revolutionized the approach to treatment of profound sensorineural loss. The management of tinnitus remains difficult, and specific treatments are often ineffective. Patients with a specific cause for the problem usually have the most potential for improvement. Idiopathic high-pitched tinnitus may diminish with avoidance of caffeine, other stimulants, and alcohol. A masking device used in quiet environments may also provide some relief. For patients with intolerable idiopathic tinnitus, a trial of a tricyclic amine antidepressant may be of benefit.

TABLE 22.3

Anticholinergic Agent Scopolamine 0.2 mg PO q 4–6 h, or 0.5 mg transdermally q 3 days Benzodiazepines Diazepam 5 or 10 mg PO, IM, IV q 4–6 h Lorazepam 0.5–2 mg PO, IM, IV q 6–8 h Phenothiazine Prochlorperazine

The complete reference list is available online at https://expertconsult. inkling.com/.

5 or 10 mg PO or IM q 6 h, or 25 mg suppository q 12 h

Benzamide Metoclopramide

5 or 10 mg PO, IM, or IV q 4–6 h

IM, Intramuscular; IV, intravenous; PO, oral. *Huppert, D., Strupp, M., Muckter, H., et al., 2011. Which medication do I need to manage dizzy patients? Acta Otolaryngol 131, 228–241. †Usual adult starting dosage; maintenance dosage can be increased by a factor of 2–3. The most common side effect is drowsiness.

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23 Cerebellar Ataxia Sheng-Han Kuo, Chih-Chun Lin, Tetsuo Ashizawa

OUTLINE Function of the Cerebellum, 288 Signs and Symptoms for Cerebellar Ataxia, 289 Neurological Examination of Cerebellar Ataxia, 289 Laboratory Tests for Cerebellar Ataxia, 290 Neuroimaging for Cerebellar Ataxia, 291 Other Diagnostic Tests for Ataxia, 291 Acquired Causes for Ataxia, 291 Nutritional, 291 Autoimmune, 292 Infections, 295 Toxins, 295 Vascular Disease, 296 Superficial Siderosis, 296 Neoplastic, 296 Genetic Causes for Ataxia, 296 Autosomal Dominant Cerebellar Ataxias, 298 Somatic Instability of Expanded Repeats, 301

Noncoding Repeat Spinocerebellar Ataxias, 301 Repeat Associated Non-AUG Translation, 302 Transcripts from the Opposite Strand, 302 Other Mutations Causing Spinocerebellar Ataxias, 302 Autosomal Recessive Cerebellar Ataxias, 303 Autosomal Recessive Cerebellar Ataxias with Abnormal Mitochondrial Function, 306 X-linked Ataxia, 307 Degenerative Causes, 307 Idiopathic Late-Onset Cerebellar Ataxia, 307 Multiple System Atrophy—Cerebellar Type, 308 Functional (Psychogenic) Ataxia, 308 Management, 308 Pharmacological Treatments, 308 Nonpharmacological Treatments, 309 Targeted Molecular Therapy, 309

The cerebellum, a unique brain structure with distinctly organized neuronal circuits, is critical for motor and cognitive functions. The cerebellum has dense neuronal connections with almost all regions of the cerebral cortex and brainstem, and can serve as a “hub” to regulate the many brain functions. While cerebellar dysfunction has been implicated in tremor, dystonia, and autism, the prototypical disorder of the cerebellum is cerebellar ataxia, a clinical sign that can have a variety of causes, including nutritional deficiency, immunological dysfunction, vascular and degenerative etiologies, and genetic mutations. Searching for genetic causes for ataxia is particularly relevant because the genetic mutations for ataxia often have very high penetrance; therefore, genetic identification for cerebellar ataxia is often diagnostic. In addition, there are many genetic mutations associated with cerebellar ataxia, which indicates that these genetic mutations converge at the dysfunction of the cerebellar circuitry, highlighting the complex biological processes required to maintain the integrity of this brain structure. The diagnosis of cerebellar ataxia is often regarded as very complicated by neurologists. To simplify and streamline the search for the causes of cerebellar ataxia, this chapter aims to provide a step-bystep approach. In brief, the first step is to recognize the signs and symptoms for ataxia and associated neurological features. The second step is to search for the structural, nutritional, and immunological causes of ataxia. If genetic ataxias are considered, repeat expansions needed to be determined before genetic sequencing for mutations because repeat expansion–associated ataxias are much more common, and more difficult to detect using conventional sequencing technologies. Finally, degenerative etiologies are likely the causes for ataxia onset at an old

age. Of note, a significant portion of ataxia patients might eventually have no identifiable causes during life; these patients usually follow a slowly progressive clinical course. Complex environmental and genetic interactions, epigenetic alterations, or regional genetic somatic mosaicism might explain some of these cases; these remain underexplored areas in cerebellar ataxia. This chapter describes clinical features, imaging findings, and genetics for the differential diagnoses of cerebellar ataxia, providing a guide for clinicians. However, the detailed genetic diagnosis of cerebellar ataxia can be very extensive, and is beyond the scope of this chapter. Instead, this chapter only includes the common causes of genetic ataxia.

FUNCTION OF THE CEREBELLUM The motor part of the cerebellum receives sensory inputs from the outside environment to calculate the proper movements in response. These sensory inputs could be either from tactile sensory nerves or from the vestibular system; therefore, the dysfunction of these systems is sometimes difficult to distinguish from the primary problems of the cerebellum. The current understanding of how the cerebellum integrates sensorimotor information is based on Marr-Albus-Ito theory, in which the cerebellum can function as a neuronal learning machine (Boyden et al., 2004). This theory is based on the physiological recording and anatomical connections of the cerebellar circuitry that are capable of altering synaptic strength in responses to motor learning. Dysfunction of the cerebellar circuitry thus results in erroneous motor

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Ataxia

Clearly secondary to a known underlying sporadic disease on initial workup? NO

YES

Family history?

Genetic basis already identified in family member?

Genetic ataxia panel.

YES

NO

WGS /WES

Specific genetic ataxia

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YES Full recessive ataxia work-up (WGS/WES).

Unknown genetic ataxia

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NO

Autonomic dysfunction, parkinsonism, and other characteristics of MSA? YES

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ILOCA

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NO

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YES YES

MSA

Limited screen for dominant and recessive ataxias.

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YES Specific genetic testing.

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NO DNA test for CANVAS and FXTAS.

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Re-evaluation of clinicaI presentation and, if appropriate, further testing for rare causes of sporadic ataxia.

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NO

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YES WGS /WES

YES

Fig. 23.1 The Diagnostic Workflow for Cerebellar Ataxia. AD, Autosomal dominant; AR, autosomal recessive; CANVAS, cerebellar ataxia, neuropathy, vestibular areflexia syndrome; Cbl, cerebellum; FA, Friedreich ataxia; FXTAS, fragile X-associated tremor and ataxia syndrome; GAD, glutamate decarboxylase; ILOCA, idiopathic late-onset cerebellar ataxia; MSA, multiple system atrophy; RBD, rapid eye movement behavior disorder; SCA, spinocerebellar ataxia; WES, whole exome sequencing; WGS, whole genome sequencing. (Modified from Continuum, 2019.)

learning and improper motor predictions and commands, leading to symptoms of ataxia and/or tremor. The same principles that hold for the motor cerebellum can be applied to nonmotor regions of the cerebellum, which have many connections to frontal, parietal, and temporal areas of the cerebral cortex. Therefore, dysfunction of the nonmotor cerebellum has been postulated to cause inappropriate prediction of emotional and cognitive responses; this is known as cerebellar cognitive affective syndrome (Schmahmann and Sherman, 1998). Further studies in physiology and anatomy of the cerebellum will provide a more comprehensive understanding of cerebellar function and will accelerate therapy development for cerebellar ataxia.

SIGNS AND SYMPTOMS FOR CEREBELLAR ATAXIA Recognizing the early symptoms of cerebellar ataxia is an important first step in establishing the symptom onset and the chronicity of the disease. Table 23.1 lists the common early symptoms of cerebellar ataxia. The first symptom is usually gait difficulty (Luo et al., 2017), which can manifest as “walking as if one is drunk,” difficulty in running, turning, walking on high heels, and walking up or down stairs without holding on to the railings. These symptoms could be intermittent in the very early stage and patients might experience these symptoms only after ingestion of small amount of alcohol. Later on, these symptoms could become constant. Beyond abnormal gait, slurred speech, from occasional word pronunciation difficulty to persistent speech problems, is often encountered. Tremor of the hands is also commonly experienced by patients with ataxia (Gan et al., 2017). Clumsiness and bad handwriting are sometimes described by patients. Dizziness (vertiginous or nonvertiginous) is another @

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symptom associated with cerebellar ataxia. Double vision, particularly when patients turn their heads quickly, is also another common symptom. In the later stages of cerebellar ataxia, patients might experience falls, swallowing difficulty, blurry vision, and loss of hand dexterity in performing daily activities such as dressing and using utensils. After establishing the symptoms of cerebellar ataxia, the next step is to determine the chronicity of these symptoms (acute vs. subacute vs. chronic) and the rate of progression, which will be important for the differential diagnosis (Table 23.2). In acute-onset cerebellar ataxia, infectious, vascular, and toxic causes need to be considered. For subacute-onset cerebellar ataxia, immune-mediated etiology would be on top of the differential diagnoses. Genetic and degenerative cerebellar ataxias usually have insidious onset with progressive clinical courses. Another category is episodic cerebellar ataxia, which encompasses various causes (see Table 23.2). Besides recognizing the symptoms of cerebellar ataxia, identification of associated neurological signs is equally important, because these additional symptoms can often provide diagnostic clues. The commonly associated symptoms are peripheral neuropathy, parkinsonism, dystonia, tremor, sleep dysfunction, autonomic symptoms, seizures, and hearing loss.

NEUROLOGICAL EXAMINATION OF CEREBELLAR ATAXIA The neurological examination of cerebellar ataxia constitutes five domains: eyes, speech, hands, legs, and gait. Scale for Assessment and Rating of Ataxia (SARA) is a commonly used clinical scale to assess different domains of cerebellar ataxia, except for the eye movements (Schmitz-Hubsch et al., 2006). The SARA scale encompasses the D1 F CD @ 2C @ C

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Common Neurological Problems normally. Variable stride length and/or veering toward one side are common gait patterns in the early stage of cerebellar ataxia. A widebased gait usually develops as a compensatory mechanism in the moderate and severe stage of cerebellar ataxia (Video 23.2). In other words, depending on the disease stage and individual compensatory strategy, the ataxic gait might differ. To detect subtle difficulty in gait, observing patients running or walking up or down stairs can be useful. Ataxia patients usually have truncal sways while standing still and sometimes when sitting without back support. To further identify subtle ataxia in the stance examination, patients are asked to stand with feet together, to stand on tandem stance, to stand on either foot, or to hop on either foot. Scanning speech is a classic speech associated with cerebellar ataxia, slow, with characteristic irregular force and unnecessary hesitation between some words. Words are usually broken into separate syllables. In hand examination, three maneuvers are often used: nose-finger tests (the patient points repeatedly with his index finger from his nose to examiner’s index finger as precisely as possible), finger chase (the patient’s index finger follows examiner’s moving index finger as precisely as possible), and fast alternating movements (the patient performs repetitive alternation of pronation and supination of the hand). Patients with cerebellar ataxia often exhibit intention tremor, as increasing amplitude of oscillatory movements when voluntarily approaching a target, in the finger-nose test; over- or undershoot in the finger chase test; and slow and abnormal rhythm in the fast alternating movements. In the leg examination, ataxia patients are instructed to lift one leg, point with the heel to the opposite knee, and slide down along the shin to the ankle. Ataxia patients often have the heel falling off the shin during the slide. Functionally, one can consider this as the leg equivalent of the nose-finger test. In patients with cerebellar ataxia, abnormal eye movements are common and sometimes can be diagnostic (Video 23.3). Neurologists should assess eyes in the fixation position, during smooth pursuit, and in saccadic movements. Certain eye movement abnormalities might be associated with specific types of ataxias: for example (1) squarewave jerks (saccadic intrusion in the fixed gaze) in Friedreich ataxia, (2) end-gaze nystagmus in many types of ataxia, (3) hypo- or hypermetric saccades, also in many types of ataxia, (4) breakdown of smooth pursuit (saccadic pursuit) in spinocerebellar ataxia type 3 (SCA3), (5) slow saccades in SCA2 (Video 23.4), (6) ophthalmoplegia/ophthalmoparesis in sensory axonal neuropathy with dysarthria and ophthalmoplegia (SANDO) syndrome with DNA polymerase gamma-1 (POLG) mutations, (7) ptosis in SANDO syndrome and mitochondrial ataxia, and (8) impaired vertical saccades in Niemann-Pick type C. Many mimickers resemble cerebellar ataxia or present with overlapping symptoms (Table 23.3). As such, neurological examinations should also assess the associated signs, such as tremor, dystonia, myoclonus, parkinsonism, sensory neuropathy, muscle weakness, and pyramidal signs. Note that sensory neuropathy could be a predominant feature in certain ataxia syndromes in the early stage of the disease, such as Friedreich ataxia and POLG-ataxia. Detailed physical examination sometimes can yield additional information for the diagnosis, such as telangiectasia for ataxia telangiectasia, splenomegaly for Niemann-Pick type C, scoliosis and pes cavus for Friedreich ataxia.

Signs and Symptoms for Cerebellar Ataxia TABLE 23.1

Early Signs and Symptoms Difficulty in running Difficulty in walking Difficulty in turning Difficulty in walking in high heels Difficulty in walking up and down stairs without holding on to the railings Sensitive to alcohol; balance become worse after a small amount of alcohol Slurred speech; occasionally difficult to be understood Clumsiness in handwriting Dizziness Double vision, particularly when turning head quickly Incidental finding of cerebellar atrophy on neuroimaging studies Hand tremor Late Signs and Symptoms Falls Swallowing difficulty Blurry vision Clumsiness in hands, difficulty in dressing and using utensils

TABLE 23.2 Acute, Subacute, Chronic, and Episodic Causes of Cerebellar Ataxia Acute Causes of Cerebellar Ataxia (Minutes to Few Days) Vascular causes: ischemic or hemorrhagic cerebellar strokes Alcohol intoxication Toxins (mercury, thallium, toluene, solvents) Medication-related (phenytoin, carbamazepine, phenobarbital, lithium) Multiple sclerosis Meningitis, particularly basilar meningitis Viral cerebellitis Cerebellar abscess Wernicke encephalopathy/thiamine deficiency Subacute Causes of Cerebellar Ataxia (Weeks to Months) Paraneoplastic cerebellar degeneration Brain tumors Creutzfeldt-Jakob disease Superficial siderosis Anti-GAD ataxia* Tuberculosis meningitis Chronic Causes of Cerebellar Ataxia (Months to Years) Ataxia associated with gluten sensitivity Genetic ataxia Mitochondrial disease Multiple system atrophy Idiopathic late-onset cerebellar ataxia Episodic Causes of Cerebellar Ataxia Genetic episodic ataxia Psychogenic ataxia Mitochondrial disease Multiple sclerosis

LABORATORY TESTS FOR CEREBELLAR ATAXIA

*GAD, Glutamate decarboxylase.

following: (1) gait, (2) stance, (3) sitting, (4) speech, (5) finger chase, (6) nose-finger, (7) fast alternating hand movements, and (8) heelshin slide. Video 23.1 demonstrates a complete examination of the SARA scale. For the gait examination, ataxia patients are asked to walk @

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Serum and cerebrospinal fluid (CSF) biomarkers can be useful in diagnosing nutritional, immune-mediated, and autosomal recessive ataxia with metabolic dysfunction (certain forms of the latter). Serum levels of vitamin B1, B12, and E should be tested for deficiency. Vitamin B1 deficiency causes Wernicke encephalopathy and can occur in a variety of clinical settings, such as cancer and malnutrition, besides alcoholism (Kuo et al., 2009). Vitamin E deficiency is relatively rare and can occur D1 F CD @ 2C @ C

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CHAPTER 23 Cerebellar Ataxia Video 23.1 Neurological Examinations of a Case of SCA1. While walking, the patient exhibits variable stride length and walking directions. In the stance examination, she has increased body sways and difficulty in tandem stance. She has mild truncal sways while sitting and dysarthria while talking. She has overshoot in her finger-chase examination and intention tremor in her finger-nose examination. Her rapid alternating movements are slow. Finally, her heel falls off her shin several times during the heel-shin slide examination.

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Video 23.2 Different Gait difficulties in Ataxia Patients. Turning difficulty in a patient with SCA1 (Segment 1). Variable stride length and different walking directions in a patient with POLG-ataxia (Segment 2). A slight wide-based gait in a patient with SCA6 (Segment 3). A marked wide-based gait in a patient with SCA35 (Segment 4).

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Video 23.3 Various Eye Movement Abnormalities in Cerebellar Ataxia. End-gaze nystagmus in POLG-ataxia (Segment 1). Slow saccades in SCA2 (Segment 2). Hypermetric saccades in SCA1 (Segment 3). Hypometric saccades in multiple system atrophy, cerebellar type (Segment 4). Impaired vertical saccades with relatively preserved horizontal saccades in Niemann-Pick type C (Segment 5).

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Video 23.4 A Case of SCA2. Dysarthria, slow saccades, dysmetria in the finger-chin test, impaired rapid alternating movements, overshoot in the finger-chase examination, hyporeflexia, and a wide-based gait with variable walking directions.

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Differential Diagnosis and Conditions That Might Mimic Cerebellar Ataxia TABLE 23.3

Sensory neuropathy Parkinsonism Magnetic gait/normal-pressure hydrocephalus Vestibular problems Upper motor neuron symptoms/spasticity Muscle weakness Orthopedic issues Pain-related gait disturbance

in two forms of recessive ataxia: ataxia with vitamin E deficiency and abetalipoproteinemia. Serum autoantibodies can indicate specific immune-mediated causes of ataxia, such as ataxia associated with anti-glutamate acid decarboxylase (GAD) antibodies, anti-thyroperoxidase (TPO) antibodies (for steroid-responsive encephalopathy), paraneoplastic antibodies, anti-gliadin and anti-tissue transglutaminase antibodies (for gluten ataxia). Serum antibody levels are often diagnostic, especially when high levels of antibodies are present; occasionally, these autoantibodies can be only be detected in the CSF. Therefore, a lumbar puncture is warranted when immune-mediated ataxia is suspected, especially in cases with subacute onset of ataxia without marked cerebellar atrophy in the imaging studies. Infectious and inflammatory etiologies should also be examined in the CSF. CSF analysis can provide additional information; for instance, a high protein 14-3-3 level can be seen in Creutzfeldt-Jakob disease (CJD), whereas a low CSF glucose level might point toward ataxia with glucose transporter type 1 deficiency. Serum metabolic biomarkers sometimes can be helpful in identifying several forms of autosomal recessive ataxia. Ataxia telangectasia and ataxia with oculomotor apraxia type 2 both have elevated serum alpha fetoprotein levels, and cerebrotendinous xanthomatosis can have elevated blood cholestanol levels.

NEUROIMAGING FOR CEREBELLAR ATAXIA Brain magnetic resonance imaging (MRI) should be obtained in ataxia patients. This enables visualization of demyelinating, vascular, and structural causes for ataxia, such as multiple sclerosis, brain tumors, abscess, and ischemic or hemorrhagic strokes. Cerebellar cortical atrophy is the most common finding, and clinicians should assess the degree of the cerebellar atrophy in different cerebellar lobules and in vermis, paravermis, and hemisphere (Fig. 23.2, A–C). Prominent CSF space between cerebellar folia indicates the underlying degeneration. An enlarged fourth ventricle is often associated with cerebellar atrophy (see Fig. 23.2, D). The cerebellum is divided into motor (predominantly anterior) and nonmotor (predominantly posterior) regions (Stoodley and Schmahmann, 2010). Therefore, clinicians should pay special attention to patients with prominent atrophy in the posterior lobules of the cerebellum and assess their cognitive dysfunction and emotional liability. In addition, speech and gait ataxia is associated with vermal atrophy, whereas appendicular ataxia is associated with paravermal atrophy. As mentioned above, certain forms of ataxia have predominant sensory neuropathy in the early stage (e.g., Friedreich ataxia, ataxia with vitamin E deficiency and POLG-ataxia); therefore, there might be no obvious cerebellar atrophy on the brain MRI. Clinicians should also look for specific changes associated with certain forms of cerebellar ataxia. Fragile X–associated tremor and ataxia syndrome has T2-hyperintensity in the bilateral middle

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cerebellar peduncles (see Fig. 23.2, E). Wernicke encephalopathy has T2 hyperintensity in the mamillary bodies, periaqueductal gray, and paraventricular thalamus (Kuo et al., 2009). and adult-onset Alexander disease can have prominent subcortical white matter changes. POLG-ataxia, adult-onset Alexander disease, and ataxia with gluten sensitivity can have T2 hyperintensity in the bilateral inferior olivary nucleus (see Fig. 23.2, F). Multiple system atrophy can have either a hot-cross-bun sign (a T2 hyperintense cross sign in the pons, associated with the cerebellar type, Fig. 23.2, G) or linear T2 hyperintensity along the outer rim of the striatum (associated with the parkinsonism type, Fig. 23.2, H). Superficial siderosis has hypointensity along the surface of the cerebellum and brainstem in the gradient echo sequence (GRE; see Fig. 23.2, I). CJD has cortical ribboning on the diffusion-weighted imaging (DWI). While the presence of these features can help with the diagnosis, the absence of these features does not exclude these causes of cerebellar ataxia. In addition to brain MRI, a dopamine transporter scan can be used to test the involvement of the dopamine system, which can be seen in multiple system atrophy.

OTHER DIAGNOSTIC TESTS FOR ATAXIA In addition to brain imaging studies, physiological measures can help to identify the involvement of additional systems. Autonomic nervous tests for orthostatic hypotension and/or urinary disturbance together with a sleep study to demonstrate rapid eye movement behavior disorder suggest the diagnosis of MSA. Electromyography and conduction studies can assess the associated motor-sensory neuropathy. In patients with ataxia and sensory neuropathy, the diagnosis of POLG-ataxia can be supported by muscle biopsy, demonstrating increased succinate dehydrogenase (SDH) expression as the result of mitochondrial proliferation (Fig. 23.3, A). In patients with CJD, an electroencephalogram may show typical periodic sharp-wave complexes, and brain biopsy may demonstrate spongiform changes (see Fig. 23.3, B).

ACQUIRED CAUSES FOR ATAXIA Before one starts searching for genetic causes of cerebellar ataxia in a patient, it is important to identify acquired causes of ataxias, as some of them are potentially treatable or partially reversible, in contrast to genetic cerebellar ataxias. Common acquired causes of ataxias include metabolic (nutrition, toxins), vascular insults (ischemic stroke, bleed), neoplasms, infections, and autoimmune reactions (Table 23.4).

Nutritional

Vitamin B1/Thiamine

Thiamine deficiency can lead to Wernicke encephalopathy, which may present with altered mental status, ophthalmoplegia, and ataxia (Zubaran et al., 1997). While thiamine deficiency is frequently associated with chronic alcohol use, there is evidence that thiamine deficiency can cause cerebellar dysfunction independent of alcohol toxicity (Collins and Converse, 1970). Proposed mechanisms of thiamine-deficiency-induced ataxia include tissue edema, altered blood-brain barrier integrity, impaired energy metabolism, reduced thiamine-utilizing enzymes in cerebellum and subsequent loss of amino acids, lactic acidosis, excitotoxicity, mitochondrial uncoupling, oxidative stress, reactive microglia, apoptosis, and microvascular damage (Mulholland, 2006).

Vitamin E (α-Tocopherol) Acquired vitamin E (α-tocopherol) deficiency can occur in patients with insufficient intake or poor absorption. Vitamin E deficiency can also be hereditary, stemming from mutations in the gene for α-tocopherol

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Fig. 23.2 Sagittal T1 brain magnetic resonance imaging (MRI) demonstrates cerebellar atrophy in a patient with idiopathic late onset cerebellar ataxia. There is prominent cerebellar foliation and sulci in the vermis (A), paravermis (B), and hemisphere (C). Prominent sulci also noted in the axial fluid-attenuated inversion recovery (FLAIR) sequence in the same individual (D). T2 sequence of the axial brain MRI demonstrates hyperintensity in the bilateral cerebellar peduncles in a patient with fragile X–associated tremor and ataxia syndrome (arrows, E). T2 sequence of the axial brain MRI demonstrates hyperintensity in the bilateral inferior olivary nuclei in a patient with POLG-ataxia (arrows, F). T2 sequence of the axial brain MRI shows the hyperintensity of a cross sign in the pons (hot-cross-bun sign) in a patient with multiple system atrophy (G). Another patient with multiple system atrophy has bilateral linear hyperintensity in the outer rim of the striatum in the FLAIR sequence (arrows, H). Gradient echo sequence (GRE) of the axial brain MRI demonstrates linear hypointensity surrounding the brainstem in a patient with superficial siderosis (arrows, I).

transfer protein in ataxia with vitamin E deficiency or mutations in the MTTP gene in abetalipoproteinemia (Harding et al., 1985; Ouahchi et al., 1995). Patients typically present with progressive cerebellar ataxia with limb and gait changes, titubation of the head, and evidence of peripheral neuropathy. Ataxia with vitamin E deficiency and abetalipoproteinemia are further discussed under genetic ataxias (see below). @

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Autoimmune

Paraneoplastic Cerebellar Degenerations Paraneoplastic cerebellar degenerations (PCDs) are the most frequently encountered paraneoplastic neurological syndrome (around 24.3%; Giometto et al., 2010). Patients with PCDs usually present with a subacute-onset cerebellar syndrome over several months (Shams’ili D1 F CD @ 2C @ C

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B Fig. 23.3 Muscle biopsy demonstrates mitochondrial dysfunction in a patient with POLG-ataxia. Combined succinate dehydrogenase (SDH) (blue) and cytochrome c oxidase (COX) (brown) stain shows COX-negative fibers with strong SDH expression, indicating that these muscle fibers have respiratory chain defects with corresponding mitochondrial proliferation as a compensatory response (arrows, A). (Modified from Kuo et al., 2017. Neurology 89, e1–e5.) Postmortem examination of the basal ganglia in a case of Creutzfeldt-Jakob disease demonstrates spongiform changes (B).

Acquired Causes of Ataxia

TABLE 23.4 Entity

Diagnostic Process

Vascular Disease Hypoxic encephalopathy Demyelinating disease Tumors in the posterior fossa Cranio-vertebral junction anomalies Toxic Disorders Alcohol Chemotherapy (5-fluorouracil, ara-C, methotrexate) Metals (mercury, bismuth, lithium, lead) Solvents (toluene) Anticonvulsants (phenytoin) Infectious/Inflammatory Disease Acute cerebellar ataxia of childhood, acute cerebellitis Post-infectious Bickerstaff encephalitis Human immunodeficiency virus (HIV) Creutzfeldt-Jakob disease (CJD) Whipple disease Autoimmune: Paraneoplastic Gluten sensitivity Anti-GAD ataxia Anti-GluRδ2 ataxia Superficial siderosis Nutritional: Vitamin B1 deficiency Vitamin B12 deficiency Vitamin E deficiency

History of strokes, imaging History of hypoxic episodes Remitting and relapsing episodes, imaging, CSF analysis Imaging Imaging History

History, imaging, serology, CSF analysis History, imaging, CSF analysis Imaging, CSF analysis Serology CSF 14-3-3, imaging, electroencephalogram, biopsy Small intestine biopsy Serology Anti-Hu, anti-Yo, anti-Ri, others Anti-gliadin, anti-tissue transglutaminase Anti-GAD Anti-GluRδ2 Imaging Blood Vitamin B1 level Vitamin B12 level Vitamin E level

CSF, Cerebrospinal fluid; GAD, glutamate decarboxylase.

et al., 2003). Neurological symptoms may precede the diagnosis of the neoplasm (Ducray et al., 2014; Shams’ili et al., 2003). Brain MRI typically demonstrates cerebellar atrophy, although it may be normal at an early stage (de Andres et al., 2006; Mitoma et al., 2017). Onconeural

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antibodies associated with PCDs include anti-Yo, anti-Hu, anti-Ma, anti-Ri, anti-VGCC, anti-CV2/CRMP5, anti-Tr/DNER, and antimGluR1 (Ducray et al., 2014; Shams’ili et al., 2003). The most common cancers associated with PCDs are small-cell lung cancer, ovarian

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Fig. 23.4 A 51-year-old man with bilateral hearing loss and progressive ataxia. Brain magnetic resonance imaging (MRI) demonstrates hyperintensity in the left medial temporal region on an axial fluid-attenuated inversion recovery (FLAIR) sequence (A) and cerebellar atrophy on a sagittal T1 sequence (B). Postmortem examination shows the granuloma in the cerebellar cortex (C), confirming the diagnosis of neurosarcoidosis.

tumor, breast cancer, and Hodgkin lymphoma (Ducray et al., 2014; Shams’ili et al., 2003). The role of onconeural antibodies is still unclear as most of the targets are intracellular antigens, which limits antibody accessibility (Mitoma et al., 2017). The mainstream treatment is to identify and treat underlying cancer. However, the response to either immunotherapy or to the tumor itself has been poor (Hoffmann et al., 2008; Shams’ili et al., 2003).

Neurosarcoidosis Sarcoidosis is a chronic inflammatory disease with formation of non-caseating granulomas. About 3%–10% of patients with sarcoid have involvement of the central nervous system (CNS; Ungprasert and Matteson, 2017). Cerebellar symptoms arise when the cerebellum or its in- or outflow tracts are affected by neurosarcoid. The brain MRI typically shows hyperintensity changes on fluid-attenuated inversion recovery (FLAIR) images (Fig. 23.4, A). In chronic cases, cerebellar atrophy may be seen (see Fig. 23.4, B). Confirmation of diagnosis requires biopsy demonstrating non-caseating granulomas (see Fig. 23.4, C).

Gluten-Sensitive Ataxia Gluten-sensitive ataxia was initially categorized as part of the extra-intestinal manifestation of celiac disease (gluten-sensitive enteropathy), but increasing evidence suggests that these and gluten-sensitivity with skin involvement (dermatitis herpetiformis) may all belong to the spectrum of “gluten sensitivity” (Hadjivassiliou et al., 2003). Patients with gluten-sensitive ataxia manifest with progressive ataxia, with limb, truncal, and ocular involvement that worsens slowly over the years (Hadjivassiliou et al., 2003). Thirteen percent of the patients have gastrointestinal symptoms, suggesting an overlapping syndrome with gluten-sensitive enteropathy. Similar to celiac disease, adopting a gluten-free diet may improve the symptoms of glutensensitive ataxia (Hadjivassiliou et al., 2003a, 2003b, 2013). In addition to anti-gliadin antibodies found in patients with gluten sensitivity, antibodies against transglutaminase 6 (anti-TG6) are recently found to be associated with gluten-sensitive ataxia (Hadjivassiliou et al., 2008). Injection of antibodies with reactivity to TG2 and

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TG6 to mice can cause ataxia, suggesting that anti-TG6 may have a pathogenic role (Boscolo et al., 2010).

Anti-Glutamic Acid Decarboxylase Ataxia Antibodies against GAD, the rate-limiting enzyme for γ-aminobutyric acid (GABA) synthesis, are associated with neurological conditions including stiff person syndrome, limbic encephalitis, epilepsy, and cerebellar ataxia (Saiz et al., 2008). Most of the patients with cerebellar ataxia with anti-GAD antibodies present with an insidious-onset gait and limb ataxia, dysarthria, and nystagmus. Peripheral neuropathy or rigidity in the leg may also be seen (Honnorat et al., 2001). It is more commonly seen in women (80%–90%; Mitoma et al., 2017). MRI may show cerebellar atrophy (Honnorat et al., 2001). The pathogenic role of anti-GAD antibody is still unclear, although rats infused with anti-GAD antibodies seem to have more irregular gait (Manto et al., 2015). In patients with subacute-onset anti-GAD ataxia treated with intravenous immunoglobulin (IVIG) with corticosteroid or other immunosuppressors, 35% showed improvement (Arino et al., 2014).

Steroid-Responsive Encephalopathy Associated with Autoimmune Thyroiditis Steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT) is also called Hashimoto encephalopathy. It is an encephalopathy associated with antithyroid antibodies (e.g., antithyroperoxidase and antithyroglobulin antibodies; Castillo et al., 2006). The role of antithyroid antibodies is still unclear, and there is still debate whether its presence is coincidental. Another antibody associated with SREAT is anti-NAE, an antibody against the N-terminus of α-enolase, and its pathogenic role is again undetermined (Yoneda et al., 2007). Patients may present with a wide range of neuropsychiatric symptoms, including altered mental status, psychosis, cognitive impairment, seizure, cerebellar ataxia, and other involuntary movements (Brain et al., 1966; Shaw et al., 1991).

Acute Cerebellitis Acute cerebellitis is an inflammatory process involving the cerebellum, affecting children more than adults. Clinical presentation includes

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CHAPTER 23 Cerebellar Ataxia ataxia, nausea, vomiting, headache, dysarthria, fever, nystagmus, vertigo, and altered mental status. The onset of symptoms is typically preceded by a viral infection or recent vaccination (Connolly et al., 1994; De Bruecker et al., 2004; van der Maas et al., 2009). The delayed onset of ataxia after a prodromal infection and the specific targeting of cerebellum suggest acute cerebellitis is more likely an immune-mediated inflammatory disorder rather than the result of a direct infection to the cerebellum. The infectious agent may be detected by polymerase chain reaction (PCR) or by elevated serum immunoglobulin M (IgM) titer against an organism, but in most cases, the etiology was never identified. Organisms associated with acute cerebellitis include varicella zoster virus, Epstein-Barr virus, mumps, influenza, herpes simplex virus 7, cytomegalovirus, Coxsackie virus, enterovirus, and Mycoplasma pneumoniae (Desai and Mitchell, 2012; Sawaishi and Takada, 2002; Van Samkar et al., 2017). The prognosis is usually self-limiting, but severe cases may sustain permanent neurological deficits.

Bickerstaff Encephalitis Bickerstaff encephalitis is characterized by progressive ophthalmoplegia, ataxia, and altered consciousness or hyperreflexia (Bickerstaff and Cloake, 1951). Bickerstaff encephalitis is similar to Fisher syndrome, which consists of ophthalmoplegia, ataxia, and areflexia (Fisher, 1956). Both are associated with elevated serum anti-GQ1b antibodies (Chiba et al., 1992; Yuki et al., 1993), and now the two are considered entities that are in the same spectrum. Patients with Bickerstaff encephalitis may have hyperintensity on the T2-weighted images, involving brainstem, cerebellum, thalamus, or subcortical white matter (Odaka et al., 2003). The imaging findings of cerebellar and brainstem involvement as well as the few autopsy cases (Al-Din et al., 1982; Bickerstaff, 1957; Odaka et al., 2003) suggest that the ataxia in Bickerstaff encephalitis is more likely to be cerebellar. In contrast, the ataxia in Fisher syndrome is more likely the result of proprioception impairment: namely, sensory ataxia. However, patients with Fisher syndrome may also have abnormalities on MRI, making the debate unsettled (Ito et al., 2008).

CLIPPERS As the name indicates, chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a chronic inflammatory process of the pontine region that responds to steroids, and pathological findings showed predominant perivascular lymphocytic inflammation (Tobin et al., 2017). Patients present with subacute-onset gait ataxia and diplopia along with dysarthria, tingling of the face, dizziness, nystagmus, and paraparesis (Pittock et al., 2010). MRI shows small punctate of gadolinium enhancement (Tobin et al., 2017). Corticosteroid is the treatment of choice, but maintenance immunosuppressant is required. Most patients experienced improvement with treatment, and in a study 10 out of 23 patients had complete resolution of MRI findings (Tobin et al., 2017).

Infections

Creutzfeldt-Jakob Disease CJD can present with mainly cerebellar ataxia before developing other cognitive symptoms (Jellinger et al., 1974). CJD is a form of rapidly progressive dementia caused by misfolded prion protein, PrP, encoded by the gene PRNP (Goldgaber et al., 1989; Prusiner, 1998). Polymorphism of the PRNP gene affects the clinical phenotype (Parchi et al., 1999). In patients expressing a 21 kDa PrP with homozygous methionine at codon 129 (MM1), 33% presented with cerebellar ataxia at symptoms onset, whereas in patients carrying heterozygous methionine/valine at codon 129 (MV1), 75% presented with cerebellar

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ataxia at onset (Parchi et al., 1999). Diagnostic tools include MRI DWI sequence showing cortical ribbon sign and double hockey stick sign, elevated CSF 14-3-3 protein, CSF RT-QuIC and protein misfolding cyclic amplification (PMCA) test, electroencephalogram with periodic sharp wave complex, and spongiform pathology on brain biopsy (see Fig. 23.3, B).

Whipple Disease Whipple disease is a chronic multisystemic infectious disease caused by Tropheryma whipplei. The incidence is about 1 per 1,000,000 (Sieracki, 1958). It predominantly affects the gastrointestinal tract, leading to abdominal pain, diarrhea, and weight loss. Involvement of the CNS can occur in 6%–43% of the patients (Louis et al., 1996). Among the patients with CNS Whipple disease, 11%–45% have cerebellar ataxia. Other neurological symptoms include cognitive impairment, seizure, psychiatric symptoms, supranuclear gaze palsy, cranial nerve involvement, upper motor neuron signs, and myoclonus. The pathognomonic symptoms for CNS Whipple disease, oculomasticatory myorhythmia, and oculo-facial-skeletal myorhythmia, occur in about 20% of patients (Compain et al., 2013; Louis et al., 1996; Matthews et al., 2005). PCR can detect T. whipplei in CSF in 92% of patients with CNS Whipple disease (Compain et al., 2013).

Listeria Encephalitis Infection caused by Listeria monocytogenes typically presents as self-limited gastroenteritis. However, L. monocytogenes can also cause meningitis, encephalitis, and brain abscess owing to its CNS tropism (Lorber, 2007; Moragas et al., 2011; Streharova et al., 2007). Interestingly, Listeria encephalitis tends to involve just the brainstem: hence the term “rhombencephalitis”. Clinical symptoms may include cranial nerve palsy (single or multiple), altered mental status, and cerebellar ataxia. Arrhythmia or respiratory compromise may occur, depending on the extent of the brainstem involvement. Although less frequent, basal ganglia, thalami, cerebral cortex, and spinal cord may also be affected (Arslan et al., 2018).

Human Immunodeficiency Virus In patients with human immunodeficiency virus (HIV) infection, neurological symptoms may arise from direct toxicity of HIV to the nervous system, opportunistic infection, side effects of antiretroviral agents, and increased risk of developing CNS lymphoma (Gerstner and Batchelor, 2010). Cerebellar ataxia can be the result of lymphoma or a localized opportunistic infection in the posterior fossa (e.g., progressive multifocal leukoencephalopathy [PML] or toxoplasmosis). PML is caused by the death of the oligodendrocytes and loss of myelination as the result of JC virus reactivation in immunocompromised patients. Initiation of antiretroviral agents may unmask or worsen PML because of immune reconstitution inflammatory syndrome (PML-IRIS; Sidhu and McCutchan, 2010). A study reviewed literature between 1998 and 2016, finding that 28% of patients with PML-IRIS have cerebellar ataxia (Fournier et al., 2017). In rare cases, HIV patients may develop a pure cerebellar syndrome not associated with cognitive impairment, opportunistic infection, or CNS lymphoma (Elsheikh et al., 2010; Pedroso et al., 2018; Tagliati et al., 1998).

Toxins

Ethanol Cerebellar symptoms can occur in both acute and chronic alcohol intoxication, in addition to other neurological symptoms including

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cognitive impairment, seizure, slurred speech, and peripheral neuropathy. Ethanol has a direct effect on ion channels such as receptors for N-methyl-d-aspartate (NMDA), GABA, and glycine as well as neuronal nicotinic receptors and potassium channels (Harris et al., 2008). Ethanol can cause secondary thiamine deficiency from malnutrition and direct impairment of thiamine metabolism (Laforenza et al., 1990), leading to Wernicke encephalopathy, characterized by the triad of altered mental status, ophthalmoplegia, and ataxia (Zubaran et al., 1997).

Anticonvulsants Multiple anticonvulsants can cause ataxia, including phenytoin, valproic acid, carbamazepine, oxcarbazepine, lamotrigine, zonisamide, lacosamide, vigabatrin, and gabapentin (van Gaalen et al., 2014). The majority of cases are reversible with discontinuation or reduction of the offending medication. Chronic phenytoin use can cause cerebellar atrophy, but cerebellar symptoms may not always be present, and most seemed to correlate with supratherapeutic serum level of phenytoin (Koller et al., 1981; Luef et al., 1994; McLain et al., 1980). Valproic acid can itself cause ataxia, but more often it acts through lowering the metabolism of other medications. Benzodiazepine-related ataxia occurs more often in children, and symptoms are usually milder and reversible (van Gaalen et al., 2014).

cerebellar hemisphere. Patients may present with acute-onset vertigo, unsteady gait, limb ataxia, hemifacial sensory loss to pain and temperature, and hoarseness. In addition to cerebellar signs, a neurological examination may reveal asymmetric elevation of the soft palate, nystagmus, and Horner syndrome (because of the involvement of the descending sympathetic tract). Infarct of the AICA affects the inferior lateral pons part of the middle cerebral peduncle, the anterior cerebellum, and the flocculus. Clinical symptoms are very similar to PICA infarct, including vertigo, cerebellar ataxia, nystagmus, hemifacial sensory loss, as well as Horner syndrome. Patients may have acute-onset hearing loss, owing to the labyrinth artery arising from AICA, distinguishing itself from a PICA syndrome. Sometimes AICA infarct is indistinguishable from PICA infarct, requiring neuroimaging for accurate assessment. The superior cerebellar artery is responsible for the superior aspect of the cerebellar hemisphere, and part of the midbrain tectum. In addition to cerebellar ataxia and gaze-evoked nystagmus, the oculomotor or trochlear nucleus may be involved. Ataxia-hemiparesis can be caused by a lacunar stroke located at the corona radiata, posterior limb of internal capsule, or ventral pons contralateral to the side of symptoms.

Superficial Siderosis

Several chemotherapy agents can cause cerebellar ataxia among other neurological symptoms, including 5-fluorouracil (5-FU), capecitabine (prodrug of 5-FU), cytarabine, and methotrexate (Boesen et al., 1988; Dworkin et al., 1985; Gonzalez-Suarez et al., 2014; Lam et al., 2008; Pazdur et al., 1992).

Superficial siderosis is the result of iron and/or hemosiderin deposition at the pial and subpial regions. Involvement of cerebellum can lead to cerebellar ataxia. Superficial siderosis can be the result of subarachnoid hemorrhage or from arteriovenous malformation. More recently it is linked to cerebral amyloid angiopathy (Linn et al., 2008, 2010). The actual mechanism of how deposition of iron and/or hemosiderin can cause ataxia is still unclear.

Metronidazole

Neoplastic

Metronidazole is associated with cerebellar toxicity and reversible hyperintensity signal on T2 FLAIR, DWI, and apparent diffusion coefficient map (Heaney et al., 2003).

Among all primary CNS tumors, 2% are located in the cerebellum (Ostrom et al., 2016). Neoplasms in the posterior fossa are more common in children between 4 to 10 years old and relatively rare in adults. For adults, metastases account for the majority of cerebellar neoplasms (Pfiffner et al., 2014). The common origins of the metastatic tumors include lung, breast, and gastrointestinal tract (Yoshida and Takahashi, 2009). Primary CNS tumors include medulloblastoma, ependymoma, hemangioblastoma, low-grade glioma, dysplastic gangliocytoma, atypical teratoid/rhabdoid tumors, and embryonal tumors with abundant neuropil and true rosettes (ETANTR, also known as embryonal tumors with multilayered rosettes, ETMR. These were formerly known as primitive neuroectodermal tumors, PNETs). Diagnosis largely depends on neuroimaging studies and biopsy.

Chemotherapy Agents

Heavy Metals Lithium overdose may result in action tremor, cerebellar ataxia, and altered mental status. Methylmercury can cause cerebellar ataxia, tunnel vision, hearing deficits, and peripheral neuropathy. Lead poisoning can result in cognitive impairment, attention deficits, motor-predominant neuropathy, and cerebellar edema. Excessive intake of bismuth subsalicylate has been associated with ataxia, confusion, and myoclonus (Gordon et al., 1995).

Toluene Toluene exposure can result in cognitive impairment, seizure, encephalopathy, postural tremor, and cerebellar ataxia (King, 1982; Saito and Wada, 1993). Sources of exposure are typically organic solvent in paint spray, paint thinner, or glues.

Vascular Disease Blood supply to the cerebellum consists of three arteries of the vertebral-basilar system: the posterior inferior cerebellar artery (PICA), anterior inferior cerebellar artery (AICA), and superior cerebellar artery (Fig. 23.5). Clinical presentation of a stroke depends on which of the three arteries is involved, although symptoms of more than vascular territory may be seen if the site of an arterial occlusion is a vertebral or basilar artery. PICA (Wallenberg) syndrome involves the lateral medulla, inferior cerebellar peduncle, inferior vermis, cerebellar tonsils, and inferior

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GENETIC CAUSES FOR ATAXIA Genetic diagnostic approaches for common cerebellar ataxias involve screening for repeat expansions, then sequencing (see Fig. 23.1). Genetic mutations are a major cause of ataxia. These should be looked for when the patient has one or more affected family members. However, family history is frequently lacking in autosomal recessive cerebellar ataxias (ARCAs). The absence of family history may also be attributable to early death of the affected parent or separation from them, adoption, non-paternity, or germline mutation, in autosomal dominant ataxias. Furthermore, a recent study suggests an unexpectedly high prevalence of premutation alleles which could serve as a reservoir for de novo mutations in some SCAs caused by repeat expansions (Gardiner et al., 2019).

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Posterior Inferior Cerebellar Artery Anterior Inferior Cerebellar Artery Superior Cerebellar Artery AICA

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ARCAs are usually, but not always, early onset. Patients are usually under the care of pediatric neurologists, geneticists, or pediatricians. However, when these patients reach adulthood, they may come to visit neurologists who work with adults. For example, patients with Friedreich ataxia, the most common inherited ataxia in regions where people speak Indo-European and Afro-Asiatic languages (Bidichandani and Delatycki, 1993; Labuda et al., 2000), typically develop symptoms in childhood, and usually survive into adulthood. The transition to adult care can be challenging and disruptive without appropriate expertise of adult neurologists. The prevalence of autosomal recessive cerebellar ataxias may have been underestimated in lateonset ataxic disorders. A recent study showed that an autosomal recessive mutation with intronic pentanucleotide repeat expansions causing cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) and related disorders may account for up to 20% of unexplained ataxias (Cortese et al., 2019). Thus, recessive ataxias are commonly overlooked but must be taken into the differential diagnoses of ataxic disorders in adult clinics. For a patient with familial ataxias, one should attempt to obtain available results of genetic testing of any relative who may have the same disease. If no such relative is available, genetic testing of common ataxias should be done. For dominantly inherited ataxia, common SCAs are caused by an expansion of a short tandem repeat, and for ARCA autosomal cerebellar, Friedreich ataxia and several other common recessive ataxias should be tested. Expanded repeats are not readily detectable by whole exome sequencing (WES) or whole genome sequencing (WGS) based on next-generation sequencing (NGS) technology. Thus, unless the phenotype of the test subject points to a specific diagnosis, a panel of repeat expansion mutations should be done first (see Fig. 23.1). If these diagnoses are excluded, then WES is considered. If the WES result includes only variations of unknown significance (VUS), pedigree analysis for co-segregation of the VUS and the disease and biological functional testing in experimental systems may be needed in determining the pathogenicity. Synonymous mutations (that do not change the amino acid coding) are unlikely to be, but cannot be dismissed as, the pathogenic mutation. Similar genetic testing approaches should be considered for apparently sporadic disorders if secondary causes (especially those that are treatable) of ataxia are excluded. The remaining sporadic ataxias may be classified into two major types by clinical manifestations: (1) idiopathic late-onset cerebellar ataxia (ILOCA), and (2) multiple system atrophy—cerebellar type (MSA-C; Ashizawa et al., 2018; see Fig. 23.1). Among the secondary causes of progressive ataxia, immune-mediated ataxias may present with neurodegenerative features, which may respond to timely immunotherapy. However, the presence of autoantibodies does not necessarily mean they are pathogenic, and consequently immune-mediated ataxias may be overdiagnosed. In genetic ataxias, on the other hand, pathogenic mutations may be frequently labeled as VUS, and structural genomic mutations such as large deletions, inversions, duplications, and translocations, and repeat expansions are not readily captured by the WES. Therefore, limitations in detecting the mutation and interpreting genetic test results may lead to underdiagnosing many genetic disorders.

Autosomal Dominant Cerebellar Ataxias Spinocerebellar ataxias (SCAs) are a group of autosomal dominant disorders presented with ataxia variably accompanied by extracerebellar manifestations. Most SCAs are progressive adult-onset neurodegenerative disorders affecting the cerebellum and its afferent and efferent pathways. In the genetic nomenclature, SCAs are numbered in the order of discovery of the genetic locus, and the number has recently reached 48.

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Frequency of Spinocerebellar Ataxia The collective prevalence of all known types of SCAs has been estimated as 1.0–5.6 in 100,000 (Leone et al., 1995; Ruano et al., 2014; van de Warrenburg et al., 2002). Thus, all SCAs are rare diseases by the United States government’s definition (Mulberg et al., 2019). A recent study of expanded polyglutamine (polyQ) alleles of known disease loci in five large population-based European cohorts showed that 10.7% had at least one CAG repeat expansion allele within the intermediate range, while up to 1.3% had a CAG repeat number within the disease range, mostly in the lower pathological range associated with elderly onset (Gardiner et al., 2019). Although intermediate alleles potentially mutable to become the disease-range allele may be overestimated due to including interrupted alleles (e.g., SCA1 repeat), the size of reservoir populations for polyQ SCA may be alarmingly high.

Regional and Ethnic Distributions of Spinocerebellar Ataxia SCAs 1, 2, 3, 6, 7, and 8 are most common in the United States and Europe, while geographic predilection of specific SCAs and distinctive founder effects exist in various parts of the world (Fig. 23.6). For example, a high prevalence has been found for SCA1 in Poland; SCA2 in Cuba, Mexico, and Italy; SCA6 in UK, Germany, and Japan; SCA7 in South Africa, Mexico, and Venezuela; SCA10 in Latin America; SCA12 in India and Italy; while SCA3 is the most common SCA worldwide. However, only limited population-based data (Coutinho et al., 2013) exist for incidence and prevalence of SCAs, and estimated frequency of SCAs in a given region is often reflecting founder effects.

Genetic Mutations in Spinocerebellar Ataxia SCA 1, 2, 3, 6, 7, 17 and (Dentatorubral-pallidoluysian atrophy) are all caused by an expansion of a CAG repeat encoding a polyQ peptide in respective genes (Ashizawa et al., 2018; Klockgether et al., 2019; Paulson et al., 2017). The mutation of SCA8 is an expanded CTG repeat in the 3′ untranslated region (3′UTR) of the ATXN8OS gene, while the same repeat on the opposite strand encodes polyQ in the ATXN8 gene. SCA10, SCA31, and SCA37 are autosomal dominant ataxias caused by a large expanded intronic pentanucleotide repeat. SCA36 is the only SCA caused by an hexanucleotide repeat expansion (Fig. 23.7) (Ashizawa et al., 2018). The pathogenic mechanism of polyQ SCAs points to toxic gain of function by the mutant protein products, while SCAs caused by intronic repeat expansions are thought to be caused by toxic untranslated RNAs that contain large repeats (Table 23.5) (Ashizawa et al., 2018; Paulson et al., 2017). Most other mutations in remaining SCAs are missense mutations, which may lead to either toxic gain of function of the mutant protein or dominant negative effect (Table 23.6). There are a handful of SCAs caused by deletions (SCA15/16 and SCA14), translocation (SCA27), and duplications (SCA20), of which SCA15/16 and SCA27 show loss of function of the gene (haploinsufficiency) (Iwaki et al., 2008; Misceo et al., 2009). Haploinsufficiency may also play a pathogenic role in SCA47 (Gennarino et al., 2018). These mechanisms have important implications in the ongoing and future development of disease-modifying molecular therapy. Repeat expansion and missense mutations are generally good targets of RNA silencing therapy, while haploinsufficiency would be addressed by gene replacement therapy or transcription enhancers to increase the lacking protein.

Genotype-Phenotype Correlation Phenotypically, Harding has classified SCAs into three types: autosomal dominant cerebellar ataxia (ADCA) I, II, and III (Harding, 1982). ADCA I is a phenotype with cerebellar ataxia plus variable extracerebellar (mainly CNS) signs, e.g., slow saccades in SCA2 (see Video 23.4) and dystonia in SCA3 (Fig. 23.8, A). Patients with ADCA II show

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Prevalence of ADCAs by country 100 90 80

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SCA1 SCA2 SCA3 SCA6 SCA7 SCA8 DRPLA Rare Unclassified Fig. 23.6 The Prevalence of Spinocerebellar Ataxia (SCA) by Country. The category “Rare” includes other spinocerebellar ataxias (SCAs), e.g., SCA10, SCA12, SCA17, etc. Note that in Mexico, SCA10 represents 13.9% of all SCA patients. ADCA, Autosomal dominant cerebellar ataxia. (Worldwide: Bird, T.D., 1993. Hereditary ataxia overview. In: Adam, M.P., Ardinger, H.H., Pagon, R.A., et al. (Eds.), GeneReviews((R)). Seattle, WA. USA: Moseley, M.L., Benzow, K.A., Schut, L.J., et al., 1998. Incidence of dominant spinocerebellar and Friedreich triplet repeats among 361 ataxia families. Neurology. 51(6), 1666–1671. https://doi.org/10.1212/ wnl.51.6.1666. Mexico: Velazquez Perez, L., Cruz, G.S., Santos Falcon, N., et al., 2009. Molecular epidemiology of spinocerebellar ataxias in Cuba: insights into SCA2 founder effect in Holguin. Neurosci. Lett. 454(2), 157– 160. https://doi.org/10.1016/j.neulet.2009.03.015. Cuba: Velazquez Perez, L., Cruz, G.S., Santos Falcon, N., et al., 2009. Molecular epidemiology of spinocerebellar ataxias in Cuba: insights into SCA2 founder effect in Holguin. Neurosci. Lett. 454(2), 157–160. https://doi. org/10.1016/j.neulet.2009.03.015. The Netherlands: van de Warrenburg, B.P., Sinke, R.J., Verschuuren-Bemelmans, C.C., et al., 2002. Spinocerebellar ataxias in the Netherlands: prevalence and age at onset variance analysis. Neurology. 58(5), 702–708. https://doi.org/10.1212/wnl.58.5.702. Germany: Schols, L., Amoiridis, G., Buttner, T., et al., 1997. Autosomal dominant cerebellar ataxia: phenotypic differences in genetically defined subtypes? Ann. Neurol. 42(6), 924–932. https://doi.org/10.1002/ ana.410420615. Portugal/Brazil: Silveira, I., Miranda, C., Guimaraes, L., et al., 2002. Trinucleotide repeats in 202 families with ataxia: a small expanded (CAG)n allele at the SCA17 locus. Arch. Neurol. 59(4), 623–629. https://doi. org/10.1001/archneur.59.4.623. Italy: Brusco, A., Gellera, C., Cagnoli, C., et al., 2004. Molecular genetics of hereditary spinocerebellar ataxia: mutation analysis of spinocerebellar ataxia genes and CAG/CTG repeat expansion detection in 225 Italian families. Arch. Neurol. 61(5), 727–733. https://doi.org/10.1001/archneur.61.5.727. Poland: Krysa, W., Sulek, A., Rakowicz, M., et al., 2016. High relative frequency of SCA1 in Poland reflecting a potential founder effect. Neurol. Sci. 37(8), 1319–1325. doi:10.1007/s10072-016-2594-x. China: Wang, J., Shen, L., Lei, L., et al., 2011. Spinocerebellar ataxias in mainland China: an updated genetic analysis among a large cohort of familial and sporadic cases. Zhong Nan Da Xue Xue Bao Yi Xue Ban 36(6), 482–489. https://doi.org/10.3969/j.issn.1672-7347.2011.06.003. Taiwan: Soong, B.W., Lu, Y.C., Choo, K.B., et al., 2001. Frequency analysis of autosomal dominant cerebellar ataxias in Taiwanese patients and clinical and molecular characterization of spinocerebellar ataxia type 6. Arch. Neurol. 58(7), 1105–1109. https://doi.org/10.1001/archneur.58.7.1105. Japan: Maruyama, H., Izumi, Y., Morino, H., et al., 2002. Difference in disease-free survival curve and regional distribution according to subtype of spinocerebellar ataxia: a study of 1,286 Japanese patients. Am. J. Med. Genet. 114(5), 578–583. https://doi.org/10.1002/ajmg.10514. India: Krishna, N., Mohan, S., Yashavantha, B. S., et al., 2007. SCA 1, SCA 2 and SCA 3/MJD mutations in ataxia syndromes in southern India. Indian J. Med. Res. 126(5), 465–470. South Africa: Bryer, A., Krause, A., Bill, P., et al., 2003. The hereditary adult-onset ataxias in South Africa. J. Neurol. Sci. 216(1), 47–54. doi:10.1016/s0022-510x(03)00209-0.)

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Common Neurological Problems

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Fig. 23.7 Ataxias Caused by Repeat Expansions. 3′UTR, 3′ Untranslated region; 5′UTR, 5′ untranslated region; CANVAS, cerebellar ataxia, neuropathy, vestibular areflexia syndrome; FXTAS, fragile X associated tremor ataxia syndrome.

pigmentary macular degeneration, and SCA7 is the only known ADCA II among SCAs (see Fig. 23.8, B and Video 23.5). Patients with ADCA III present almost pure cerebellar signs throughout the course of disease, and SCA6 could be considered in this category. Cerebellar cognitive affective syndrome (CCAS or Schmahmann syndrome) (Schmahmann, 2004), which consists of underrecognized cognitive impairments may be present in patients with SCAs. The onset of most SCAs is typically with balance loss and gait ataxia, although oculomotor abnormalities may be present early on examination. Besides SCA7, different SCAs may show some distinct clinical features. These features, combined with information about ethnicity and anticipation, may provide a useful guidance for efficient genetic testing in some families (see Tables 23.5 and 23.6).

Anticipation Progressively earlier onset of the disease in successive generations with increasing severity within a family, known as genetic anticipation, is a hallmark of most polyQ SCAs (McInnis, 1996). Anticipation is attributed to intergenerational increase of the number of CAGs. It is the mechanism underlying the juvenile-onset disease and de novo cases of polyQ SCAs. The small size of CAG repeat expansion in SCA6 and CAA interruptions within the expanded CAG repeat of SCA17 make the mutant expanded allele stable, leading to the lack of anticipation in these SCAs. Anticipation has also been reported in SCA5, SCA10, and SCA31. The instability of repeat size would explain anticipation in SCA10 and SCA31. However, the case of SCA5 is puzzling because the SCA5 is not a repeat expansion disorder and caused by point mutations in the SPNBII gene. Additional mechanisms of observed anticipation other than repeat size changes, such as ascertainment bias and epigenetics, may need to be explored (Petronis et al., 1997).

Genetic Testing The National Ataxia Foundation posts its guidelines for genetic testing (https://ataxia.org/wp-content/uploads/2017/07/SCA-Making_ an_Informed_Choice_About_Genetic_Testing.pdf), which are similar to those established for Huntington disease. While genetic testing

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of subjects who are exhibiting clinical ataxia is straightforward, presymptomatic testing involves the issue of “to know or not to know” (Robins Wahlin, 2007), and this issue is further complicated in testing at-risk subjects before adulthood (Quarrell et al., 2018). When efficacious treatments become available, the guidelines for presymptomatic genetic diagnosis would be changed to enable early diagnosis and treatment. Although preimplantation genetic diagnosis (PGD) of SCAs is technically feasible, no report of PGD has emerged in the literature for SCAs. Genetic counseling is always recommended before and after the genetic testing.

Pathogenic Mechanism PolyQ Spinocerebellar Ataxias. The pathogenic mechanism of polyQ SCAs is a toxic gain of function by the protein that the mutant gene encodes (Coarelli et al., 2018). The toxic effect differs from one SCA to another depending on the structural and functional context of the mutant protein(s), including the splice variants and posttranslational modifications (Ashizawa et al., 2018; Carroll et al., 2018; Du et al., 2013, 2019, Friedrich et al., 2018; Karam and Trottier, 2018; Klockgether et al., 2019; Paulson et al., 2017; Perez Ortiz and Orr, 2018; Scoles and Pulst, 2018; Ward et al., 2019; Yang et al., 2016). Interruption(s) of the SCA1 CAG repeat by histidine-coding CAT units decreases the pathogenicity (Opal and Ashizawa, 1993). Although interruptions of CAG repeats by synonymous CAA units would not change the PolyQ repeat in the protein product, it may change the stability of the repeat length and might affect the age at onset and the severity of the disease (Menon et al., 2013; Wright et al., 2019). Patients with SCA2 expansions may present with l-dopa responsive parkinsonism or amyotrophic lateral sclerosis, and long normal ATXN2 alleles are risk factors for amyotrophic lateral sclerosis (Antenora et al., 2017). Existing data suggest that pathogenic pathways involved in the toxic gain of function in different SCAs may interact with each other in the ataxia interactome (Fernandez-Funez et al., 2000; Vazquez et al., 2019). The interaction of polyQ tract of ATXN3 and beclin 1 can be affected by polyQ tracts of other SCAs, individually leading

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Spinocerebellar Ataxias Caused by Expanded Microsatellite Repeats

TABLE 23.5

Gene and Protein (Repeat Location) Normal

Disease

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REPEATS, PRINCIPAL REPEAT UNIT Intermediate

SCAs Caused by Polyglutamine-Coding CAG Repeat Expansions SCA1 ATXN1 6–39* 40

41–83

SCA2 SCA3

ATXN2 ATXN3

168

Time of cEEG monitoring to record first seizure [h] Fig. 35.17 Time from Onset of Continuous Electroencephalographic (cEEG) Monitoring to the occurrence of the First Seizure. (Reprinted with permission from Claassen, J., Mayer, S.A., Kowalski, R.G., et al., 2004. Detection of electrographic seizures with continuous EEG monitoring in critically ill patients. Neurology 62[10], 1743–1748.)

part, been driven by increased awareness of the prevalence of NCSs in certain groups of critically ill patients. The reported prevalence of NCSs in critically ill patients undergoing cEEG has varied considerably, depending on both the population studied and the study design (DeLorenzo et al., 1998; Towne et al., 2000; Treiman et al., 1998). Retrospective cohort studies in both adults and children undergoing EEG monitoring based on the clinical suspicion of NCSs report seizure detection rates between about 15% and 40% (Abend et al., 2013; Claassen et al., 2004; Jette et al., 2006). An important finding common to these studies is that the great majority (75%–92%) of critically ill adults and children who are found to have seizures had pure NCSs (Abend et al., 2013; Claassen et al., 2004). Risk factors for NCSs in the general ICU population include prior history of epilepsy, intracerebral and subarachnoid hemorrhage, CNS infection, brain tumors, severe traumatic brain injury, and sepsis. Patients with sepsis in the medical ICU setting are also at risk for NCSs (Oddo et al., 2009). In children, NCSs have most commonly been reported in the setting of coma following convulsive seizures as well as among patients with a past history of epilepsy, hypoxic brain injury, and traumatic brain injury (Abend et al., 2013; McCoy et al., 2011). Fig. 35.17 illustrates that about 90% of critically ill patients who ultimately have seizures experience their first seizure within the first 24 hours of monitoring, and that half of these patients will have the first seizure within the first hour. Accordingly, many centers now monitor for 24 hours and then continue to record for 24 hours after the last electrographic seizure or for 24 hours after a change in therapy that might provoke seizures (such as tapering of anticonvulsant infusions or rewarming following hypothermia). The absence of epileptiform discharges during the first few hours of cEEG monitoring appears to predict a lower seizure risk (Shafi et al., 2012).

Electrographic Identification of Nonconvulsive Seizures Fig. 35.18 depicts an unequivocal NCS. The discharge lasts more than 10 seconds and has the classic electrographic features of a seizure, with clear evolution in frequency, amplitude, morphology, and spatial extent. However, not all NCSs are as clear cut, and the lack of

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concordant clinical signs can make some NCSs difficult to identify. Box 35.2 lists proposed criteria for NCS (Chong and Hirsch, 2005). Some cEEG patterns resemble electrographic seizures, but fail to meet all of these criteria. When the EEG pattern is equivocal, a therapeutic trial of benzodiazepines can be helpful. However, the interpretation of the benzodiazepine trial may itself be difficult, because clinical improvement may be delayed, and because electrographic and clinical improvement may require loading doses of other anticonvulsant medications.

The “Ictal-Interictal Continuum” In the ICU setting, the distinction between recurrent interictal epileptiform discharges and ictal discharges can be challenging. Electrographic patterns often wax and wane, evolving from patterns that are clearly ictal to those that are clearly interictal and vice versa. This can frustrate consistent EEG reporting; more importantly, it can present challenges to clinicians who must decide which EEG patterns warrant treatment and how aggressively they should be treated. Most experts recommend treating unequivocal NCSs and equivocal patterns with a clear clinical correlate. There is less consensus on treatment of equivocal patterns without clinical correlate. Chong and Hirsch have proposed a conceptual framework termed the “ictal-interictal continuum” (Chong and Hirsch, 2005; Fig. 35.19), in which various electrographic patterns are plotted according to their likelihood to represent an ictal phenomenon and their potential to cause secondary neuronal injury. Standardized terminology for rhythmic and periodic EEG patterns occurring during critical care EEG recordings has recently been developed by a committee of the American Clinical Neurophysiology Society (Hirsch et al., 2013).

Periodic Discharges PDs are characterized by spikes, sharp waves, or sharply contoured slow waves that recur periodically or pseudo-periodically, usually every 1 to 2 seconds. PDs may be generalized (GPDs: generalized PDs, formerly called GPEDs; Fig. 35.20), unilateral (LPDs: lateralized PDs, formerly called PLEDs), or bilaterally independent (BIPDs: bilateral independent PDs, formerly called BIPLEDs; Fig. 35.21). PDs are frequently associated with focal brain injury such as ischemia, hemorrhage, or

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Fig. 35.18 Nonconvulsive Seizure (Arising From Left Hemisphere, Spreading to Right Hemisphere).

Seizures

Criteria for Nonconvulsive

Reprinted with permission from Chong, D.J., Hirsch, L.J., 2005. Which EEG patterns warrant treatment in the critically ill? Reviewing the evidence for treatment of periodic epileptiform discharges and related patterns. J Clin Neurophysiol 22(2), 79–91.

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Ictal Interictal Fig. 35.19 The Ictal-Interictal Continuum. EPC, epilepsia partialis continua; GCSE, generalized convulsive status epilepticus;GPEDs, Generalized periodic discharges; PLEDs, lateralized periodic discharges; NCS, nonconvulsive seizures; NCSE, nonconvulsive status epilepticus; SIRPIDs, stimulus-induced rhythmic, periodic, or ictal discharges TW, triphasic waves. (Reprinted with permission from Chong, D.J., Hirsch, L.J., 2005. Which EEG patterns warrant treatment in the critically ill? Reviewing the evidence for treatment of periodic epileptiform discharges and related patterns. J Clin Neurophysiol 22[2], 79–91.)

Secondary Criterion Significant improvement in clinical state or appearance of a previously absent normal electroencephalographic (EEG) pattern (such as a posterior dominant rhythm) temporally coupled to acute administration of a rapid-acting antiepileptic drug. Resolution of the “epileptiform” discharges, leaving diffuse slowing without clinical improvement and without appearance of previously absent normal EEG patterns, would not satisfy the secondary criterion.

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Primary Criteria 1. Repetitive generalized or focal spikes, sharp waves, spike-and-wave or sharp- and slow-wave complexes at three per second or greater. 2. Repetitive generalized or focal spikes, sharp waves, spike-and-wave, or sharp- and slow-wave complexes at three per second or less and the secondary criterion. 3. Sequential rhythmic, periodic, or quasi-periodic waves at one per second or greater and unequivocal evolution in frequency (gradually increasing or decreasing by at least one per second—for example, from two–three per second), morphology, or location (gradual spread into or out of a region involving at least two electrodes). Evolution in amplitude alone is not sufficient. Change in sharpness without any other change in morphology is not adequate to satisfy evolution in morphology.

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Any pattern lasting at least 10 seconds satisfying any one of the following three primary criteria.

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BOX 35.2

infection. By definition, they do not meet the formal criteria for a seizure. However, they frequently occur following prolonged seizures. There is controversy about the meaning of PDs, their potential contribution to secondary brain injury, and consequently the need for their treatment. They may simply be markers of encephalopathy or focal brain injury rather than a pathological entity that requires treatment.

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However, PDs have been associated with poor outcome following status epilepticus (Jaitly et al., 1997; Nei et al., 1999).

Stimulus-Induced Rhythmic, Periodic, or Ictal Discharges The periodic epileptiform discharges described earlier generally occur spontaneously and do not change in response to arousal or external stimulation. However, occasionally, electrographic patterns consistently occur following stimulation or arousal of a comatose patient (Fig. 35.22). These stimulus-sensitive EEG patterns have been termed stimulus-induced rhythmic, periodic, or ictal discharges, or SIRPIDs (Hirsch et al., 2004). It is often unclear whether SIRPIDs represent ictal phenomena such as reflex seizures or interictal phenomena such as an abnormal arousal pattern. There is debate about how aggressively these patterns should be treated. Most SIRPIDs are not accompanied by clinical signs, although occasionally they may correlate with focal motor seizures, in which case the case for treatment may be more compelling (Hirsch et al., 2008).

Quantitative Electroencephalogram Increasing awareness and concern about NCSs has led to a growing demand for continuous EEG monitoring in ICUs, generating large volumes of data that can be overwhelming to interpret using conventional reviewing techniques that display 10–20 seconds of raw EEG data per screen. To address this challenge and facilitate interpretation of prolonged EEG recordings, several quantitative EEG (QEEG) display tools have been developed to provide insight into trends in the EEG over time and to highlight significant electrographic events. However, it is important to emphasize that QEEG tools should not replace careful review of the underlying raw EEG. Table 35.1 lists QEEG display tools commonly available from various manufacturers and their primary clinical applications. One of the most appealing applications of QEEG displays is their potential use as a screening tool for seizures. Fig. 35.23,

A and B illustrate the typical appearance of seizures on amplitude-integrated EEG (aEEG) and color density spectral array (CDSA) displays, respectively. aEEG is a technique that displays time-compressed and rectified EEG amplitude on a semilogarithmic scale. The top and bottom margins of the aEEG tracing reflect the maximum and minimum EEG amplitudes at a given time. CDSA is a technique that applies fast-Fourier transformation (FFT) to convert raw EEG signals into a time-compressed and color-coded display, also termed a color spectrogram. Frequency-specific EEG power is depicted on the y-axis, with varying degrees of EEG power (power = amplitude2) depicted using a color-coded scale. The sensitivity of QEEG displays for seizure identification can reach as high as 80%; however, sensitivity varies by seizure type. Seizures of low amplitude or shorter duration are more challenging to identify by QEEG (Stewart et al., 2010). Many types of artifact may also resemble seizures on QEEG, leading to “false positives.” Therefore QEEG trending displays should always be interpreted in conjunction with careful review of the accompanying raw EEG tracing.

Magnetoencephalography Additional text available at http://expertconsult.inkling.com.

EVOKED POTENTIALS Additional text available at http://expertconsult.inkling.com.

INTRAOPERATIVE MONITORING Additional text available at http://expertconsult.inkling.com. The complete reference list is available online at https://expertconsult. inkling.com/.

Fig. 35.20 Generalized Periodic Discharges.

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CHAPTER 35 Electroencephalography and Evoked Potentials

Fig. 35.21 Bilateral Independent Periodic Discharges.

Fig. 35.22 Stimulus-Induced Rhythmic, Periodic, or Ictal Discharges in Response to Noise.

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TABLE 35.1

Display Tools

Neurological Investigations and Interventions

Overview of Commonly Available Quantitative Electroencephalographic (EEG)

Quantitative EEG Display Tool

Primary Clinical Applications

Amplitude-integrated EEG (aEEG) Envelope trend Color spectrogram (CDSA, CSA, DSA) Total power Rhythmicity spectrogram Alpha-delta ratio Alpha variability Asymmetry indices Burst suppression index

Background assessment, seizure identification Seizure identification Seizure identification Seizure identification Seizure identification Background assessment, ischemia detection Background assessment, ischemia detection Background assessment, ischemia detection Background assessment

CDSA, color density spectral array; CSA, color spectral array; DSA, density spectral array

A

B Fig. 35.23 A, Recurrent seizures depicted on an 8-hour amplitude-integrated electroencephalogram (aEEG) display. B, Recurrent seizures depicted on an 8-hour color density spectral array (CDSA) display. Electrographic seizures identified on the raw EEG are indicated by the blue bars at the top of each figure. An eight-channel double-distance longitudinal bipolar montage. On the aEEG display (A), seizures are associated with a rise in both the bottom and top margin of the aEEG tracing. On the CDSA display (B), seizures are associated with bright bands of color, indicating higher-power EEG activity across a wider range of frequencies. F ECF

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Magnetoencephalography

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MEG is a measure of brain function equivalent to EEG in that the same neuronal sources that generate electrical activity also give rise to magnetic fields. However, MEG differs from EEG in several ways that have theoretical usefulness. Whereas electrical potentials are substantially attenuated and distorted by the overlying CSF, dura, and skull, magnetic fields pass readily through these tissues, possibly permitting more sensitive and accurate localization of deeper epileptic foci. Whereas EEG is better able to measure current sources that are perpendicular to the cortical surface (radially oriented dipoles), MEG more accurately measures current sources that are parallel to the cortical surface (tangential dipoles). Despite these differences, MEG recordings appear substantially similar to EEG recordings, and, when interpreted by visual inspection, appear to have sensitivities for epileptiform activity similar to those of sleep-deprived EEGs (Colon et al., 2009). Although MEG may be potentially more “patient-friendly” than EEG because it does not require placement of electrodes on the scalp, its substantially greater cost has largely precluded its routine use. The main application of MEG has been to localize sources of evoked potentials and focal epileptiform activity, usually in consideration of epilepsy surgery. The limitations that apply to dipole source localization of EEG signals, however, apply similarly to MEG signals. For this reason, interpretation of MEG findings requires caution, and the technique is best viewed as an adjunct to established methods of localization such as intracranial electroencephalography (Cappell et al., 2006).

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Visual Evoked Potentials Cerebral visual evoked potentials (VEPs) are responses of the visual cortex to appropriate stimuli. Recording of the composite retinal response to visual stimuli, or electroretinography, may be performed separately. Obtaining the cerebral VEP is accomplished by averaging the responses from occipital scalp electrodes generated by 100 or more sequential stimuli. Stimulus characteristics are critically important in determining the portion of the visual system to test by the VEP and the sensitivity of the

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Evoked potentials are electrical signals generated by the nervous system in response to sensory stimuli. The sensory systems involved, and the corresponding sequence of neural structures activated, determine the timing and body surface location of these signals. The stimulus paradigms used in clinical practice evoke sufficiently stereotypical responses to allow normal limits to be clearly defined. Violation of these limits indicates dysfunction of the sensory pathways under study. Guidelines 9 to 11 and 15 of The American Clinical Neurophysiology Society provide an overview of recording methodology, criteria for abnormality, and limitations of use (American Clinical Neurophysiology Society, 2014). Because of their low voltage, it is generally necessary to present stimuli repeatedly, averaging the time-locked brain or spinal cord responses to a series of identical stimuli while allowing unrelated noise to average out. Exceptions are the visual responses evoked by transient flash stimuli, which the routine EEG displays as photic driving. In the clinical setting, evoked potential studies are properly viewed as an extension of the neurological examination. As with any neurological sign, they help to reveal the existence and often suggest the location of neurological lesions. Evoked potentials, therefore, are most useful when they detect clinically silent abnormalities that might otherwise go unrecognized or when they assist in resolving vague or equivocal symptoms and findings. As in the case of EEG, evoked potential studies are tests of function; the findings are not usually etiologically specific.

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Fig. 35.24 Distributions of latencies of the major occipital positivity to flash (A) and pattern-shift (B) stimulation in healthy control subjects and in the affected and unaffected eyes of patients with optic neuritis. The superior sensitivity of pattern-shift visual evoked potentials to demyelinating lesions is clearly demonstrated. EP, evoked potential. (Reprinted with permission from Halliday, A.M., 1982. The visual evoked potential in the investigation of diseases of the optic nerve. In: Halliday, A.M. (Ed.), Evoked Potentials in Clinical Testing. Churchill Livingstone, New York.)

test needed. Initial clinical applications of VEPs used a stroboscopic flash stimulus, but the great variability of responses among normal persons and its relative insensitivity to clinical lesions severely limited the utility of the flash-evoked VEP (Fig. 35.24, A and B). Occasionally, flash VEPs may provide limited information about the integrity of visual pathways when the preferred pattern-reversal stimulus is not usable, as in young children or older patients unable to cooperate for more sensitive testing methods.

Normal Visual Evoked Potentials More sensitive and reliable responses are obtained using a pattern-reversal stimulus. The subject focuses on a high-contrast checkerboard of black and white squares displayed on a video or optical projection screen. The stimulus is the change of black squares to white and of white squares to black (pattern reversal). When appropriate check sizes are used (15–40 minutes of arc at the subject’s eye), the VEP is generated primarily by foveal and parafoveal elements. Monocular full-field stimulation almost always is used, so the test is most sensitive to lesions of the optic nerve anterior to the chiasm. It is possible, however, to modify the stimulus presentation so that only selected portions of the visual field are stimulated, thereby permitting detection of postchiasmatic abnormalities as well. VEPs elicited by pattern-reversal stimuli show less intersubject variability than flash VEPs and are much more sensitive to lesions affecting the visual pathways.

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Neurological Investigations and Interventions The primary basis for interpretation of the VEP is measurement of the latency of the P100 component (the major positive wave having a nominal latency of approximately 100 ms in normal persons) after stimulation of each eye separately. After the absolute P100 latency for each eye is measured, the intereye P100 latency difference is determined. Comparison of these values with normative laboratory data will indicate the normal or abnormal nature of the response. Whenever possible, the clinical significance of the findings is interpreted in the context of other relevant clinical data. VEP latencies are affected significantly by the specific characteristics of the stimulator used (e.g., brightness, contrast); it is therefore important that laboratories performing VEP testing obtain their own normative data. Because optic nerve fibers from the temporal retina decussate at the chiasm, unilateral prolongation of P100 latency after full-field monocular stimulation implies an abnormality anterior to the optic chiasm on that side. Bilateral lesions either anterior or posterior to the optic chiasm or a chiasmal lesion will cause bilateral delay of the P100, demonstrated by separate stimulation of each eye. Unilateral hemispherical lesions do not alter the latency of the full-field P100 (because of the contribution from the intact hemifield) but do alter the scalp topography of the response.

A normal pattern-reversal VEP to full-field monocular stimulation is illustrated in Fig. 35.25. The VEP waveform is deceptively simple. It is the sum of many waveforms generated simultaneously by various areas of the retinotopically organized occipital cortex. By selectively stimulating portions of the visual field, it is possible to dissect the full-field VEP wave into its component waveforms. For example, Fig. 35.26, recorded from the same patient as in Fig. 35.25, illustrates VEPs to right and left hemifield stimulation. It is apparent that the full-field VEP is the sum of the two hemifield responses. In principle, it is possible to divide the visual fields into progressively smaller and smaller components and to record the VEP to each independently.

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Visual Evoked Potentials in Neurological Disease Acute optic neuritis is accompanied by marked attenuation or loss of P100 wave amplitude following pattern-reversal stimulation of the affected eye. After the acute attack, the VEP shows some recovery, but P100 latency usually remains prolonged even with restoration of functionally normal vision. In patients with a past history of optic neuritis, P100 latency is typically prolonged, but waveform amplitude and morphology are often relatively well preserved (Fig. 35.27). Factors contributing to changes in P100 probably include the combined effects of patchy conduction block, areas of variably slowed conduction, temporal dispersion of the afferent volley in the optic nerve, loss of some components of the normal VEP, and the appearance of previously masked components. Pattern-shift VEPs are abnormal in nearly all patients with a definite history of optic neuritis. More important, the pattern-shift VEP is a sufficiently sensitive indicator of optic nerve demyelination that it can reveal asymptomatic and clinically undetectable lesions. Thus 70% to 80% of patients with definite multiple sclerosis (MS) but no history of

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2 µV 20 msec Fig. 35.25 Normal pattern-reversal visual evoked potentials to full-field monocular stimulation. The MO electrode is in the posterior midline over the occiput. RO and RT are 5 and 10 cm, respectively, to the right of MO, and LO and LT are 5 and 10 cm, respectively, to the left of MO. All electrodes are referred to Fpz (a midline frontopolar electrode). The response is largest at MO and symmetrically distributed left and right of midline. LO, left occipital; LT, left temporal; MO, midline occipital; RO, right occipital; RT, right temporal;

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Fig. 35.26 Normal pattern-shift visual evoked potentials to right and left hemifield stimulation of one eye. Same subject as in Fig. 35.25. Partialfield responses are asymmetrical about the midline, with the largest positivities ipsilateral to the stimulated field.

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CHAPTER 35 Electroencephalography and Evoked Potentials optic neuritis or visual symptoms have abnormal VEPs. Many patients with abnormal VEPs have normal neuro-ophthalmological examination results. Pattern-reversal VEPs are highly sensitive to demyelinating lesions but are not specific for MS. Box 35.3 provides a partial list of other causes of abnormal VEPs. VEPs may be helpful in distinguishing hysteria or malingering from blindness. A normal pattern-reversal VEP is strong evidence in favor of psychogenic illness. Rare cases have been reported, however, in which essentially normal VEPs were present in cortical blindness because of bilateral destruction of Brodmann area 17 with preservation of areas 18 and 19, or bilateral occipital infarcts with preservation of area 17 (Green, 2012).

Brainstem Auditory Evoked Potentials Brainstem auditory evoked potentials (BAEPs) are generated in the auditory nerve and brainstem after an acoustic stimulus. A brief stimulus, usually a sharp click, is given to one ear through an earphone while hearing in the opposite ear is masked with white noise to prevent its stimulation by transcranially conducted sound. The normal BAEP waveform consists of a series of waves that occur within the first 10 msec

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after the stimulus. The BAEP is of low voltage (only ≈0.5 mV), and approximately 1000–2000 responses must typically be averaged to resolve the BAEP waveform.

Normal Brainstem Auditory Evoked Potentials Unlike VEPs, which are cortical responses, BAEPs are generated in or caudal to the mesencephalon. BAEPs are characteristically quite resistant to the effects of metabolic disturbances and pharmacological agents. Indeed, in the absence of anatomical lesions, BAEPs persist essentially unchanged into deep coma or in the presence of general anesthesia. Fig. 35.28 illustrates a normal BAEP recording. Summated neuronal activities in anatomical structures activated sequentially by the afferent sensory volley produce the components designated by roman numerals. Some uncertainty exists regarding the relative contributions to the scalp-recorded BAEP of synaptic potentials occurring in nuclear structures and compound action potentials in nearby fiber tracts. Although the following electroanatomical relationships may be somewhat oversimplified, they are useful for purposes of clinical localization. Wave I, corresponding to N1 of the electrocochleogram, represents the auditory nerve compound action potential, which arises in the most distal portion of the nerve. The potential represented by wave II is generated mainly in the proximal eighth nerve but probably also includes a contribution from the intra-axial portion of the nerve and perhaps the cochlear nucleus as well. The wave III potential is generated in the lower pons in the region of the superior olive and trapezoid body. The

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Fig. 35.27 Pattern-shift visual evoked potentials recorded in a patient with right optic neuritis, illustrating marked delay of the P100 component from the right eye. As is typical with demyelinating optic neuropathies, the waveform is relatively preserved.

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Some Causes of Abnormal Visual Evoked Potentials

BOX 35.3

Ocular disease: Major refractive error Lens and media opacities Glaucoma Retinopathies Compressive lesions: Extrinsic tumors Optic nerve tumors Noncompressive lesions: Demyelinating disease Ischemic optic neuritis Nutritional and toxic amblyopias (including those due to pernicious anemia) Leber hereditary optic atrophy Diffuse central nervous system disease: Adrenoleukodystrophy Spinocerebellar degeneration Parkinson disease

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.25 µV 1 msec Fig. 35.28 Normal Brainstem Auditory Evoked Potentials. Major waveform components are labeled with roman numerals and are discussed more fully in the text. M2 is an electrode over the mastoid process ipsilateral to the stimulated ear, in this case the right. Left and right mastoid electrodes are connected to an electrode at the vertex (Cz).

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Neurological Investigations and Interventions generators of waves IV and V lie in the upper pons and the midbrain, as high as the inferior colliculus. Waves II and IV are inconsistently identified in some normal persons; therefore clinical interpretation of BAEPs is based primarily on latency measurements of waves I, III, and V. Despite decussation of brainstem auditory pathways at multiple levels, clinical experience indicates that unilateral BAEP abnormalities usually reflect lesions ipsilateral to the stimulated ear.

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Brainstem Auditory Evoked Potentials in Neurological Disease Auditory nerve pathology has several effects on the BAEP, related in part to the nature and size of the lesion. Findings range from prolongation of the I–III interpeak interval, to preservation of wave I with distortion or loss of later components, to loss of all BAEP components. Any of these abnormalities occur with acoustic neurinomas and other cerebellopontine angle tumors (Fig. 35.29). In fact, the BAEP is a highly sensitive screening test for acoustic neurinoma, detecting abnormalities in greater than 90% of patients. The sensitivity of the test can be extended further by using a range of stimulus intensities and evaluating the effect on components of the BAEP (latency intensity study; Fig. 35.30). In patients with focal brainstem lesions that impinge on the auditory pathways, the BAEP is abnormal and the type of abnormality reflects the lesion’s location and extent. For example, Fig. 35.31 illustrates a BAEP recorded in a patient with a brainstem hemorrhage that involved the rostral two-thirds of the pons but spared the caudal third. Waves IV and V are absent, but waves I, II, and III are relatively normal. BAEPs are normal when brainstem lesions do not involve auditory pathways, as is often the case in the locked-in syndrome produced by ventral pontine infarction or with Wallenberg lateral medullary syndrome. By contrast, pontine gliomas nearly always produce abnormal BAEPs.

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Fig. 35.29 Brainstem Auditory Evoked Potentials Recorded in a Patient With a Left Acoustic Neurinoma. The interval from I to III on that side is prolonged, and the overall response is not as well formed as that from the normal ear.

#2519, 52 y.o. woman L acoustic neuroma, intracanalicular

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Fig. 35.30 Brainstem auditory evoked potential wave V latency plots as a function of increasing stimulus intensity from 20 to 70 decibel sound level (dBSL) in a woman with a left intracanalicular acoustic neurinoma. Brainstem auditory evoked potentials at 70 dBSL are normal bilaterally, but responses at lower intensities are quite asymmetrical, and the response threshold is elevated on the left. Hearing thresholds are expressed in dBnHL, or dB hearing threshold. AD, Auris dextra (right ear); AS, auris sinistra (left ear).

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Fig. 35.31 A, Brainstem auditory evoked potentials recorded in a patient with a brainstem hemorrhage sparing the lower third of the pons. Waves I, II, and III are preserved, but later components are lost. B, Coronal section through the pons; A is at the pontomesencephalic border, and B is at the pontomedullary border. (Reprinted with permission from Chiappa, K.H., 1985. Evoked potentials in clinical medicine. In: Baker, A.B., Baker, L.H. (Eds), Clinical Neurology. Harper & Row, New York.)

Nearly 50% of patients with definite MS have abnormal BAEP results. Of greater clinical importance, approximately 20% of patients with possible or probable MS have abnormal BAEPs even in the absence of clinical signs or symptoms referable to the brainstem. In such cases, abnormalities usually consist of absence or decreased amplitude of BAEP component waves, most often of waves IV and V, or increased III-to-V interpeak latency. Occasionally, prolongation of the I-to-III interpeak interval occurs, probably reflecting involvement of the central myelin that covers the proximal and immediately intra-axial portion of the auditory nerve. BAEPs may document brainstem involvement in patients with nonfocal neurological disease, especially diseases affecting myelin, such as metachromatic leukodystrophy and adrenoleukodystrophy. In such diseases, BAEP testing may also show electrophysiological abnormalities in clinically asymptomatic heterozygotes. BAEPs are useful for assessing hearing in young children and in patients otherwise unable to cooperate with standard audiological testing. A latency intensity study, discussed previously, permits characterization of the response threshold for wave V as well as the relationship between wave V latency and stimulus intensity. Such testing allows estimation of hearing threshold and may distinguish between conductive and sensorineural types of hearing impairment. Brainstem audiometry, however, is not really a hearing test per se but rather a measure of the brainstem’s sensitivity to auditory input. The BAEP is normal in the rare patient with deafness due to bilateral cortical lesions. On the other hand, patients with MS or a pontine glioma often have abnormal BAEP results but normal hearing (although their ability to localize sound accurately in space may diminish). One limitation to the use of BAEPs to test hearing is that the brainstem must be intact, so that BAEP alterations reflect dysfunction in the peripheral hearing apparatus (Legatt, 2012).

Somatosensory Evoked Potentials On electrical stimulation of a peripheral nerve, recordings from electrodes placed over the spine and scalp reveal a series of waves that reflect sequential activation of neural structures along the afferent somatosensory pathways. The dorsal column–lemniscal system is the major substrate of the somatosensory evoked potential (SEP), although other nonlemniscal systems such as the dorsal spinocerebellar tract have been shown to contribute to SEP generation. In clinical

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practice, SEPs are usually elicited by stimulation of the median nerve at the wrist, the common peroneal nerve at the knee, or the posterior tibial nerve at the ankle.

Median Nerve Somatosensory Evoked Potentials Fig. 35.32 shows a normal SEP elicited by median nerve stimulation. The accompanying diagram indicates presumed generator sources for the various components of the SEP. An electrode at the Erb point ipsilateral to the stimulated arm registers the afferent volley as it passes through the brachial plexus. The Erb point potential serves as a reference point against which the latencies of subsequent components are measured. Electrodes over the midcervical dorsal spine record two potentials with independent but partially overlapping waveforms that reflect local activity in the spinal cord. The first of these, designated DCV (for dorsal column volley), is the afferent volley in the cuneate tract. The second, N13, reflects postsynaptic activity in the central gray matter of the cervical cord, generated by input from axon collaterals off the primary large-fiber afferents. A simultaneous potential of opposite polarity (P13) over the anterior neck accompanies the N13. Lesions that disrupt the central gray matter, such as syringomyelia, may selectively affect the N13/P13. An electrode placed on the scalp away from the primary sensory area best records the SEP components generated in the brainstem. This electrode “sees” subcortical activity that is volume-conducted to the scalp surface. Generation of the P14 is in the cervicomedullary region, probably by the caudal medial lemniscus. Following the P14 is the N18, seen as a long-duration negative wave whose origin is uncertain but probably includes postsynaptic activity from multiple generators in the brainstem. Fig. 35.33 illustrates preservation of the P14 but loss of the N18 and all later waves in a patient with an arteriovenous malformation of the right pons. This pattern probably is the electrophysiological equivalent of functional transection of the medial lemniscus at a pontine level. The initial cortical response to the afferent sensory volley is designated N20 and is best recorded by a scalp electrode placed directly over the primary sensory cortex contralateral to the stimulated side. The N20 waveform is a composite made up of signals from multiple generators within or close to the primary cortical receiving area. This can be demonstrated by selective stimulation of cutaneous and muscle-spindle afferent fibers in the median nerve, which are known to project to adjacent but distinct cortical regions, or by observation of state-dependent changes

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Fig. 35.32 Presumed Generator Sources of Median Nerve Somatosensory Evoked Potentials. Central-parietal scalp locations are contralateral (Cc) and ipsilateral (Ci) to the stimulated nerve. They are 2 cm posterior to the C3 and C4 placements of the International Ten-Twenty System. EP and SC5 are electrodes located over the Erb point and the spinous process of the fifth cervical vertebra, respectively. NC is a noncephalic (such as elbow) reference. DCV, Dorsal column volley.

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ANT CERV CERV P13 L ERBS 2 µV 2 msec Fig. 35.33 Somatosensory evoked potentials from the left median nerve recorded in a patient with a right pontine arteriovenous malformation. All components after P14 (cervicomedullary potential) are absent. Unless otherwise labeled, a right elbow reference was used.

in the N20 (Fig. 35.34). Sleep, for example, attenuates small inflections that are often present on the waking N20 wave, a phenomenon probably caused by downward modulation of some generators contributing to N20 and to alterations in thalamic input to cortex during sleep.

Posterior Tibial Nerve Somatosensory Evoked Potentials SEPs to posterior tibial nerve stimulation are in many ways analogous to median nerve SEPs. When the posterior tibial nerve is stimulated, recordings from electrodes over the lumbar spine show two distinct potentials (Fig. 35.35). One of these, PV, is produced by the afferent volley in the lumbar nerve roots and gracile tract, and the other, N22, is a summated synaptic potential generated in the gray matter of the lumbar cord. Because of its stability, fixed latency, and relatively high voltage, the clinical use of the N22 lumbar potential is as a reference point against which latencies of subsequent components are measured.

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Subcortical activity from posterior tibial nerve stimulation consists of P31, seen on the EEG as a positive wave, followed by N34, seen as a long-duration negative wave (Fig. 35.36). These components are analogous to the P14 and N18 occurring after median nerve stimulation and probably are generated by the afferent volley in the caudal medial lemniscus and by postsynaptic activity in the rostral brainstem, respectively. The initial cortical response to posterior tibial nerve stimulation is a prominent positivity (P38) that is recorded from scalp electrodes placed at the vertex and central parasagittal regions, close to the cortical areas representing the leg (see Fig. 35.36). This positive potential usually is maximal just lateral to the vertex, ipsilateral to the stimulated nerve. This apparently paradoxical localization of the P38 reflects the mesial location of the primary sensory area for the leg and foot within the interhemispherical fissure.

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Fig. 35.34 Somatosensory evoked potentials from the right median nerve recorded in a normal subject awake and then asleep after sedation with diazepam. Note the state-dependent change in morphology of the N20. Multiple small inflections present on the rising limb of N20 during wakefulness disappear during sleep.

or even loss of one or more SEP components. Abnormally large SEPs involving exaggeration of cortical components occurring after N20 (from the median nerve) are characteristic of patients with progressive myoclonic epilepsy, some patients with photosensitive epilepsy, and children with late infantile ceroid lipofuscinosis (Fig. 35.37; Emerson and Pedley, 2003). An important application of SEPs is as an aid to prognosis in patients resuscitated following cardiopulmonary arrest. In that setting, bilateral absence of the N20 is accurately predictive of a poor neurological outcome (Wijdicks et al., 2006; Fig. 35.38).

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Fig. 35.36 Normal Posterior Tibial Somatosensory Evoked Potentials. The lower channel is a bipolar recording between two electrodes over the popliteal fossa.

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Motor Evoked Potentials and Magnetic Coil Stimulation

L1 L3 L5 .5 µV 5 msec Fig. 35.35 Recordings over the lumbar and lower thoracic spinal segments obtained after posterior tibial nerve stimulation. Recording electrodes are referenced to the iliac crest. Note increasing latency of the propagated volley (PV) and the appearance at T12 of a second stationary potential (N22). See text for further details.

Somatosensory Evoked Potentials in Neurological Disease Several different conditions that disturb conduction within the somatosensory system produce SEP abnormalities. These include focal lesions (tumors, strokes, cervical spondylosis) and diseases that affect the nervous system more diffusely (hereditary ataxias, subacute combined degeneration, vitamin E deficiency). Up to 90% of patients with definite MS have either upper- or lower-limb SEP abnormalities. Furthermore, an abnormal SEP occurs in 50% to 60% of patients with MS even in the absence of symptoms or signs referable to the large-fiber sensory system. Other diseases that affect myelin (e.g., Pelizaeus-Merzbacher disease, metachromatic leukodystrophy, adrenoleukodystrophy, adrenomyeloneuropathy) also produce SEP abnormalities. With adrenoleukodystrophy and adrenomyeloneuropathy, SEP abnormalities are demonstrable in heterozygotes. Many lesions alter the SEP by producing a conduction delay or block. This results in prolonged interpeak latencies or in attenuation

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It is possible to assess the functional integrity of the descending motor pathways using motor evoked potentials (MEPs). MEP studies generally entail stimulating the motor cortex and recording the evoked compound motor action potential over appropriate target muscles. The motor cortex may be stimulated either by directly passing a brief high-voltage electrical pulse through the scalp or by using a time-varying magnetic field to induce an electric current within the brain. Whereas transcranial electrical stimulation is painful, magnetic coil stimulation is painless. Therefore the use of transcranial electrical stimulation is typically restricted to intraoperative motor system monitoring in anesthetized patients whereas magnetic stimulation is used in studies of awake subjects and patients. Direct electrical stimulation of the motor cortex produces a series of signals that are recordable from the pyramidal tract. The earliest wave, the D (direct) wave, results from direct activation of the pyramidal axons. Subsequent signals, the I (indirect) waves, probably reflect indirect transsynaptic activation of pyramidal cells. Transcranial electrical stimulation is capable of eliciting both D and I waves, but transcranial magnetic stimulation (TMS) generally elicits only I waves. For this reason, MEPs evoked by TMS occur at slightly greater latency and are less stable than those evoked by transcranial electrical stimulation. It is possible to measure the central motor conduction time by subtracting the latency of the MEP elicited by cervical or lumbar stimulation from that obtained by TMS. For MEPs elicited by TMS, this interval actually encompasses the time required for activation of cortical interneurons, transsynaptic activation of pyramidal neurons, and conduction of the efferent volley through the pyramidal tract and depolarization of the spinal motor neuron.

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Fig. 35.38 Left (A) and right (B) median nerve sensory evoked potentials recorded in a 45-year-old man with a history of a cardiomyopathy, 2 days following cardiopulmonary arrest and resuscitation. Erb point and subcortical (P14, N18) waves are present, but N20 is absent bilaterally (top channel).

MEPs can provide information about motor pathways that complements data about sensory pathways obtained from SEPs. MEPs frequently are abnormal in patients with myelopathies caused by cervical spondylosis (Fig. 35.39), in whom they appear to be sensitive to early preclinical spinal cord compression. Often, delay occurs in patients with MS, and MEPs may be more sensitive to demyelinating lesions than VEPs or SEPs. In motor neuron disease, pyramidal tract conduction delays are demonstrable in patients without upper motor neuron signs. MEPs also offer insights into the pathophysiology and evolution of disorders affecting the motor system. Patients with cerebral palsy may demonstrate enhanced MEPs in some muscle groups because of aberrant corticospinal projections. In Parkinson disease, MEP latencies

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are normal but may show increased amplitude, possibly because of spinal disinhibition or corticomotoneuronal hyperexcitability. MEPs have been used to study brain plasticity and to document cortical reorganization after spinal cord injury and amputation. Transcranial magnetic coil stimulation provides a means of studying normal cortical physiology by transiently interrupting the regional function. Disruption of cortical processing produced by single or repetitive magnetic stimuli has been useful for studying not only the function of the motor system but also cortical somatosensory, visual, and language processing function. Finally, proposed therapeutic uses for TMS include stroke, epilepsy, parkinsonism, dystonia, and depression (Rossini et al., 2010).

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Spine 12.9 msec Fig. 35.39 Motor evoked potentials (MEPs) recorded from biceps and first dorsal interosseous (FDI) muscles in a patient with cervical spondylosis producing C5–C7 spinal cord compression. MEPs recorded from biceps are normal after magnetic stimulation over both motor cortex and cervical spine. MEPs recorded from FDI are normal after stimulation over the cervical spine but are abnormally low voltage and polyphasic after cortical stimulation. (Reprinted with permission from Maertens de Noordhout, A., Remade, J.M., Pepin, J.L., et al., 1991. Magnetic stimulation of the motor cortex in cervical spondylosis. Neurology. 41, 75–80.)

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Electrophysiological monitoring is routinely used to assess the functional integrity of the brain and spinal cord during certain neurosurgical and orthopedic procedures. Such monitoring reduces neurological morbidity by detecting adverse effects at a time when prompt correction of the cause can avoid permanent neurological injury. In addition, monitoring may provide information about the mechanisms of postoperative neurological abnormalities and occasionally lead to changes in surgical approach or technique. Monitoring can be done using EEG, sensory evoked potentials (usually BAEPs or SEPs), and MEPs. Which monitoring modality or combination of modalities is used depends on the type of surgery and the neural structures judged to be most at risk. Because neurological injury can occur suddenly and may be irreversible, the ideal monitoring method is one that detects impending, not permanent, damage. A detailed discussion on interoperative monitoring is provided in Chapter 39.

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36 Clinical Electromyography Bashar Katirji

OUTLINE Nerve Conduction Studies, 447 Principles, 447 Motor Nerve Conduction Studies, 448 Sensory Nerve Conduction Studies, 449 Mixed Nerve Conduction Studies, 450 Segmental Stimulation in Short Increments, 450 Physiological Variability and Common Sources of Error, 451 Electrodiagnosis by Nerve Conduction Studies, 452

Needle Electromyographic Examination, 457 Principles and Techniques, 457 Insertional and Spontaneous Activity, 457 Voluntary Motor Unit Action Potentials, 461 Electrodiagnosis by Needle Electromyography, 462 Specialized Electrodiagnostic Studies, 465 Late Responses, 465 Repetitive Nerve Stimulation, 467 Single-Fiber Electromyography, 470

Clinical electromyography is a distinct medical discipline that plays a pivotal role in the diagnosis of peripheral nerve and neuromuscular disorders (Katirji and Kaminsky, 2002). The designations clinical electromyography (EMG), electrodiagnostic (EDX) examination, and electroneuromyography (ENMG) are used interchangeably to encompass the electrophysiological study of peripheral nerve, neuromuscular junction, and muscle; the terms needle electromyography and needle electrode examination are reserved for the specific testing that involves needle electrode evaluation of muscle. Although many still refer to all such testing as simply electromyography, use of the word without a descriptor is discouraged because it can be confusing, often implying only the needle electrode part of the evaluation. For clarity, the terms clinical EMG refers to the entire EDX study whereas needle EMG refers to the needle electrode component. These terms are used in this chapter. The clinical EMG examination is an important diagnostic tool that helps localize a neuromuscular problem at the motor or sensory neuron cell body, nerve root, peripheral nerve, neuromuscular junction, muscle membrane, or muscle. It also helps to establish the underlying process in these disorders and assess their management and prognosis. EDX testing provides the most valuable diagnostic information when the clinical assessment suggests a short list of differential diagnoses. The clinician should perform a detailed or focused neurological examination before referring the patient for a clinical EMG, which in turn serves as an independent procedure to provide an objective assessment of the peripheral nervous system (PNS; Katirji, 2002). Patients with complex clinical pictures are best served by neurological consultations prior to performing EDX testing. The clinical EMG examination is composed of two main tests: nerve conduction studies (NCSs) and needle EMG. These tests complement each other, and both are often necessary for a definite diagnosis. Additional EDX procedures include assessment of F waves, H reflexes, and blink reflexes; repetitive nerve stimulation (RNS); and single-fiber EMG (SFEMG). A focused history and examination will help the electromyographer design the most appropriate EDX study Katirji, 2018; (Preston and Shapiro, 2013). The electromyographer

must be proficient in using modern EDX equipment and applying EDX techniques, know the normal values for commonly and uncommonly examined NCSs and for motor unit action potentials (MUAPs) in different muscles, and be familiar with the specific and nonspecific EDX findings in different neuromuscular disorders.

NERVE CONDUCTION STUDIES Principles Electrical stimulation of nerve fibers initiates impulses that travel along motor, sensory, or mixed nerves and evoke a compound action potential. The three types of NCSs are motor, sensory, and mixed. Analysis of the compound muscle action potential (CMAP), which is evoked by stimulating a nerve while recording from a muscle, indirectly assesses the conduction characteristics of motor fibers. Analysis of the sensory nerve action potential (SNAP) assesses the sensory fibers by stimulating a nerve and recording directly from a cutaneous nerve. Mixed NCSs directly assess the sensory and motor fibers simultaneously by stimulating and recording from a mixed nerve and analyzing the mixed nerve action potential (MNAP). Use of standard NCSs enables the precise localization of a lesion and accurate characterization of peripheral nerve function.

Stimulators NCSs use two different kinds of surface (percutaneous) electrical stimulators. Constant voltage stimulators regulate voltage output so that current varies inversely with the impedance of the system, including the skin and subcutaneous tissues. Constant current stimulators change voltage according to impedance so that the amount of current that reaches the nerve is within the limits of skin resistance. As the current flows between the cathode (negative pole) and the anode (positive pole), negative charges accumulate under the cathode and positive charges under the anode, depolarizing and hyperpolarizing the nerve, respectively. In bipolar stimulation, both electrodes are over the nerve trunk, with the cathode closer to the recording site. Anodal conduction

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block of the propagated impulse may occur with inadvertent reversal of the cathode and anode of the stimulator. The cause of the block is hyperpolarization at the anode. This may prevent the nerve impulse evoked by the depolarization occurring under the cathode from proceeding past the anode. Supramaximal stimulation of a nerve that results in depolarization of all available axons is a paramount prerequisite to accurate and reproducible NCS measurements. To achieve supramaximal stimulation, one slowly increases the current (or voltage) intensity until it reaches a level at which the recorded potential does not increase in size. Then, increasing the current an additional 20%–30% ensures that the potential does not change further.

Distal amplitude

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Recording Electrodes Surface electrodes record the CMAP, SNAP, or MNAP. The advantages of surface recording are reproducible evoked responses that change only slightly with the position of the electrodes in relation to the recording muscle or nerve. In contrast, needle electrode recording registers only a small portion of the muscle or nerve action potentials; as a result, the evoked responses are variable and not reproducible, although they have less interference from neighboring discharges. Needle recordings improve the recording from small atrophic muscles or a proximal muscle that is not excitable in isolation. Most recording electrodes used in clinical practice are disk electrodes; ring electrodes are convenient for recording the antidromic sensory potentials from digital nerves over the proximal and distal interphalangeal joints.

Recording Procedure A prepulse preceding the stimulus triggers the sweep on a storage oscilloscope. The amplifier sensitivity determines the size (amplitude) of the potential. Overamplification truncates the response and underamplification prevents accurate measurements of the exact takeoff point from baseline. Digital averaging is very useful in recording low-amplitude SNAPs. Signals that are time locked to the stimulus summate with averaging at a constant latency and appear as an evoked potential distinct from the background noise. The signal-to-noise ratio increases in proportion to the square root of the trial number. For example, four trials give twice as big a response as a single stimulus, and nine trials give three times the amplitude. Most current instruments digitally indicate the latency and amplitude by cursors when the desired spot on the waveform is marked. The operator can override these cursors if needed.

Motor Nerve Conduction Studies The performance of motor NCSs requires stimulating a motor or mixed peripheral nerve while recording the CMAP from a muscle innervated by that nerve. Ideal muscles to record from are well isolated from neighboring muscles, which eliminates volume conduction. A pair of recording electrodes consists of an active lead, G1, placed on the belly of the muscle, and a reference (indifferent or inactive) lead, G2, placed on the tendon (belly-tendon recording). The propagating muscle action potential, originating under G1 located near the motor point, gives rise to a simple biphasic waveform with an initial negativity. Initial positivity suggests incorrect positioning of the active electrode away from the motor end-plate zone or a volume-conducted potential from distant muscles activated by anomalous innervation or by accidental spread of stimulation to other neighboring nerves, thus generating potentials from distant muscles The nerve is usually stimulated, whenever technically feasible, at two or more points along its course. Shorter nerves—such as the axillary, femoral, and facial nerves—are stimulated at only one point, because the more proximal portions of the nerves are

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Fig. 36.1 Motor nerve conduction study of the median nerve, revealing a typical compound muscle action potential (CMAP) with distal (wrist) and proximal (elbow) stimulations; it shows the distal and proximal latencies and CMAP amplitudes, durations, and areas. The proximal CMAP has a lower amplitude (12.6 mV vs. 11.3 mV) and area (37.3 mV/ ms vs. 34.50 mV/ms) than the distal CMAP because of physiological temporal dispersion and phase cancellation. The proximal conduction velocity is calculated by measuring the distance of the elbow-to-wrist segment and using the formula:Thus, for the conduction velocity in this example, 210 mm/6.9 ms − 3.5 ms = 62 m/sec.

Motor conduction velocity =

Distance Proximal latency–Distal latency

inaccessible. Otherwise, the nerve is typically stimulated distally near the recording electrode and more proximally to evaluate one or more proximal segments. Motor NCSs evaluate several measurements (Fig. 36.1): CMAP amplitude: The usual measure of amplitude is from baseline to negative peak and is expressed in millivolts. When recorded with surface electrodes, CMAP amplitude is a semiquantitative measure of the number of axons conducting between the stimulating and recording points. CMAP amplitude also depends on the relative conduction speed of the axons, the integrity of the neuromuscular junctions, and the number of muscle fibers that are able to generate action potentials. CMAP duration: This measurement is usually the duration of the negative phase of the evoked potential and is expressed in milliseconds. It is a function of the conduction rates of the various axons forming the examined nerve and the distance between the stimulation and recording electrodes. As a result of physiological temporal dispersion and phase cancellation, the CMAP generated from proximal stimulation is slightly longer in duration and lower in amplitude than that obtained from distal stimulation (see forthcoming section). CMAP area: This is usually limited to the negative phase area under the waveform and shows linear correlation with the product of amplitude and duration. Measurement is in millivolts per millisecond and requires electronic integration using computerized equipment. The ability to measure CMAP area has practically replaced the need to record its duration. Latencies: Latency is the time interval between nerve stimulation (shock artifact) and the CMAP onset. Expression of latency is in milliseconds and reflects the conduction rate of the fastest

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CHAPTER 36 Clinical Electromyography conducting axon. Whenever technically possible, the nerve is stimulated at two points: a distal point near the recording site and a more proximal point. The measures obtained are the distal latency and proximal latency, respectively. Both latencies depend mostly on the length of the nerve segment and, to a much lesser extent, on neuromuscular transmission time and propagation time along the muscle membrane. When anatomically feasible, several proximal stimulation points may be done, generating several proximal latencies; in these situations the exact site of stimulation should be specified—for example, below elbow, above elbow, or axilla—referring to stimulation sites while the ulnar nerve is being tested. Conduction velocity: This is a computed measurement of the speed of conduction expressed in meters per second. Measurement of conduction velocity allows comparison of the speed of conduction of the fastest fibers between different nerves and subjects irrespective of the length of the nerve. The calculation requires measurement of the length of the nerve segment between distal and proximal stimulation sites. Measuring the surface distance along the course of the nerve estimates the nerve length; it should be more than 10 cm to improve the accuracy of surface measurement. Motor conduction velocity =

1 Peak latency

Area

Amplitude

Duration Onset latency

Distance Proximal latency–Distal latency

As with latencies, motor conduction velocity measures the speed of conduction of the fastest axon. In contrast with motor latency, however, motor nerve conduction velocity is a pure nerve conduction time because neuromuscular transmission time and muscle fiber propagation time are common to both stimulation sites, and the latency difference between two points is the time required for the nerve impulse to travel from one stimulus point to the other. When the nerve is stimulated at multiple proximal sites, several proximal conduction velocity segments may be calculated, such as above-elbow to below-elbow segment and below-elbow to wrist segment when the ulnar nerve is being tested.

Shock artifact

20 µV

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2 ms

Sensory axons are evaluated by stimulating a nerve while the transmitted potential from the same nerve is recorded at a different site. Therefore SNAPs are true nerve action potentials. The measurement of antidromic sensory NCSs requires recording potentials directed toward the sensory receptors, whereas obtaining orthodromic responses requires recording potentials directed away from these receptors. Sensory latencies and conduction velocities are identical with either method, but SNAP amplitudes are generally higher in antidromic studies. Orthodromic responses are sometimes low in amplitude, necessitating the use of averaging techniques. Action potentials from distal muscles may obscure antidromic responses because the thresholds of some motor axons are similar to those of large myelinated sensory axons. Fortunately, accurate measurement of SNAPs is still possible because the large-diameter sensory fibers conduct 5%–10% faster than motor fibers. This relationship may change in disease states that selectively affect different fibers. SNAPs may be obtained by several methods: (1) stimulating and recording a pure sensory nerve (such as the sural and radial sensory nerves); (2) stimulating a mixed nerve while recording distally over a cutaneous branch (such as the antidromic median and ulnar sensory responses); or (3) stimulating a distal cutaneous branch while recording over a proximal mixed nerve (such as in orthodromic median and

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Fig. 36.2 Antidromic median sensory nerve conduction study after stimulation at the wrist, revealing peak and onset latencies and sensory nerve action potential amplitude, duration, and area. The shock artifact interferes with accurate determination of onset latency, whereas peak latency is easily determined.

ulnar sensory studies). Similar to their motor counterparts, sensory NCSs record several measurements (Fig. 36.2): SNAP amplitude: This semiquantitatively measures the number of sensory axons that conduct between the stimulation and recording sites. The calculation is from the baseline to negative peak or from positive peak to negative peak and is expressed in microvolts. SNAP duration and area may be measured, but such measurements are not useful because of significant temporal dispersion and phase cancellation (see later discussion). Latencies: Sensory distal latencies are measured (in milliseconds) from the stimulus artifact to the peak of the negative phase (peak latency) or from the stimulus artifact to the onset of the SNAP (onset latency). A large shock artifact, a noisy background, or a wavy baseline may obscure onset latency. Although peak latency

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does not reflect the fastest conducting sensory fibers, it is easily defined and more precise than onset latency. Conduction velocity: This requires stimulation at a single site only because the latency consists of just the nerve conduction time from the stimulus point to the recording electrode. As with motor velocity, the calculation may also be done using both distal and proximal stimulations. Only onset latencies (not peak latencies) are useful for calculating velocities to assess the speed of the fastest conducting fibers. Sensory conduction velocity =

Distance Onset latency

or =

Distance Proximal latency – Distal latency

Mixed Nerve Conduction Studies Stimulating and recording from nerve trunks containing sensory and motor axons constitute mixed NCSs. Often these tests require stimulating a nerve trunk distally and recording more proximally because large CMAPs contaminate the reverse by obscuring the lower-amplitude MNAPs. The MNAP may be of low amplitude or not elicitable when the nerve is deeply situated (as at the elbow or knee) because of tissue interposed between the nerve and the recording electrode. Therefore MNAPs are limited to assessing mixed nerves in distal nerve segments in the hand or foot, such as the mixed palmar and mixed plantar studies used to evaluate carpal tunnel syndrome and tarsal tunnel syndrome, respectively.

Segmental Stimulation in Short Increments Routine NCSs are usually sufficient to localize the site of involvement in most patients with entrapment neuropathies. During the evaluation of a focal demyelinating lesion, however, inclusion of the unaffected nerve segment in a relatively long distal latency or conduction velocity calculation dilutes the effect of slowing at the injured site and decreases the sensitivity of the test. Therefore incremental stimulation across a shorter nerve segment is useful to help localize an abnormality that might otherwise escape detection. Localization that is more precise entails “inching” the stimulus in short increments along the course of the nerve. The study of short segments provides better resolution of restricted lesions. For example, a nerve impulse may be found to conduct at a rate of 0.2 ms per 1.0 cm (50 m/sec). For a 1-cm segment, then, demyelination would double the conduction time to 0.4 ms/cm. In a 10-cm segment, normally covered in 2.0 ms, a 0.2-ms increase would constitute a 10% change, or approximately 1 standard deviation, or well within the normal range of variability. However, the same 0.2-ms increase would represent a 100% change in latency if it were measured over a 1-cm segment. The large per-step increase in latency more than compensates for the inherent measurement error associated with stimulating multiple times in short increments. The inching (or actually “centimetering”) technique is particularly useful in assessing nerve conduction in patients with carpal tunnel syndrome or an ulnar neuropathy at the elbow or wrist (McIntosh et al., 1998). For example, stimulation of a normal median nerve in 1-cm increments across the wrist results in latency changes of approximately 0.16–0.21 ms/cm from midpalm to distal forearm (Fig. 36.3). A sharply localized latency increase across a 1-cm segment indicates a focal abnormality of the median nerve (Fig. 36.4). An abrupt change in waveform usually accompanies the latency increase across the site of compression.

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B

Fig. 36.3 A, Twelve sites of stimulation in 1-cm increments along the length of the median nerve. The 0 level is at the distal crease of the wrist, corresponding to the origin of the transverse carpal ligament. Sensory nerve action potentials (SNAPs) and compound muscle action potentials are recorded from the second digit and abductor pollicis brevis, respectively. B, SNAPs in a normal subject recorded after stimulation of the median nerve at multiple points across the wrist. The site of each stimulus is indicated on the left. The latency changes increased linearly (approximately 0.16–0.21 ms) as the stimulus site was moved proximally in 1-cm increments. (B, Reprinted with permission of the author and publisher from Kimura, J., 1979. The carpal tunnel syndrome: localization of conduction abnormalities within the distal segment of the median nerve. Brain 102, 619–635. By permission of Oxford University Press.)

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This measurement correlates linearly with the subcutaneous and intramuscular temperatures. If the skin temperature falls below 33°C, the limbs are warmed by immersion in warm water or by the application of warming packs or a hydrocollator. Adding 5% of the calculated conduction velocity for each degree below 33°C theoretically normalizes the result. The use of such conversion factors is based on evidence obtained in healthy persons; however, this may not be applicable in patients with abnormal nerves.

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Age .5

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Because myelination is incomplete at birth, nerve conduction velocities are half the adult values in full-term newborns; in 23- to 24-week premature newborns, velocities are one-third the values for term newborns. They attain adult values at 3–5 years. Motor and sensory nerve conduction velocities tend to increase slightly in the arms and decrease in the legs during childhood up to the age of 19 years. Conduction velocities slowly decline after age 50, so the mean conduction velocity is reduced by approximately 10% at 60 years of age. Aging also diminishes SNAP and CMAP amplitudes, which decline slowly after age 60. SNAP amplitudes are affected more prominently, so much so that normal upper limb SNAP amplitude drops to 50% by age 70 and lower limb SNAPs in many healthy persons older than 60 are low in amplitude or unevokable. Therefore the absence of lower extremity SNAPs in older adults must be interpreted with caution; the finding is not necessarily abnormal without other confirmatory data.

MS

A

50 µV 1 ms

–6 –5 –4 –3 –2 –1 0 1 2 3 4 5

Height and Nerve Segment Lengths .5

0

B Fig. 36.4 Sensory nerve action potentials in a patient with bilateral carpal tunnel syndrome (see also Fig. 36.3 for settings). A sharply localized slowing was found from point −2 to point −1 in both hands, with a latency change measuring 0.7 ms on the left (A) and 1.1 ms on the right (B), compared with the other segments with normal latency changes of approximately 0.16–0.21 ms. Note also a distinct change in waveform of the sensory potential at the point of localized conduction delay. (Reprinted with permission of the author and publisher from Kimura, J., 1979. The carpal tunnel syndrome: localization of conduction abnormalities within the distal segment of the median nerve. Brain 102, 619–635. By permission of Oxford University Press.)

Physiological Variability and Common Sources of Error The major pitfalls in NCS usually involve technical errors in the stimulating or recording system (Kimura, 1997). Common errors include large stimulus artifact, increased electrode noise, submaximal stimulation, costimulation of an adjacent nerve not under study, eliciting an unwanted potential from distant muscles, recording or reference electrode misplacement, and errors in measurement of nerve lengths and conduction times. Other errors are attributable to intertrial and physiological variability, including the effects of temperature, age, the length of the studied nerve, anomalous innervation, and temporal dispersion.

Temperature Nerve impulse propagation slows by 2.4 m/sec, or approximately 5%, per degree centigrade from 38°C to 29°C of body temperature. Also, cooling results in a higher CMAP and SNAP amplitude and longer response duration, probably because of accelerated and slowed sodium channel inactivation (Rutkove et al., 1997). Therefore a CMAP or SNAP with high amplitude and slow distal latency or conduction velocity should raise the suspicion of a cool limb. To reduce this type of variability, a plate thermistor is used to measure skin temperature.

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An inverse relationship between height and nerve conduction velocity suggests that longer nerves conduct more slowly than shorter nerves. For example, the nerve conduction velocities of the peroneal and tibial nerves in the lower extremities are 7–10 m/sec slower than those of the median and ulnar nerves in the upper extremities. The slightly lower temperature of the legs compared with the arms is not the entire explanation. Possible factors accounting for the length-related slowing include abrupt distal axonal tapering, progressive reduction in axonal diameter, and shorter internodal distances. For similar reasons, nerve impulses propagate faster in proximal than in distal nerve segments. Adjustments of normal values are necessary for patients of extreme height; this usually is no more than 2 m/sec below the lower limit of normal.

Anomalies Several anomalous peripheral innervations may influence interpretation of the EDX study. Two of these variants, the Martin-Gruber anastomosis and the accessory deep peroneal nerve, have a significant effect on NCSs. Martin-Gruber anastomosis. In the Martin-Gruber anastomosis, anomalous fibers cross from the median to the ulnar nerve in the forearm. The communicating branches usually consist of motor axons supplying the ulnar innervated intrinsic hand muscles, particularly the first dorsal interosseous muscle, the hypothenar muscles (abductor digiti minimi), and the thenar muscles (adductor pollicis, deep head of flexor pollicis brevis), or a combination of these muscles (Uchida and Sugioka, 1992). The Martin-Gruber anastomosis occurs in approximately 15%–20% of the population and is sometimes bilateral. This anomaly manifests as a drop in the ulnar CMAP amplitude between distal and proximal stimulation sites (simulating the appearance of conduction block on ulnar NCS recording from the abductor digiti minimi or first dorsal interosseous). With distal stimulation (at the wrist), the CMAP reflects all ulnar motor fibers, whereas proximal stimulation activates only the uncrossed fibers, which are fewer in number. This anomaly can be confirmed by median nerve stimulation at the elbow, which evokes a small CMAP from the

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abductor digiti minimi or first dorsal interosseous, which is not present on median nerve stimulation at the wrist. Although in the majority of subjects the abnormal decline in CMAP amplitude occurs across the forearm segment, this pseudo-conduction block may occasionally be encountered across the elbow segment, resembling partial conduction block in a patient with ulnar neuropathy at the elbow (Whitaker and Felice, 2004). When anomalous fibers innervate the thenar muscles, stimulation of the median nerve at the elbow activates the nerve and the crossing ulnar fibers, resulting in a large CMAP, often with an initial positivity caused by volume conduction of action potential from the ulnar thenar muscles to the median thenar muscles. By contrast, distal median nerve stimulation evokes a smaller thenar CMAP without the positive dip because the crossed fibers are not present at the wrist. In addition, the median nerve conduction velocity in the forearm is spuriously fast, particularly in the presence of carpal tunnel syndrome, because the CMAP onset represents a different population of fibers at the wrist than at the elbow. Collision studies obtain an accurate conduction velocity by using action potentials of the crossed fibers (Sander et al., 1997). Accessory deep peroneal nerve. About 20%–30% of subjects have an anomalous accessory deep peroneal nerve. It is a branch of the superficial peroneal nerve and usually arises as a continuation of the muscular branch that innervates the peroneus longus and brevis muscles. It passes behind the lateral malleolus and terminates in the extensor digitorum brevis (EDB) on the dorsum of the foot. During peroneal motor NCS recording from the EDB, the peroneal CMAP amplitude is larger-stimulating proximally than distally because the anomalous fibers are not present at the ankle. Stimulation behind the lateral malleolus confirms this anomaly, which yields a small CMAP that approximately equals the difference between the CMAP amplitudes evoked with distal and proximal peroneal nerve stimulations. Complete innervation of the EDB by the accessory deep peroneal nerve is rare but should be suspected if there is preservation of function in the EDB muscle (i.e., extension of lateral toes) in a patient with severe deep peroneal neuropathy (Kayal and Katirji, 2009). Pre- and postfixed brachial plexus. In most people, the brachial plexus arises from the C5 to T1 cervical roots. In some, the plexus origin shifts one level up (prefixed), arising from C4 to C8; in others, it shifts one level down (postfixed), originating from C6 to T2. These anomalies result in error in the precise localization of cervical root lesions based on myotomal and dermatomal representation. In a prefixed plexus, the location of the cervical lesion is one level higher than concluded from findings on the clinical examination and EDX studies. In contrast, with a postfixed plexus, the cervical root lesion is one level lower. Riche-Cannieu anastomosis. Riche-Cannieu anastomosis is a communication in the palm between the recurrent motor branch of the median nerve and the deep branch of the ulnar nerve. The result is dual innervation of some intrinsic hand muscles such as the first dorsal interosseous, adductor pollicis, and abductor pollicis brevis. RicheCannieu anastomosis is rather common but is often not clinically or electrophysiologically apparent. When this anomaly is prominent, denervation in ulnar muscles may follow a median nerve lesion, and vice versa. In addition, a complete median or ulnar nerve lesion may be associated with relative sparing of some median innervated muscles or ulnar innervated muscles in the hand.

Temporal Dispersion and Phase Cancellation The CMAP, evoked by supramaximal stimulation, represents the summation of all individual MUAPs directed to the muscle through the stimulated nerve. Typically, as the stimulus site moves proximally, the CMAP slightly drops in amplitude and area and increases in duration.

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This is caused by temporal dispersion in which the velocity of impulses in slow-conducting fibers lags increasingly behind those of fast-conducting fibers as conduction distance increases. With dispersion, a slight positive and negative phase overlap occurs, and phase cancellation of MUAP waveforms is seen (Fig. 36.5). The result of temporal dispersion and phase cancellation is a prolongation of CMAP duration, reduction of CMAP amplitude, and a less obvious decrease in CMAP area. Physiological temporal dispersion affects the SNAP more than the CMAP (Fig. 36.6). This difference relates to two factors. The first relates to the disparity between sensory fiber and motor fiber conduction velocities. The range of conduction velocities between the fastest and slowest individual human myelinated sensory axons is almost twice that for the motor axons (25 m/sec and 12 m/sec, respectively). The second factor is the difference in duration of individual unit discharges between nerve and muscle. With short-duration biphasic or triphasic SNAPs, a slight latency difference could line up the positive peaks of the fast fibers with the negative peaks of the slow fibers and cancel both (Fig. 36.7). In longer-duration biphasic CMAPs, the same latency shift would only partially superimpose peaks of opposite polarity and phase cancellation would be less of a factor.

Intertrial Variability Principal factors contributing to an intertrial variability include errors in determining surface distance and measuring latencies and amplitudes of the recorded response. Amplitudes vary most, probably reflecting a shift in the recording site. NCSs are more reproducible when they are administered by the same examiner because there is a significant degree of interexaminer difference (Chaudhry et al., 1991).

Electrodiagnosis by Nerve Conduction Studies Although both NCSs and needle EMGs are required in most patients to confirm a neuromuscular diagnosis, certain peripheral nerve disorders are evident on NCSs alone.

Focal Nerve Lesions Peripheral nerve is composed of unmyelinated and myelinated axons surrounded by Schwann cells and a supporting tissue. Surrounding the unmyelinated axons are only the plasma membranes of Schwann cells. By contrast, wrapped around myelinated axons are multiple myelin layers that have a low capacitance and large resistance. Surrounding the myelinated axon is myelin, along with Schwann cells, except at certain gaps called the nodes of Ranvier, where sodium channels are highly concentrated and saltatory conduction occurs. Three supportive layers—the endoneurium, perineurium, and epineurium—surround nerves; they are highly elastic and protect the myelin and axon from external pressure and tension. Nerve fibers may be injured by a variety of mechanisms, including compression, ischemia, traction, and laceration. The classification of peripheral nerve lesions is based on the extent of injury to the elements of peripheral nerve, including axon, myelin, and supportive layers. In neurapraxia (first-degree injury), distortion of myelin occurs near the nodes of Ranvier, producing segmental conduction block without wallerian degeneration. In axonotmesis (second-degree injury), the axon is interrupted but all the supporting nerve structures remain intact. In neurotmesis, the nerve injury is severe, resulting in complete disruption of the nerve with all the supporting structures (see Chapter 63). Often, the neurotmesis group is divisible into three degrees, as follows: third-degree injury, with disruption of the endoneurium and with intact perineurium and epineurium; fourth-degree injury, with disruption of all neural elements except the epineurium; and fifth-degree nerve injury, with complete nerve transection

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S

Fig. 36.5 Compound muscle action potentials showing the relationship between fast-conducting (F) and slow-conducting (S) motor fibers. With distal stimulation (top), two unit discharges representing motor unit potentials sum to produce a muscle action potential twice as large. With proximal stimulation (bottom), motor unit potentials of long duration still superimpose nearly in phase despite the same latency shift of the slow motor fiber. Thus, a physiological temporal dispersion alters the size of the muscle action potential only minimally if at all. Phase cancellation increases substantially when the latency difference between fast- and slow-conducting fibers is increased by a demyelinating neuropathy. This gives the false impression of motor conduction block. (Reprinted with permission from Kimura, J., Machida, M., Ishida, T., et al., 1986. Relation between size of compound sensory or muscle action potentials and length of nerve segment. Neurology 36, 647–652.)

resulting in complete discontinuity of the nerve. EDX studies alone cannot accurately distinguish between the five degrees of nerve injuries, but they can separate the first (neurapraxia) from the other axonloss types (Wilbourn, 2002). Demyelinative mononeuropathy. When focal injury to myelin occurs, conduction along the affected nerve fibers may alter. This may result in conduction slowing or block along the nerve fibers. The cause of conduction block is interruption of action potential transmission across the nerve lesion; it is the electrophysiological correlate of neurapraxia and usually results from loss of more than one myelin segment (segmental or internodal demyelination). Bracketing two stimulation points, one distal and one proximal to the site of injury, best localizes a nerve lesion with conduction block. With such lesions, stimulation distal to the lesion elicits a normal CMAP, whereas proximal stimulation evokes a response with reduced amplitude or fails to evoke any response; these are respectively defined as partial or complete conduction block (Fig. 36.8, A). There are several limitations to the diagnosis of demyelinative conduction block: 1. Phase cancellation between peaks of opposite polarity may reduce CMAP size because of abnormally increased temporal dispersion. Such excessive desynchronization often develops in acquired demyelinative neuropathies. If the distal and proximal responses have dissimilar waveforms, the discrepancy in amplitude or area between the two may be the result of phase cancellation rather than conduction block. Therefore, for a diagnosis of partial conduction block, findings should include a significantly lower CMAP amplitude as well as CMAP area with stimulation proximal to the injury site than with the CMAP distal to it, and without any significant prolongation of CMAP duration. More than 50% decay of both the

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CMAP amplitude and area across the lesion is usually the criterion for definite conduction block. 2. Distal demyelinating lesions causing conduction block of the nerve segment between the most distal stimulating point and the recording site manifest as unelicitable or low CMAP amplitudes at both distal and proximal stimulation sites. This finding mimics the NCSs seen with axonal degeneration. Repeated NCSs often show rapid improvement of CMAP within weeks, consistent with remyelination but not with axonal loss and reinnervation. 3. Conduction block may also follow axonal loss before the completion of wallerian degeneration. This is referred to as axon-loss conduction block, or axon-discontinuity conduction block. Repeated NCSs will show rapid decline of distal CMAP within a week, resulting in equal CMAPs at all points of stimulation (see “Axon-loss mononeuropathy,” later). 4. The prominent temporal dispersion normally seen in evaluating SNAPs precludes the use of sensory potentials to diagnose conduction block. Focal slowing of conduction is usually the result of widening of the nodes of Ranvier (paranodal demyelination). Slowing, often synchronized, affects all large myelinated fibers equally. This results in prolongation of distal latency if the focal lesion is distal (see Fig. 36.8, B, a), or slowing in conduction velocity if the focal lesion is proximal (see Fig. 36.8, B, b). CMAP amplitude, duration, and area, however, are normal and do not change when the nerve is stimulated proximal to the lesion. Desynchronized slowing (differential slowing) occurs when conduction velocity reduces at the lesion site along a variable number of the medium-sized or small nerve fibers (average- or slower-conducting axons). Here the CMAP disperses with prolonged duration on stimulations proximal to the lesion. The

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MEDIAN NERVE STIMULATION P W

CMAP

E

A

Axilla

SNAP Elbow

P

5 µV

W

5 ms

E A Wrist Palm

20 µV 5 ms Fig. 36.6 Simultaneous recordings of compound muscle action potentials (CMAPs) from the thenar eminence and sensory nerve action potentials (SNAPs) from index finger after stimulation of the median nerve at palm (P), wrist (W), elbow (E), and axilla (A). With progressively more proximal stimulation, CMAPs remained nearly the same; for SNAPs, however, both amplitude and the area under the waveform became much smaller.

Individual responses

Summated response

F

S

F

S Fig. 36.7 Sensory Nerve Action Potentials. A model for phase cancellation between fast-conducting (F) and slow-conducting (S) sensory fibers. With distal stimulation (top), two unit discharges sum in phase to produce a sensory action potential twice as large. With proximal stimulation (bottom), a delay of the slow fiber causes phase cancellation between the negative peak of the fast fiber and positive peak of the slow fiber, resulting in a 50% reduction in size of the summated response. (Reprinted with permission from Kimura, J., Machida, M., Ishida, T., et al., 1986. Relation between size of compound sensory or muscle action potentials and length of nerve segment. Neurology 36, 647–652.)

speed of conduction along the injury site (latency or conduction velocity) is normal because of sparing of at least some of the fastest-conducting axons (see Fig. 36.8, C). When synchronized and desynchronized slowing coexist, slowing of distal latency or conduction velocity accompanies the dispersed CMAP with prolonged duration.

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Axon-loss mononeuropathy. After acute focal axonal damage, the distal nerve segment undergoes wallerian degeneration. Characteristically, unelicitable or low CMAP amplitudes with distal and proximal stimulations are signs of complete or partial lesions, respectively, involving motor axonal loss. The CMAP amplitudes provide a reliable estimate of the amount of axonal loss except in the chronic phase, in which effective reinnervation via collateral sprouting may increase the CMAP and give a misleadingly low estimate of the extent of original axonal loss. In partial axon-loss lesions, distal latencies and conduction velocities are normal or borderline. Selective loss of fast-conducting fibers associated with more than a 50% reduction in mean CMAP amplitude may slow conduction velocity up to 80% of the normal value because the velocity represents the remaining slow-conducting fibers. Motor conduction velocity may slow to 70% of normal value with a reduction of CMAP amplitude to less than 10% of the lower limit of normal. Soon after axonal transection (i.e., for the first 48 hours), the distal axon remains excitable. Therefore stimulation distal to the lesion elicits a normal CMAP, whereas proximal stimulation elicits a response with reduced amplitude and area, producing a conduction block pattern (see Fig. 36.8, D, middle panel). This pattern is axonal noncontinuity, early axon loss, or axon-discontinuity conduction block. Soon, however, the distal axons undergo wallerian degeneration, and the distal CMAP decreases in size to equal the proximal CMAP (see Fig. 36.8, D, lower panel). With wallerian degeneration, the distal CMAP decreases in amplitude and area starting 1 or 2 days after nerve injury and reaches its nadir in 5–6 days. In contrast, the distal SNAP lags slightly behind and reaches its nadir in 10 or 11 days (Fig. 36.9). The difference between the decline of the SNAP and CMAP amplitudes and areas after axon loss probably relates to neuromuscular transmission failure, which affects only the CMAP amplitude and area. Supporting this hypothesis is the fact that MNAPs recorded directly from nerve trunks follow the time course of SNAPs. The study is repeated after 10 or 11 days, when degenerating axons have lost excitability, to distinguish between conduction block due to demyelination and that due to axonal loss. A reduction in amplitude and area of the evoked potential from stimulation above and below the lesion indicates axonal loss (see Fig. 36.8, D). By contrast, if the distally evoked CMAP still has preserved amplitude and area greater than that of the proximally elicited response, it indicates partial segmental demyelination. Identification of conduction block in the early days of axonal loss is extremely helpful in localizing a peripheral nerve injury, particularly the closed type in which the exact site of lesion is not apparent. Awaiting the completion of wallerian degeneration leads to diffusely low or unevokable CMAPs (regardless of stimulation site), which does not allow accurate localization of the injury site. Needle EMG study is useful, but localization by this method is suboptimal (see later discussion). Preganglionic (intraspinal canal) lesions. Damage to the sensory axons in the nerve roots located proximal to the dorsal root ganglion does not affect the SNAP amplitude because the peripheral sensory axons originating from the unipolar dorsal root ganglion neurons remain intact. Because the dorsal root ganglia are usually located outside the spinal canal and within the intervertebral foramina, intraspinal canal lesions involving axonal loss (such as radiculopathies or root avulsions) have no effect on SNAP amplitudes. However, these nerve root lesions often result in the degeneration of motor axons, as reflected by abnormal needle EMG findings and, when severe, by CMAPs of low amplitude and area. In contrast to intraspinal canal lesions that are preganglionic, extraspinal lesions with axonal loss (such as plexopathies) are postganglionic and, when mixed nerves

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CHAPTER 36 Clinical Electromyography

R

Ulnar nerve S

S

Ulnar nerve

a

R

S

b S Normal

Normal 3.0 ms

55 m/s

3.0 ms Partial (±60%) conduction block

3.0 ms

455

55 m/s Prolonged distal latency

a

53 m/s

6.0 ms Total (±100%) conduction block

55 m/s Slowed conduction velocity

b 3.0 ms

3.0 ms

A

45 m/s

B

R

Ulnar nerve S

R

S

Ulnar nerve S

S Normal

Normal 3.0 ms

55 m/s

3.0 ms

55 m/s

3.0 ms

53 m/s

Axondiscontinuity conduction block (days 1–3)

Dispersed response 3.0 ms

55 m/s

C

Conduction failure (day 7 on) 3.0 ms

53 m/s

D Fig. 36.8 Findings on Nerve Conduction Studies. A, Demyelinative conduction block. Note the proximal compound muscle action potential (CMAP) is either low in amplitude (partial block) or absent (complete block). B, Focal synchronized slowing of the distal nerve segment (a) or the proximal nerve segment (b). C, Focal desynchronized slowing of the forearm nerve segment, resulting in significant dispersion of the proximal CMAP. D, Axon loss (partial), studied early and late after nerve trauma. R, Recording; S, stimulation. (Reprinted with permission from Wilbourn, A.J., 2002. Nerve conduction studies. Types, components, abnormalities and value in localization. Neurol Clin 20, 305–338.)

undergo wallerian degeneration, affect the CMAP as well as the SNAP amplitudes.

Generalized Polyneuropathies NCSs are essential in diagnosing peripheral polyneuropathies. They are very useful for endorsing the diagnosis or suggesting alternative diagnoses such as small-fiber sensory neuropathies or entrapment neuropathies. When confirmed, NCSs will also aid in establishing the types of fibers affected (large-fiber sensory, motor, or both). Of greatest importance, NCSs often identify the primary pathological process of the various polyneuropathies: axonopathy (axonal degeneration) versus myelinopathy (segmental demyelination). This helps greatly in identifying the cause of the polyneuropathy (Fig. 36.10, A, B & C). Axonal polyneuropathies. Axonal polyneuropathies produce length-dependent dying-back degeneration of axons. The major

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change on NCS is decrease of the CMAP and SNAP amplitudes and areas, more marked in the lower extremities. By contrast, conduction velocities and distal latencies are usually normal (Fig. 36.10, B). As with axonal loss mononeuropathies, selective loss of many fast-conducting fibers associated with more than a 50% reduction in CMAP amplitude may slow conduction velocity to more than 70%–80% of normal value. Demyelinating polyneuropathies. The hallmark of demyelinating polyneuropathies is a widespread increase in conduction time caused by impaired saltatory conduction. Therefore NCS findings are characterized by significant slowing of conduction velocities (130% of the upper limit of normal). With distal stimulation, demyelination delays the distal latency and there is usually a moderate reduction of the CMAP amplitude because of abnormal temporal dispersion and phase cancellation. With proximal stimulation, the CMAP amplitude is lower

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and the proximal conduction velocity markedly slows because the action potentials travel a longer distance, with an increased probability for the nerve action potentials to pass through demyelinated segments (see Fig. 36.10, C). The proximal CMAP amplitude and/or area decay is the result of more prominent temporal dispersion and phase cancellation as well as possible conduction block along some fibers. NCSs further separate chronic demyelinating polyneuropathies into inherited and acquired polyneuropathies. Characteristic of inherited demyelinating polyneuropathies, such as Charcot-Marie-Tooth disease type I, is uniform slowing, resulting in symmetrical abnormalities as well as the absence of conduction blocks. By contrast, acquired demyelinating polyneuropathies, such as chronic inflammatory

demyelinating polyneuropathy, are often associated with nonuniform slowing, which results in asymmetrical nerve conductions even in the absence of clinical asymmetry. In addition, multifocal conduction blocks and excessive temporal dispersions at nonentrapment sites are characteristic of acquired demyelinating polyneuropathies. In the most common form of Guillain-Barré syndrome, acute inflammatory demyelinating polyneuropathy, multifocal demyelination that fulfills the criteria for demyelination is evident in 35%–50% of patients during the first 2 weeks of illness, compared with 85% by the third week (Al-Shekhlee et al., 2005; Albers et al., 1985). Two other suggestive nerve conduction findings in this disorder are (1) abnormal upper extremity SNAPs with normal sural SNAPs (called sural sparing pattern), an unusual

% amplitude

100

CMAP amplitude

80

SNAP amplitude

60 40 20 0 1

2

3

4

5

6

7

8

9

10

11

12

Days from acute axonal injury Fig. 36.9 Distal compound muscle action potential (CMAP) and sensory nerve action potential (SNAP) amplitudes during wallerian degeneration after an acute axonal nerve injury. (Reprinted with permission from Katirji, B., 2018. Electromyography in Clinical Practice: A Case Study Approach, third ed. Oxford University Press, New York.)

A

B

C

Fig. 36.10 Computerized model of motor nerve conduction study of a peripheral nerve. A, Normal nerve. B, Nerve after axonal degeneration. C, Nerve with segmental demyelination. (Reprinted with permission from Brown, W.F., Bolton, C.F. [Eds], 1989. Clinical Electromyography. Butterworth-Heinemann, Boston.)

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CHAPTER 36 Clinical Electromyography pattern in axonal length–dependent polyneuropathy, and (2) diffuse absence of F waves with normal results on motor conduction studies, findings consistent with proximal peripheral nerve or spinal root involvement.

NEEDLE ELECTROMYOGRAPHIC EXAMINATION Principles and Techniques The motor unit consists of a single motor neuron and all the muscle fibers it innervates. A single motor unit innervates either type I or type II muscle fibers but never both. All muscle fibers in one motor unit discharge simultaneously when stimulated by synaptic input to the lower motor neuron (LMN) or by electrical stimulation of the axon. The ratio of muscle fibers per motor neuron (innervation ratio or motor unit size) is variable and ranges from 3 to 1 for extrinsic eye muscles to several thousand to 1 for large limb muscles. The smaller ratio is generally characteristic of muscles that perform fine gradations of movement. The distribution of a single motor unit’s muscle fibers in a muscle is wide, with significant overlap between different motor units. The muscle fiber has a resting potential of 90 mV, with negativity inside the cell. The generation of an action potential reverses the transmembrane potential, which then becomes positive inside the cell. An extracellular electrode, as used in needle EMG, records the activity resulting from this switch of polarity as a predominantly negative potential (usually triphasic, positive-negative-positive waveforms). When they are recorded near a damaged region, however, action potentials consist of a large positivity followed by a small negativity. Concentric and Teflon-coated monopolar needle electrodes are equally satisfactory in recording muscle potentials, with little appreciable difference. Although monopolar needles are less painful, they require an additional reference electrode placed nearby, which often results in greater electrical noise caused by electrode impedance mismatch between the intramuscular active electrode and the surface reference disk. The electromyographer first identifies the needle insertion point by recognizing the proper anatomical landmark and the activation

TABLE 36.1 Potential End-plate noise

457

maneuver for the sampled muscle. Needle EMG evaluation requires appreciation of the following technical considerations: 1. Inserting or slightly moving the needle causes insertional activity that results from needle injury of muscle fibers. 2. Moving the needle a small distance and pausing a few seconds assesses spontaneous activity in relaxed muscle. From a single cutaneous insertion, relocating the needle in four quadrants of the muscle completes the evaluations. 3. Minimal contraction assesses the morphology of several MUAPs measured on the screen. The needle should be moved slightly (pulled back or moved deeper) if sharp MUAPs are not seen with minimal contraction. 4. Increasing the intensity of muscle contraction assesses the recruitment pattern of MUAPs. Maximal contraction normally fills the screen, producing the interference pattern. An amplification of 50 µV per division best defines the insertional and spontaneous activity, whereas 200 µV per division is suited for voluntary activity. Most laboratories use a screen with sweep speeds of 10–20 ms per division for insertional, spontaneous, and voluntary activities.

Insertional and Spontaneous Activity

Normal Insertional and Spontaneous Activity Brief bursts of electrical discharges accompany insertion and repositioning of a needle electrode into the muscle, slightly outlasting the movement of the needle. On average, insertional activity lasts for a few hundred milliseconds. It appears as a cluster of positive or negative repetitive high-frequency spikes, which make a crisp static sound over the loudspeaker. At rest, muscle is silent, with no spontaneous activity except in the motor end-plate region, the site of neuromuscular junctions, which are usually located along a line crossing the center of the muscle belly. Table 36.1 lists normal and abnormal insertional and spontaneous activities (Katirji et al., 2014). Two types of normal end-plate

Insertional and Spontaneous Activity on Needle Electromyography

Source Generator and Morphology Miniature end-plate potentials (monophasic negative)

Sound on Loudspeaker Seashell

Muscle fiber initiated by terminal axonal twig (brief spike, diphasic, initial negative)

Stability —

Firing Rate (Hz) 20–40

Firing Pattern Irregular (hissing)

Sputtering fat in a frying pan

—

5–50

Irregular (sputtering)

Fibrillation (brief Muscle fiber (brief spike, diphasic spike) or triphasic, initial positive)

Rain on a tin roof or ticktock of a clock

Stable

0.5–10 (occasionally up Regular to 30)

Positive sharp wave

Muscle fiber (diphasic, initial positive, slow negative)

Dull pops, rain on a tin roof, Stable or tick-tock of a clock

0.5–10 (occasionally up Regular to 30)

Myotonia

Muscle fiber (brief spike, initial positive, or positive wave)

Revving engine or dive bomber

Waxing and waning ampli- 20–150 tude

Waxing and waning

Complex repeti- Multiple muscle fibers time-linked tive discharge together

Machine or motorcycle on highway

Usually stable, may change 5–100 in discrete jumps

Perfectly regular

Fasciculation

Motor unit (motor neuron or axon)

Corn popping

Low (0.1–10)

Irregular

Myokymia

Motor unit (motor neuron or axon)

Marching soldiers

1–5 (interburst), 5–60 (intraburst)

Bursting

Cramp

Motor unit (motor neuron or axon)

—

High (20–150)

Interference pattern or several individual units

Neuromyotonia

Motor unit (motor neuron or axon)

Decrementing amplitude

Very high (150–250)

Waning

End-plate spike

Pinging

Adapted with permission from Katirji, B., Kaminski, H.J., Ruff, R.L. (Eds), 2014. Neuromuscular Disorders in Clinical Practice. Springer, New York.

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spontaneous activity occur together or independently: end-plate noise and end-plate spikes (Fig. 36.11). End-plate noise (see Video 36.1). The tip of the needle approaching the end-plate region often registers recurring irregular negative potentials, 10–50 µV in amplitude and 1–2 ms in duration. These potentials are the extracellularly recorded miniature endplate potentials, or nonpropagating depolarizations caused by spontaneous release of acetylcholine quanta. They produce a characteristic sound on the loudspeaker much like that of a seashell held to the ear. End-plate spikes (see Video 36.2). End-plate spikes are intermittent spikes, 100–200 µV in amplitude and 3–4 ms in duration, firing irregularly at 5–50 impulses per second. Their characteristic waveform (initial negative deflection) and irregular firing pattern distinguish them from the regular-firing fibrillation potentials. Furthermore, they are often associated with end-plate noise and sound on the loudspeaker like that of sputtering fat in a frying pan. The end-plate spikes are discharges of single muscle fibers generated by activation of intramuscular nerve terminals irritated by the needle. The similarity of the firing pattern of endplate spikes to discharges of muscle spindle afferents suggests that they may originate in the intrafusal muscle fibers.

Abnormal Insertional and Spontaneous Activity Prolonged versus decreased insertional activity. An abnormally prolonged (increased) insertional activity indicates instability of the muscle membrane, as is often seen in conjunction with denervation, myotonic disorders, or necrotizing myopathies such as inflammatory myopathies. Insertional positive waves, initiated by needle movements only and identical to the spontaneous discharges, may follow the increased insertional activity and last for a few seconds. This isolated activity usually signals early denervation of muscle fibers, such as occurs 1–2 weeks after acute loss of motor axons. A marked reduction or absence of insertional activity suggests either fibrotic or severely atrophied muscle or functionally inexcitable muscle, as during the paralytic attack of periodic paralysis. A benign increased insertional activity, named by Wilbourn as “snap, crackle, pop” because of its characteristic sound, is a normal variant recorded from muscles of some healthy individuals (Daube and Rubin, 2009; Wilbourn 1982). This finding has no clinical significance when seen as an isolated finding but may be mistaken for abnormal types of increased insertional activity. It is much more common in men, particularly those who are well built and muscular. It is seen more often in the leg muscles than the arm muscles, most commonly in the gastrocnemius. Fibrillation potentials (see Video 36.3). Fibrillation potentials are spontaneous action potentials of denervated muscle fibers. They result from reduction of the resting membrane potential of the denervated muscle fiber to the level at which it can fire spontaneously. Fibrillation potentials, triggered by spontaneous oscillations in the muscle fiber membrane potential, typically fire in a regular pattern at a rate of 1–30 Hz. The sound they produce on the loudspeaker is crisp and clicking, reminiscent of rain on a tin roof or the tick-tock of a clock. Fibrillation potentials have two types of waveforms: brief spikes and positive waves. Brief spikes are usually triphasic with initial positivity (Fig. 36.12, A). They range from 1 to 5 ms in duration and 20–200 µV in amplitude when recorded with a concentric needle electrode. Brief-spike fibrillation potentials may be confused with physiological end-plate spikes but are distinguishable by their regular firing pattern and triphasic

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50 µV/D

20 ms/D

Fig. 36.11 End-plate noise (solid arrows) and spikes (dashed arrow) representing normal spontaneous activities.

configuration with an initial positivity. Occasionally placement of the needle electrode near the end-plate zone of a denervated muscle results in brief spikes, morphologically resembling end-plate spikes with an initial negativity. Positive waves have an initial positivity and subsequent slow negativity with a characteristic saw tooth appearance (see Fig. 36.12, B). Recordings made near the damaged part of the muscle fiber (incapable of generating an action potential) account for the absence of a negative spike. Although usually seen together, positive sharp waves tend to precede brief spikes after nerve section, possibly because insertion of a needle in already irritable muscle membrane triggers the response. Fibrillation potentials are the electrophysiological markers of muscle denervation. Based on their distribution, they are useful in localizing lesions to the anterior horn cells of the spinal cord, ventral root, plexus, or peripheral nerve. Insertional positive waves may appear within 2 weeks of acute denervation, but fibrillation potentials do not become full until approximately 3 weeks after axonal loss. Because of this latent period, their absence does not exclude recent acute denervation. In addition, late in the course of denervation, muscle fibers that are reinnervated, fibrotic, or severely atrophied show no fibrillation potentials. A numerical grading system (from 0 to 4) is the standard to semiquantitate fibrillation potentials. Their density is a rough estimate of the extent of denervated muscle fibers: 0, no fibrillations; +1, persistent single trains of potentials (50%) in seizures during experimental phase in both patient groups. Four patients using an external RNS experienced clinical and electrographic suppression of seizures (Kossoff et al., 2004). These findings encouraged a multicenter trial of implantable RNS (NeuroPace, Inc. CA, US.) that continuously monitored electrographic activity through depth and/or strip leads. The RNS delivered electrical stimulation to the seizure focus when it detected the epileptic activity (Skarpaas and Morrell, 2009). The SANTE study, involving 110 patients, found improvement at 25 months (Fisher et al., 2010). Long-term outcomes were reported in 2015, with 68% of patients having greater than 50% seizure frequency reduction at 5 years (Salanova et al., 2015). This approach recently received FDA approval. Patients with pharmaco-resistant partial-onset epilepsy were recruited for a double-blinded, sham-controlled RCT (Morrell and RNS System in Epilepsy Study Group, 2011). Seizures were reduced in the treatment compared with the sham group, with a 53% median

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CHAPTER 38 Intracranial Neuromodulation percent seizure reduction at 2 years (Heck et al., 2014), and the FDA granted approval for the Neuropace RNS device in 2014. There was a 48%–66% seizure reduction observed in the long-term, open-label study (Bergey et al., 2015). Recently, a long-term observational study of RNS in patients with intractable mesial temporal lobe epilepsy found a median 70% decrease in seizure frequency at mean follow-up of 6 years (Geller et al., 2017). A study of RNS in 126 patients with neocortical seizure foci found significant improvements without neurological deficits following stimulation in eloquent cortex (Jobst et al., 2017).

CONCLUSIONS AND THE FUTURE OF DEEP BRAIN STIMULATION

been utilized experimentally for dementia and selected neuropsychiatric indications (e.g., OCD, depression, addiction, and TS). There are several other indications now under investigation for potential DBS therapies. Recently emerging indications are treatment-resistant PTSD, obesity, and AN. Several companies have recently introduced novel lead designs and novel stimulation parameters to improve effectiveness and to reduce adverse events. It is likely that DBS therapy will continue to expand in indications and will become more personalized as the technology evolves and improves. The complete reference list is available online at https://expertconsult.inkling.com/.

In recent decades, chronic DBS has become routine for several diagnoses in neurological practice (e.g., PD, dystonia, and ET), and has

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39 Intraoperative Monitoring Marc R. Nuwer

OUTLINE Techniques, 492 Spinal Cord Monitoring, 492 Interpretation, 494 Monitoring, 494 Testing, 494

Response to Change, 494 Prediction of Deficits, 494 Anesthesia, 495 Clinical Settings, 495

Neurophysiological intraoperative monitoring (IOM) uses electroencephalography (EEG), electromyography (EMG), and evoked potentials (EPs) during surgery to improve outcome. These techniques warn the surgeon of impending complications in time to intervene and correct problems before they become worse. IOM can also identify motor or language cortex to spare them from resection. A surgeon can rely on monitoring for reassurance about nervous system integrity, allowing the surgery to be more extensive than would have been safe without monitoring. Some patients are eligible for surgery with monitoring who may have been denied surgery without monitoring because of a high risk of nervous system complications. Patients and families can be reassured that certain feared complications are screened for during surgery. In these ways, monitoring extends the safety, range, and completeness of surgery. Effective collaboration and communication are needed between surgeon, anesthesiologist, and neurophysiologist (Gertsch et al., 2019). The monitoring team maintains open communication throughout surgery. An experienced electrodiagnostic technologist applies electrodes and ensures technically accurate studies. The interpreting neurophysiologist is either in the operating room or monitors continuously online in real time.

brainstem, or spinal surgery. Electrocorticography (ECoG) measures EEG directly from the exposed cortex. ECoG guides the surgeon to resect physiologically dysfunctional or epileptogenic areas while sparing relatively normal cortex. Direct cortical stimulation applies very localized electrical pulses to cortex through a handheld wand. That electricity disrupts cortical function such as language, which can be tested in patients who are awake during a craniotomy. Direct cortical stimulation identifies language or motor regions so that they can be spared during resections. Similar direct nerve stimulation is used for cranial and peripheral nerves to locate them amid pathological tissue and to check whether a nerve is still intact. Electrical stimulation of the floor of the fourth ventricle during brainstem resection can identify tracts and nuclei of interest. The placement of spinal pedicle screws risks injury to nerve roots or spinal cord. To reduce that risk, EMG is monitored while electrical stimulation is delivered to the pedicle hole drilled in the spine or the screw. If the hole or screw has errantly broken through bone into the spinal canal or nerve foramen, the stimulation may elicit an EMG warning of misplacement. In-depth descriptions of each procedure are beyond the scope of this chapter. The reader is referred elsewhere for extensive coverage of intraoperative neurophysiological techniques (Nuwer, 2008).

TECHNIQUES

Spinal Cord Monitoring

Many IOM techniques are adapted from common outpatient testing: for example, EEG, brainstem auditory evoked potential (BAEP), and somatosensory evoked potential (SEP) tests. Box 39.1 lists various techniques used in the operating room. EEG is used when surgery risks cortical ischemia, such as aneurysm clipping or carotid endarterectomy. BAEP is used for procedures around the eighth nerve or when the brainstem is at risk in posterior fossa procedures: for example, Fig. 39.1. SEP is widely used for many procedures that risk impairment to the spinal cord, brainstem, or sensorimotor cortex. Some IOM techniques are specific to the operating room. Transcranial electrical motor evoked potential (MEP) tests are evoked by several-hundred-volt electrical pulses delivered to motor cortex through the intact skull. Recordings are made from extremity muscles. MEP monitors corticospinal tracts during cerebral,

SEP and MEP spinal cord monitoring is a good example of a common IOM technique. Electrical stimuli are delivered at a rate of several per second to the ulnar nerve at the wrist and the posterior tibial nerve at the ankle. Averaged SEP peaks are recorded at standardized surface locations over the spine and scalp. Small electrical potentials recorded during the 50 ms following stimulation indicate the transit and arrival of axonal volleys or synaptic events at peripheral, spinal, brainstem, and primary sensory cortical levels. SEP recordings are repeated every few minutes. MEP stimulating electrodes are located on the scalp over motor cortex. Electrical MEP pulses are strong enough to discharge the axon hillock of motor cortex pyramidal cells. The resulting action potentials travel down corticospinal tracts and discharge spinal anterior horn cells. MEP recordings are made from limb muscles at 25–45 ms after stimulation.

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CHAPTER 39 Intraoperative Monitoring

SEP and MEP peaks remain stable over time in uneventful spinal surgery. If values change beyond established limits, the monitoring team alerts the surgeon of increased risk of neurological impairment. Which peaks are preserved and which are changed can localize the side and level of impairment. In thoracolumbar surgery, SEP and MEP channels of the upper extremity serve as controls to separate systemic or anesthetic causes from thoracic or lumbar surgical reasons for change. The ulnar nerve is often used rather than the median nerve during cervical surgery for better coverage of the lower cervical cord. The peroneal nerve at the knee may substitute for the posterior tibial nerve at the ankle for elderly patients, those with diabetes, or others in whom a peripheral neuropathy may interfere with adequate distal peripheral conduction. Blockade of the neuromuscular junction is helpful in reducing muscle artifact in SEP but must be limited for use if MEP is monitored. Sometimes other incidental clinical problems are detected beyond the primary purpose of monitoring in the

Techniques Used for Intraoperative Monitoring and Testing

BOX 39.1

Electroencephalography Electrocorticography Direct cortical stimulation Somatosensory evoked potentials Transcranial electrical motor evoked potentials Brainstem auditory evoked potentials Deep brain and brainstem electrical stimulation Electromyography Nerve conduction studies Direct spinal cord stimulation Reflex testing Pedicle screw stimulation testing

Fig. 39.1 Typical Setup of Multimodal Intraoperative Monitoring. Several types of recordings are displayed simultaneously on one screen. Top line: electroencephalography (EEG), six channels. Left (L) brainstem auditory evoked potential (BAEP); right (R) BAEP. Each BAEP window shows ipsilateral ear and contralateral ear recordings in pairs. Each pair of tracings is the current tracing (black) compared with the baseline (gray) at the beginning of the procedure. Bottom line: Left median, right median, left posterior tibial, and right posterior tibial nerve somatosensory evoked potential (SEP). Each SEP window shows a subcortical and two cortical channel recordings in pairs. Each pair of tracings is the current tracing (black) compared with the baseline (gray) at the beginning of the procedure. Right BAEP wave V is of low amplitude because of the cerebellopontine angle tumor for which the surgery was undertaken. Other monitoring windows (not shown) assess muscle electromyography (EMG) for cranial nerve 5 and 7. Other monitoring pages available to the neurophysiologist (not shown) display a variety of other views and can be interrogated to interpret the signals online more accurately in real time.

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spinal cord, brainstem, or cortical regions. For example, a developing plexopathy or peripheral nerve compression can be spotted by loss of the peripheral peak, which may be easily treated by repositioning an arm. Occasionally, IOM changes warn of a systemic problem such as hypoxia secondary to a ventilatory problem.

RESPONSE TO CHANGE

INTERPRETATION Interpretation of intraoperative neurophysiology includes two categories. One is monitoring, in which baseline findings are established and subsequent findings are compared with baseline. Alarm criteria are set in advance based on knowledge of how much change is acceptable without risk. The other category, testing, identifies structures and sets limits of resection. Testing is used in several ways. One is to identify a structure, such as finding the facial nerve buried within pathological tissue. Another is to identify motor or language cortex prior to a resection. A third example is identifying which cauda equina root is L5, or S1, or S2, identifying which is a sensory or a motor portion of a root, or identifying roots as opposed to filum terminale during tethered cord release.

Monitoring Interpretation relies on latency and amplitude criteria for raising a monitoring alarm. SEP and BAEP use a 50% decrease in amplitude or a 10% increase in latency as alarm criteria. The criteria must account for the effects of temperature and anesthesia—for example, from boluses or increased inhalation anesthetics. Technical problems can arise from the electrodes themselves (e.g., becoming dislodged). Equipment can malfunction. Systemic factors such as hypotension or hypoxia can also cause changes in IOM. MEPs are judged more qualitatively. They either remain present or become absent. Some physicians raise an alarm if an MEP amplitude decreases by more than 80% (MacDonald et al., 2013). A 50% loss of EEG fast activity is seen when cerebral blood flow drops below 20 mL/100 g/min. Still lower blood flow causes a 50% increase in slow activity. The third and worst degree of EEG change is a 50% or more loss of signal amplitude, which can progress all the way to an isoelectric state at 10 mL/100 g/min of cerebral blood flow. EMG monitors for increased spontaneous activity. Excessive mechanical compression or ischemia can provoke a nerve to respond in a pattern referred to as a neurotonic discharge or A-train. Such a minute-long rapid firing is the same discharge as occurs when someone accidentally hits the ulnar nerve at the elbow and feels a minute-long painful sensation in the ulnar distribution. In the operating room, this warns of mechanical or ischemic nerve problems (Nichols and Manafov, 2012).

Testing Motor cortex is identified by finding the postcentral primary somatosensory gyrus by median nerve SEP testing. The N20 peak is located with good precision, thereby identifying the immediately anterior gyrus as motor cortex. For language localization, an awake surgical patient is tested repeatedly with various oral and visual verbal and nonverbal tasks. Language-active regions are identified as those where electrical stimulation disrupts the patient’s ability to complete those tasks. Corticospinal tracts in hemispheric deep white matter are identified by electrical stimulation with muscle recording. When 5-mA stimulation produces no motor responses, the corticospinal tract is at least 5 mm from the site of stimulation; the general rule is 1-mm distance for each milliampere needed to elicit muscle responses. For cranial nerve nuclei, cranial nerves, or peripheral nerves, a direct or nearby stimulation produces responses in appropriate muscles. The pattern of muscle responses can separate root structures (i.e., L5, S1, and S2 roots).

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Motor roots and nerves respond with EMG to low stimulus intensity, whereas sensory nerves or roots require a 10-fold greater intensity to provoke an EMG response through reflex pathways. That enables the surgeon to identify which root or nerve is motor and which is sensory.

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When changes occur during monitoring, the team quickly assesses whether the change is likely due to a technical, systemic, or surgical problem. Occasional transient significant changes occur without significant risk for postoperative neurological problems. Transient changes for a few minutes can occur without substantial risk of postoperative problems, especially if the neurophysiological findings shortly return to baseline. Risk of neurological complications is higher when changes remain through the end of the procedure and when they are of a major degree. For example, a very high risk situation is the complete, permanent loss of EPs that previously had been normal and easily detected. Upon being alerted of a change, the surgeon reviews actions of the preceding 15 minutes that may have caused the change. Surgical problems causing neurophysiological changes include direct trauma, excessive traction or compression, stretching from spinal distraction, vascular insufficiency from compression, clamping, embolus or thrombus, and other clinical circumstances. Clamping a carotid artery during an endarterectomy may produce EEG changes within 15 seconds. Many other changes are gradual or cumulative, so that monitoring alarms occur many minutes after the offending action. Two factors compound that delay: ischemia and compression can be tolerated for a short interval before nerves stop conducting. SEP and BAEP recordings take one to several minutes to average—sometimes longer when electrocautery or other electrical noise is ongoing—thereby delaying report of a change. Many surgical or anesthetic actions can be taken in response to IOM alerts. Remedial measures depend on the recent surgical actions. The surgical maneuver under way can be paused, stopped, or reversed. Resection can be halted. An instrument can be removed or repositioned. Blood pressure can be increased. A vascular shunt can be placed, clamped vessels can be unclamped, a clip can be adjusted, or transected aortic intercostal arteries can be reimplanted. Retractors can be repositioned. Spinal distraction can be reduced. If no IOM recovery occurs in 20 minutes, the patient can be awakened on the operating table and ordered to move his or her legs (“wake-up test”) to double check motor function. Steroids are sometimes given, although the literature about their usefulness is controversial. Causes can be sought through inspection and exploration for mechanical or hematoma nervous system impingement. Motor and language identified can be avoided during resection. Systemic or local hypothermia or barbiturate-induced coma can be implemented for nervous system protection. Lowering of cerebrospinal fluid pressure by free drainage can be used in some cases of spinal ischemia. Hemoglobin level can be increased by transfusion. Other interventions are also used.

PREDICTION OF DEFICITS IOM is effective at preventing many postoperative neurological complications (Ney et al., 2015; Nuwer et al., 2012). Risk depends on the severity and duration of IOM changes. Transient changes that revert to baseline within a few minutes are rarely followed by postoperative deficits. Many temporary changes represent clinically significant complications that are identified and then corrected promptly and completely; this is the goal of monitoring. In other cases, transient changes are false alarms. Both are combined in outcome studies as “false-positive” monitoring events since their causes cannot be directly separated. Outcomes studies show false positives in several percent of cases. New neurological

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CHAPTER 39 Intraoperative Monitoring postoperative impairment occurs in about half of cases, with persistent changes of moderate degree (Nuwer et al., 1995). Sometimes postoperative neurological impairment is less than might have occurred if monitoring had not initiated interventions that partially corrected the problem. Severe monitoring changes often predict postoperative neurological deficits. Some are due to intraoperative problems that were identified promptly but could not be adequately corrected.

ANESTHESIA Many inhalation anesthetics substantially affect cortical function (Sloan and Heyer, 2002). Commonly used agents attenuate or abolish cortical EP recordings. Limiting the dose of inhalation anesthesia often produces satisfactory anesthesia compatible with monitoring. Boluses of centrally active medication can cause transient IOM changes. Continuous-drip medication delivery is preferred. Much less susceptible to anesthetic effects are the nonsynaptic pathways such as peripheral nerve conduction. Subcortical monosynaptic pathways are less affected than cortical polysynaptic pathways. For example, in SEP monitoring, brainstem peaks remain relatively robust despite inhalation anesthesia levels that nearly eliminate cortical peaks in the same pathway. MEPs tolerate inhalation anesthesia poorly, so MEPs are often conducted with total intravenous anesthesia using propofol, a centrally excitatory anesthetic agent, along with little or no inhalation agent. Turning this effect around, anesthetic and drug effects can be monitored by the degree of EP or EEG changes. When a barbiturate-induced cortically protective burst suppression or isoelectric state is desired, EEG is the primary tool to identify that sufficient depth has been achieved. A surgical patient’s core temperature may drop by 1°C or more. Limb temperature may drop even more. Axonal conduction velocity depends on temperature, so peak latencies increase as temperature drops. Monitoring can help to identify therapeutic temperature effects. When a hypothermia-induced cortically protective isoelectric state is desired, EEG is the primary tool to identify that sufficient depth has been achieved.

CLINICAL SETTINGS Box 39.2 lists many clinical conditions and types of surgery for which IOM is used. Procedures involving the intracranial posterior fossa commonly use BAEP, SEP, and cranial nerve EMG monitoring. Typical applications include the resection of cerebellopontine angle and skull base tumors, brainstem vascular malformations and tumors, and microvascular decompressions (Møller, 1996). Intracranial supratentorial procedures include resections for epilepsy, tumors, and vascular malformations as well as aneurysm clipping. These use a combination of EEG and SEP monitoring, sometimes with functional cortical localization, direct cortical stimulation, and ECoG. Surgery of the carotid artery, aorta, or heart may use EEG to monitor hemispheric function or assess the need for shunting or testing the adequacy of protective hypothermia (Plestis et al., 1997). Some also use or prefer SEPs for these vascular procedures. Spinal surgery is the most common setting for IOM (Nuwer et al., 2013). Disorders include cervical decompression and fusion for radiculopathy or myelopathy, deformity correction for scoliosis, resection of spinal column or cord tumors, and stabilization of fractures. Both SEP and MEP are often used in these cases to assess the posterior column and corticospinal tract functions. The use of MEP depends on the case, since it requires total intravenous anesthesia and incurs some movements during surgery. As a result, occasional spinal procedures still are

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Epilepsy surgery Cerebral tumor and vascular malformation resection Intracranial aneurysm clipping Movement disorders electrode placement Mapping of nerves, tracts, and nuclei during brainstem and cranial base surgery Ear and parotid surgery near facial nerve Thyroid and aortic arch surgery near the laryngeal nerve Carotid endarterectomy Carotid balloon occlusion Endovascular spinal and cerebral procedures Correction of spinal deformity Stabilization of spinal fracture Resection of spinal tumor Decompression and fusion of cervical myelopathy Decompression and fusion of cervical radiculopathy Decompression and fusion of lumbar stenosis Tethered cord and cauda equina procedures Dorsal root entry zone surgery Brachial and lumbosacral plexus surgery Peripheral nerve surgery Cardiac and aortic procedures

done with SEP alone. In cases involving pedicle screw placement, EMG is monitored to detect screw misplacement (Shi et al., 2003). Spinal cord monitoring is also used for cardiothoracic procedures of the aorta that could jeopardize spinal perfusion (Jacobs et al., 2006). Peripheral nerve monitoring is carried out for cases risking injury to the nerves, plexus, or roots. Testing can also determine which segments of a nerve are damaged when a nerve graft is performed. Outcomes for spinal cord surgery have been assessed (Nuwer et al., 1995, 2012). In one large multicenter study of SEP IOM involving 100,000 cases of spinal surgery, half with IOM, the rate of false-positive alarms was about 1%. The rate of false-negative alarms was about 0.1%, which involved those cases with postoperative neurological deficits without a monitoring alarm. Some were minor transient changes and others were neurological deficits that started during the hours or days postoperatively. The rate of major intraoperative changes missed by SEP monitoring was 0.06%. The risk of paraplegia was 60% less among the IOM-monitored cases than among those that were not monitored. That is equivalent to avoiding paraplegia or paraparesis at a rate of 1 case in every 200 when monitoring was used. To improve even further on these SEP IOM monitoring outcomes, MEPs are now used together with SEP for many spinal procedures. With MEP the expected rate of false-negative cases and postoperative neurological deficits should be reduced still further. Comparative effectiveness studies and cost–benefit analysis favor IOM spinal cord monitoring (Ney and van der Goes, 2014). Ney and van der Goes suggest that IOM saves a hospital system between $64,075 and $102,193 in not having to deal with the effects of adverse outcomes (i.e., in having avoided such outcomes because of IOM monitoring) after accounting for the costs of IOM itself. The complete reference list is available online at www.expertconsult.com.

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40 Structural Imaging Using Magnetic Resonance Imaging and Computed Tomography Joseph C. Masdeu, Bela Ajtai, Alireza Faridar

OUTLINE Computed Tomography, 496 Magnetic Resonance Imaging, 497 Basic Principles, 497 T1 and T2 Relaxation Times, 498 Repetition Time and Time to Echo, 499 Tissue Contrast (T1, T2, and Proton Density Weighting), 500 Magnetic Resonance Image Reconstruction, 501

Structural Neuroimaging in the Clinical Practice of Neurology, 502 Brain Diseases, 502 Spinal Diseases, 536 Indications for Computed Tomography or Magnetic Resonance Imaging, 544 Neuroimaging in Various Clinical Situations, 544

COMPUTED TOMOGRAPHY Computed tomography (CT; other terms include computer assisted tomography [CAT]) has been commercially available since 1973. The term tomography (i.e., to slice or section) refers to a process for generating two-dimensional (2D) image slices of an examined organ of three dimensions (3D). CT imaging is based on the differential absorption of x-rays by various tissues. X-rays are electromagnetic waves with wavelengths falling in the range of 10–0.01 nm on the electromagnetic spectrum. X-rays can also be described as high-energy photons, with corresponding energies varying between 124 and 124,000 electron volts, respectively. X-rays in the higher range of energies, known as hard x-rays, are used in diagnostic imaging because of their ability to penetrate tissue, yet (to an extent), also be absorbed or scattered differentially by various tissues, allowing for the generation of image contrast. Owing to their high energy, x-rays are also a form of ionizing radiation, and the health risks associated with their use, although minimal, should always be accounted for in diagnostic imaging. The x-rays generated by the x-ray source of the CT scanner are shaped into an x-ray beam by a collimator, a rectangular opening in a lead shield. The beam penetrates the slab of tissues to be imaged, which will absorb/deflect it to a varying degree depending on their atomic composition, structure, and density (photoelectric effect and Compton scattering). The remaining x-rays emerge from the imaged slab and are measured by detectors located opposite the collimator. In fourth-generation CT scanners, the detectors are in a fixed position and the x-ray source rotates around the patient. As the beam of x-rays is transmitted through the imaged body part, sweeping a 360-degree arc for each slice imaged, the emerging x-rays are collected; then a computer analyzes the output of the detectors and calculates the x-ray attenuation of each individual tissue volume (voxel). The degree of x-ray absorption by the various tissues is expressed and displayed as shades of gray in the CT image. Darker shades correspond to less attenuation. The attenuation by each voxel of tissue is projected on the flat image of the scanned slice as a tiny quadrilateral,

generally square, called a pixel or picture element. Depending on the reconstruction matrix, a slice will be represented by more or fewer pixels, corresponding to more or less resolution. The shade of gray in each pixel corresponds to a number on an arbitrary linear scale, expressed as Hounsfield units (HU). This number varies between approximately −1000 and 3000+, with values of greater magnitude corresponding to tissues or substances of greater radiodensity, which are depicted in lighter tones. The −1000 value is for air; 0 is for water. Bone is greater than several hundred units, but cranial bone can be 2000 or even more. Fresh blood (with a normal hematocrit) is about 80 units; fat is −50 to −80. Tissues or materials with higher degrees of x-ray absorption, shown in white or lighter shades of gray, are referred to as hyperdense, whereas those with lower x-ray absorption properties are hypodense; these are relative terms compared with other areas of any given image. By changing the settings of the process of transforming the x-ray attenuation values to shades on the grayscale, it is possible to select which tissues to preferentially display in the image. This is referred to as windowing. Utilizing a bone window, for instance, is very useful for evaluating fractures in cases of craniofacial trauma (Fig. 40.1). In CT imaging, contrast agents are frequently used for the purpose of detecting abnormalities that cause disruption of the blood–brain barrier (BBB; e.g., certain tumors, inflammation, etc.). The damaged BBB allows for the net diffusion of contrast material into the site of pathology, where it is detected; this is referred to as contrast enhancement. Contrast materials used in CT scanning contain iodine in an injectable water-soluble form. Iodine is a heavy atom; its inner electron shell absorbs x-rays through the process of photoelectric capture. Even a small amount of iodine effectively blocks the transmitted x-rays so they will not reach the detector. The high x-ray attenuation/absorption will result in hyperdense appearance in the image. Other CT techniques requiring contrast administration are CT angiography (CTA), CT myelography, and CT perfusion studies.

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More than 20 years ago, a fast-imaging technique called spiral (or helical) CT scanning was introduced to clinical practice. With this technique, the x-ray tube in the gantry rotates continuously, but data acquisition is combined with continuous movement of the patient through the gantry. The circular rotating path of the x-rays, combined with the linear movement of the imaged body, results in a spiral or helix-shaped x-ray path—hence the name. These scanners can acquire data rapidly, and a large volume can be scanned in 20–60 seconds. This technique offers several advantages, including more rapid image acquisition. During the short scan time, patients

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can usually hold their breath, which reduces/minimizes motion artifacts. Timing of contrast bolus administration can be optimized, and less contrast material is sufficient. The short scan time, optimal contrast bolus timing, and better image quality are very useful in CTA, where cervical and intracranial blood vessels are visualized. These images can also be reformatted as 3D views of the vasculature, which are often displayed in color and can be depicted along with reformatted bone or other tissues in the region of interest (ROI; Fig. 40.2). Superfast CT scanners have become available in the past 5 years. Multiplying the number of detectors by 4 can result in obtaining 64 slices of an organ in a fraction of a second. They are particularly useful in cardiology and also allow for the acquisition of perfusion images of the entire brain. One shortcoming is a greater exposure to ionizing radiation per scan.

MAGNETIC RESONANCE IMAGING Basic Principles

Fig. 40.1 Computed Tomography Scan from a 32-Year-Old Patient After a Motor Vehicle Accident. Axial bone window computed tomography image reveals a skull fracture (arrow).

Magnetic resonance imaging (MRI) is based on the magnetic characteristics of the imaged tissue. It involves creation of tissue magnetization (which can then be manipulated in several ways) and detection of tissue magnetization as revealed by signal intensity. The various degrees of detected signal intensity provide the image of a given tissue. In clinical practice, MRI uses the magnetic characteristics inherent to the protons of hydrogen nuclei in the tissue, mostly in the form of water but to a significant extent in fat as well. The protons spin about their own axes, which creates a magnetic dipole moment for each proton (Fig. 40.3). In the absence of an external magnetic field, the axes of these dipoles are arranged randomly, and therefore the vectors depicting the dipole moments cancel each other out, resulting in a zero net magnetization vector and a zero net magnetic field for the tissue. This situation changes when the body is placed in the strong magnetic field of a scanner (see Fig. 40.3, A). The magnetic field is generated by an electric current circulating in wire coils that surround the

Fig. 40.2 Computed Tomography Angiogram with 3D Reconstruction. Reconstructed color images reveal a basilar artery aneurysm (arrows).

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A B0 Fig. 40.4 Flipping the Net Magnetization Vector. When a 90-degree radiofrequency (RF) pulse is applied, the net magnetization vector of the protons (Mo) is flipped from the vertical (z) plane to the horizontal (xy) plane. (Reprinted with permission from Hashemi, R.H., Bradley, W.G., Lasanti, C.J., 2004. MRI—The Basics, second ed. Lippincott Williams & Wilkins, Philadelphia.)

B Fig. 40.3 A, Magnetization in a magnetic resonance imaging scanner. Direction of external magnetic field is in the head–foot direction in the scanner. However, in diagrams that follow, the frame of reference is turned, so that the z direction is up (inset). B, Precession. In an external magnetic field (B0), protons spin around their own axis and “wobble” about the axis of the magnetic field. This phenomenon is called precession. (A, From Higgins, D., 2010. ReviseMRI. Available from: http://www. revisemri.com/questions/basicphysics/precession, B, Reprinted with permission from Hashemi, R.H., Bradley, W.G., Lasanti, C.J., 2004. MRI— The Basics, second ed. Lippincott Williams & Wilkins, Philadelphia.)

open bore of the scanner. Most MRI scanners used in clinical practice are superconducting magnets. Here the electrical coils are housed at near-absolute zero temperature, minimizing their resistance and allowing for the strong currents needed to generate the magnetic field without undue heating. The low temperature is achieved by cryogens (liquid nitrogen or helium). Most clinical scanners in commercial production today produce magnetic fields at strengths of 1.5 or 3.0 tesla (T). When the patient is placed in the MRI scanner, the magnetic dipoles in the tissues line up relative to the external magnetic field. Some dipoles will point in the direction of the external field (“north”), some will point in the opposite direction (“south”), but the net magnetization vector of the dipoles (the sum of individual spins) will point in the direction of the external field (“north”), and this will be the tissue’s acquired net magnetization. At this point, a small proportion of the protons (and therefore the net magnetization vector of the tissue) is aligned along the external field (longitudinal magnetization), and the protons precess with a certain frequency. The term precession describes a proton spinning about its own axis and its simultaneous wobbling about the axis of the external field (see Fig. 40.3, B). The frequency of precession is directly proportional to the strength of the applied external magnetic field. As a next step, a radiofrequency pulse is applied to the part of the body being imaged. This is an electromagnetic wave, and if its frequency matches the precession frequency of the protons, resonance

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occurs. Resonance is a very efficient way to give or receive energy. In this process, the protons receive the energy of the applied radiofrequency pulse. As a result, the protons flip and the net magnetization vector of the tissue ceases transiently to be aligned with that of the external field but flips into another plane; thereby transverse magnetization is produced. One example of this is the 90-degree radiofrequency pulse that flips the entire net magnetization vector by 90 degrees to the transverse (horizontal) plane (Fig. 40.4). What we detect in MRI is this transverse magnetization, and its degree will determine the signal intensity. Through the process of electromagnetic induction, rotating transverse magnetization in the tissue induces electrical currents in receiver coils, thus accomplishing signal detection. Several cycles of excitation pulses by the scanner with detection of the resulting electromagnetic signal from the imaged subject are repeated per imaged slice. This occurs while varying two additional magnetic field gradients along the x and y axes for each cycle. Varying the magnetic field gradient along these two additional axes, known as phase and frequency encoding, is necessary to obtain sufficient information to decode the spatial coordinates of the signal emitted by each tissue voxel. This is accomplished using a mathematical algorithm known as a Fourier transform. The final image is produced by applying a gray scale to the intensity values calculated by the Fourier transform for each voxel within the imaging plane, corresponding to the signal intensity of individual tissue elements.

T1 and T2 Relaxation Times During the process of resonance, the applied 90-degree radiofrequency pulse flips the net magnetization vectors of the imaged tissues to the transverse (horizontal) plane by transmitting electromagnetic energy to the protons. The radiofrequency pulse is brief, and after it is turned off, the magnitude of the net magnetization vector starts to decrease along the transverse or horizontal plane and return (“recover or relax”) toward its original position, in which it is aligned parallel to the external magnetic field. The relaxation process, therefore, changes the magnitude and orientation of the tissue’s net magnetization vector. There is a decrease along the horizontal or transverse plane and an increase (recovery) along the longitudinal or vertical plane (Fig. 40.5). To understand the meaning of T1 and T2 relaxation times, the decrease in the magnitude of the horizontal component of the net

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TR Fig. 40.7 Repetition Time. This pulse sequence diagram demonstrates the concept of repetition time (TR), which is the time interval between two sequential radiofrequency pulses. (Reprinted with permission from Hashemi, R.H., Bradley, W.G., Lasanti, C.J., 2004. MRI—The Basics, second ed. Lippincott Williams & Wilkins, Philadelphia.)

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Mxy Fig. 40.5 T1 and T2 Relaxation. When the radiofrequency (RF) pulse is turned off, two processes begin simultaneously: gradual recovery of the longitudinal magnetization (Mz) and gradual decay of the horizontal magnetization component (Mxy). These processes are referred to as T1 and T2 relaxation, respectively. (Reprinted with permission from Hashemi, R.H., Bradley, W.G., Lasanti, C.J., 2004. MRI—The Basics, second ed. Lippincott Williams & Wilkins, Philadelphia.)

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Decay of magnetization in x-y plane Fig. 40.6 This diagram illustrates the simultaneous recovery of longitudinal magnetization (T1 relaxation) and decay of horizontal magnetization (T2 relaxation) after the radiofrequency pulse is turned off. (Reprinted with permission from Hashemi, R.H., Bradley, W.G., Lasanti, C.J., 2004. MRI—The Basics, second ed. Lippincott Williams & Wilkins, Philadelphia.)

magnetization vector and its simultaneous increase in magnitude along the vertical plane should be analyzed independently. These processes are in fact independent and occur at two different rates, with T2 relaxation always occurring more rapidly than T1 relaxation (Fig. 40.6). The T1 relaxation time refers to the time required by protons within a given tissue to recover 63% of their original net magnetization vector along the vertical or longitudinal plane immediately after completion of the 90-degree radiofrequency pulse. As an example, a T1 time of 2 seconds means that 2 seconds after the 90-degree pulse is turned off, the given tissue’s net magnetization vector has recovered 63% of its original magnitude along the vertical (longitudinal) plane. Different tissues may have quite different T1 time values (T1 recovery or relaxation times). T1 relaxation is also known as spin-lattice relaxation. While T1 relaxation relates to the longitudinal plane, T2 relaxation refers to the decrease of the transverse or horizontal magnetization vector. When the 90-degree pulse is applied, the entire net magnetization vector is flipped in the horizontal or transverse plane. When the pulse is turned off, the transverse magnetization vector starts to decrease. The T2 relaxation time is the time it takes for the tissue to lose 63% of its original transverse or horizontal magnetization. As an example, a T2 time of 200 ms means that 200 ms after the 90-degree pulse has been turned off, the tissue will have lost 63% of its transverse or horizontal magnetization. The decrease of the net

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magnetization vector in the horizontal plane is due to dephasing of the individual proton spins as they precess at slightly different rates owing to local inhomogeneities of the magnetic field. This dephasing of the individual proton magnetic dipole vectors causes a decrease of the transverse component of the net magnetization vector and loss of signal. T2 relaxation is also known as spin-spin relaxation. Just like the T1 values, the T2 time values of different tissues may also be quite different. Tissue abnormalities may alter a given tissue’s T1 and T2 time values, ultimately resulting in the signal changes seen on the patient’s MR images.

As mentioned earlier, the amount of the signal detected by the receiver coils depends on the magnitude of the net magnetization vector along the transverse or horizontal plane. Using certain operator-dependent parameters, it is possible to influence how much net magnetization strength (in other words, vector length) will be present in the transverse plane for the imaged tissues at the time of signal acquisition. During the imaging process, the initial 90-degree pulse flips the entire vertical or longitudinal magnetization vector into the horizontal plane. When this initial pulse is turned off, recovery along the longitudinal plane begins (T1 relaxation). Subsequent application of a second radiofrequency pulse at a given time after the first pulse will flip the net magnetization vector that recovered so far along the longitudinal plane back to the transverse plane. As a result, we can measure the magnitude of the net longitudinal magnetization that had recovered within each voxel at the time of application of the second pulse, provided that signal acquisition is begun immediately afterward. The time between these radiofrequency pulses is referred to as repetition time, or TR (Fig. 40.7). It is important to realize that contrary to the T1 and T2 times, which are properties of the given tissue, the TR is a controllable parameter. By selecting a longer TR, for instance, we allow more time for the net magnetization vector to recover before we flip it back to the transverse plane for measurement. A longer TR, because it increases the amount of signal that can potentially be detected, will also result in a higher signal-to-noise ratio, with higher image quality. As described earlier, the other process that begins after the initial radiofrequency pulse is turned off is the decrease of net horizontal or transverse magnetization, owing to dephasing of the proton spins (T2 relaxation). Time to echo (TE) refers to the time we wait until we measure the magnitude of the remaining transverse magnetization. TE, just like TR, is a parameter controlled by the operator. If we use a longer TE, tissues with significantly different T2 values (i.e., different rates of loss of transverse magnetization component) will show more difference in the measured signal intensity (transverse magnetization vector size) when the signals are collected. However, there is a tradeoff. If the TE is set too high, the signal-to-noise ratio of the resulting image will drop to a level that is too low, resulting in poor image quality.

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Longer TR

Time Fig. 40.9 T2 Weighting. In tissues with different T2 relaxation times, selecting a short time to echo (TE) will not result in much T2 weighting, because there is no major difference yet between the loss of their transverse magnetizations. However, by selecting a longer TE, we allow a significant difference to develop between the amount of transverse magnetization of the two tissues, so more T2 weighting is added to the image.

Tissue Contrast (T1, T2, and Proton Density Weighting) By using various TR and TE values, it is possible to increase (or decrease) the contrast between different tissues in an MR image. Achieving this contrast may be based on either the T1 or the T2 properties of the tissues in conjunction with their proton density (PD). Selecting a long TR value reduces the T1 contrast between tissues (Fig. 40.8). Thus, if we wait long enough before applying the second 90-degree pulse, we allow enough time for all tissues to recover most of their longitudinal or vertical magnetization. Because T1 is relatively short, even for tissues with the longest T1, this is possible without resulting in excessively long scan times. Since after a long TR the longitudinally oriented net magnetization vectors of separate tissue types are all of similar magnitudes prior to being flipped into the transverse plane by the second pulse, a long TR will result in little T1 tissue contrast. Conversely, by selecting a short TR value, there will be significant variation in the extent to which tissues with different T1 relaxation times will have recovered their longitudinal magnetization prior to being flipped by the second 90-degree pulse (see Fig. 40.8). Therefore, with a short TR, the second pulse will flip magnetization vectors of different magnitudes into the transverse plane for measurement, resulting in more T1 contrast between the tissues. During T2 relaxation in the transverse plane, selecting a short TE will give higher measured signal intensities (as a short TE will not allow enough time for significant dephasing, i.e., transverse magnetization loss), but tissues with different T2 relaxation times will not show much contrast (Fig. 40.9). This is because by selecting a short time until measurement (short TE), we do not allow significant T2-related magnitude differences to develop. If we select longer TE values, tissues with different T2 relaxation times will have time to lose different amounts of transverse magnetization, and therefore by the time of signal measurement, different signal intensities will be measured from these different tissues (see Fig. 40.9). This is referred to as T2 contrast. Based on the described considerations, selecting TR and TE values that are both short will increase the T1 contrast between tissues, referred to as T1 weighting. Selecting long TR and long TE values will cause increased T2 contrast between tissues, referred to as T2 weighting.

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Fig. 40.10 Axial T1-Weighted Image of a Normal Subject, Obtained With a 3-T Scanner.

On T1-weighted images, substances with a longer T1 relaxation time (such as water) will be darker. This is because the short TR does not allow as much longitudinal magnetization to recover, so the vector flipped to the transverse plane by the second 90-degree pulse will be smaller with a lower resulting signal strength. Conversely, tissues with shorter T1 relaxation times (such as fat or some mucinous materials) will be brighter on T1-weighted images, as they recover more longitudinal magnetization prior to their proton spins being flipped into the transverse plane by the second 90-degree pulse (Fig. 40.10). Among many other applications of T1-weighted images, they allow for evaluation of BBB breakdown: areas with abnormally permeable BBB show increased signal after the intravenous administration of

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TABLE 40.1 Magnetic Resonance Imaging Signal Intensity of Some Substances Found in Neuroimaging T1-Weighted Image Air Free water/CSF Fat Cortical bone Bone marrow (fat) Edema Calcification

Fig. 40.11 Axial T2-Weighted Image of a Normal Subject, Obtained With a 3-T Scanner.

gadolinium. Gadolinium administration is contraindicated in pregnancy. Breastfeeding immediately after receiving gadolinium is generally regarded to be safe (Chen et al., 2008). Renally impaired patients are susceptible to an uncommon but serious adverse reaction to gadolinium, nephrogenic systemic fibrosis (Marckmann et al., 2006). On T2-weighted images, substances with longer T2 relaxation times (e.g., water) will be brighter because they will not have lost as much transverse magnetization magnitude by the time the signal is measured (Fig. 40.11). The T1 and T2 signal characteristics of various tissues or substances found in neuroimaging are listed in Table 40.1. What happens if we select long TR and short TE values? With the longer TR, the T1 differences between the tissues diminish, whereas the short TE does not allow much T2 contrast to develop. The signal intensity obtained from the various tissues, therefore, will mostly depend on their relative proton densities. Tissues having more PD, and thereby larger net magnetization vectors, will have greater signal intensity. This set of imaging parameters is referred to as proton density weighting.

Magnetic Resonance Image Reconstruction To construct an MR image, a slice of the imaged body part is selected; then the signal coming from each of the voxels making up the given slice is measured. Slice selection is achieved by setting the external magnetic field to vary linearly along one of the three principal axes perpendicular to the axial, sagittal, and coronal planes of the subject being imaged. As a result, protons within the slice to be imaged will precess at a Larmor frequency different from the Larmor frequency within all other imaging planes perpendicular to the axis along which the magnetic field gradient is applied. The Larmor frequency is the natural precession frequency of protons within a magnetic field of a given strength and is calculated simply as the product of the magnetic field, B0, and the gyromagnetic ratio, γ. The precession frequency of a hydrogen proton is therefore directly proportional to the strength of the applied magnetic field. The gyromagnetic ratio for any given nucleus is a constant, with a

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Mucinous material Gray matter White matter Muscle Blood products: Oxyhemoglobin Deoxyhemoglobin Intracellular methemoglobin Extracellular methemoglobin Hemosiderin

T2-Weighted Image

↓↓↓↓ ↓↓↓ ↑↑↑ ↓↓↓ ↑↑ ↓ ↓ (Heavy amounts of Ca++) ↑ (Little Ca++, some Fe+++) ↑ Lower than in T2-WI Higher than in T2-WI Similar to gray matter

↓↓↓↓ ↑↑↑ ↑ ↓↓↓ ↑ ↑↑ ↓

Similar to background ↓ ↑↑

↑ ↓ ↓

↑↑

↑↑

↓

↓↓↓

↓ Similar to gray matter

CSF, Cerebrospinal fluid; T2-WI, T2-weighted image.

value for hydrogen protons of 42.58 MHz/T. In slices at lower magnetic strengths of the gradient, the protons precess more slowly, whereas in slices at higher magnetic field strengths, the protons precess more quickly. Based on the property of nuclear magnetic resonance, the applied radiofrequency pulse (which flips the magnetization vector to the transverse plane) will stimulate only those protons with a precession frequency that matches the frequency of the applied radiofrequency pulse. By selecting the frequency of the stimulating radiofrequency pulse during the application of the slice selection gradient, we can choose which protons (those with a specific Larmor frequency) to stimulate (“make resonate”), and thereby we can select which slice of the body to image (Fig. 40.12). After excitation of the slice to be imaged, using the slice selection gradient, the spatial coordinates of each voxel within the slice must be encoded to determine how much signal is coming from each voxel of that slice. This is achieved by means of two additional gradients that are orthogonal to each other within the imaging plane, known as the frequency encoding gradient and the phase encoding gradient. The phase encoding gradient briefly alters the precession frequency of the protons along the axis to which it is applied, thereby changing the relative phases of the precessing protons along this in-plane axis. The frequency encoding gradient, applied orthogonally to the phase encoding gradient within the imaging plane, alters the precession frequency of the protons along the axis to which it is applied, during the acquisition of the MRI signal. As a result of these encoding steps, each voxel will have its own unique frequency and its own unique phase shift, which upon repeating the acquisition with several incremental changes in the phase encoding gradient will allow for deduction of the spatial localization of different intensity values for each voxel using a mathematical algorithm known as a Fourier transform. Phase encoding takes time; it has to be performed for each row of voxels in the image along the

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Slice Fig. 40.12 Slice Selection Gradient. Using a gradient coil, a magnetic strength gradient is applied parallel to the long axis of the subject’s body in the scanner. As a result, the magnetic field is weakest at the feet and gets gradually stronger toward the head. In this example, magnetic field strength is 1.4 T at the feet, 1.5 T at the mid-body, and 1.6 T at the head. Accordingly, protons in these regions will precess at different frequencies (ω): slowest in the feet and with gradually higher frequencies toward the head as the magnetic field gets gradually stronger. Since the radiofrequency (RF) pulse will resonate with those protons (and flip their magnetization vectors) that precess with the same frequency as that of the RF pulse, by selecting the frequency of the RF pulse, we can select which body region’s protons to stimulate (i.e., which body slice to image). (Reprinted with permission from Hashemi, R.H., Bradley, W.G., Lasanti, C.J., 2004. MRI—The Basics, second ed. Lippincott Williams & Wilkins, Philadelphia.)

phase encoding axis. Therefore, the higher the resolution of the image along the phase encoding axis, the longer the time required to acquire the image for that slice of tissue.

In the online version of this chapter (available at http:// www.expertconsult.com), there is a discussion of the nature and application of the following MRI sequences or techniques: spin echo and fast (turbo) spin echo; gradient-recalled echo (GRE) sequences, partial flip angle; inversion recovery sequences (FLAIR, STIR); fat saturation; echoplanar imaging; diffusion-weighted magnetic resonance imaging (DWI); perfusion-weighted magnetic resonance imaging (PWI); susceptibility-weighted imaging (SWI); diffusion tensor imaging (DTI); and magnetization transfer contrast imaging.

STRUCTURAL NEUROIMAGING IN THE CLINICAL PRACTICE OF NEUROLOGY For an expanded version of this section, go to http://www. expertconsult.com.

Brain Diseases Although a description of brain findings on CT and MRI with their differential diagnosis would be helpful (Masdeu et al., 2016), in this chapter we have chosen the traditional approach of listing the imaging findings caused by various brain diseases.

Brain Tumors Epidemiology, pathology, etiology, and management of cancer in the nervous system are discussed in Chapters 71–76. From the standpoint of structural neuroimaging, a useful anatomical classification distinguishes two main groups: intra-axial and extra-axial tumors. Intra-axial tumors are within the brain parenchyma, extra-axial tumors are outside the brain parenchyma (involving the meninges or,

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less commonly, the ventricular system). Intra-axial tumors are usually infiltrative with poorly defined margins. Conversely, extra-axial tumors, even though they often compress or displace the adjacent brain, are usually demarcated by a cerebrospinal cleft or another tissue interface between tumor and brain parenchyma. For differential diagnostic purposes, intra-axial primary brain neoplasms can be further divided into the anatomical subgroups of supratentorial and infratentorial tumors (Table 40.2). For evaluation of brain tumors, the structural imaging modality of choice is MRI. Due to their gradual expansion and often infiltrative nature, most brain tumors are already visible on MRI by the time patients become symptomatic. Exceptions to this rule are tumors that tend to involve the cortex or corticomedullary junction, such as small oligodendrogliomas or metastases, which may cause seizures early, even before being clearly visible on noncontrast MRI. Meningeal involvement is also often symptomatic, for instance by causing headaches and confusion, but may not be appreciated on noncontrast images. Higher magnetic field strength (e.g., a 3-T scanner) and contrast administration (in double or triple dose if necessary) can improve detection of small or clinically silent neoplastic lesions. Neuroimaging is particularly useful in the assessment of brain tumors. Unlike destructive lesions such as ischemic strokes, brain tumors often cause clinical manifestations that are difficult to interpret. Sometimes the clinical presentation may provide clues to localization—for example, a seizure is suggestive of an intra-axial tumor, whereas cranial nerve involvement tends to signal an extra-axial pathology. But edema, mass effect, obstructive hydrocephalus, and elevated intracranial pressure (ICP) can give rise to nonspecific symptoms (e.g., headache, visual disturbance, altered mental status), and false localizing signs may also appear, such as oculomotor or abducens nerve compression due to an expanding intra-axial mass. Neoplastic tissues most commonly prolong the T1 and T2 relaxation times, appearing hypointense on T1- and hyperintense on T2-weighted images, but different tumors differ in this property, facilitating tumor identification on MRI. MRI is also very sensitive for detection of other pathological changes that can be associated with tumors, such as calcification, hemorrhage, necrosis, and edema. The structural detail provided by MRI is useful for assessing involved structures and determining the number and macroscopic extent of the neoplasms, thereby guiding surgical planning or other treatment modalities.

Intra-axial Primary Brain Tumors Certain brain tumor types are discussed in the online version of this chapter, available at http://www.expertconsult.com.

Ganglioglioma and gangliocytoma. Gangliogliomas (WHO grade I or II) are mixed tumors containing both neural and glial elements. Gangliocytomas (WHO grade I) are less common and contain well-differentiated neuronal cells without a glial component. Less commonly, gangliogliomas may exhibit anaplasia within the glial component and are classified as anaplastic ganglioglioma (WHO grade III). A rare type of gangliocytoma, dysplastic gangliocytoma of the cerebellum (also known as Lhermitte-Duclos disease) exhibits a characteristic “tiger-striped” appearance and is often present in association with Cowden disease, a phakomatosis. The peak age of onset for gangliogliomas is the second decade. This tumor is usually supratentorial and is most commonly located in the temporal lobe. It is well demarcated, and a cystic component and mural nodule are often observed. Calcification is common.

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Spin Echo and Fast (Turbo) Spin Echo Techniques Conventional spin echo imaging is time consuming because the individual echoes are obtained one by one, using a unique strength for the phase encoding gradient at each step in the acquisition of a given slice. The signal from each echo is acquired after a time period equal to one TR after the prior echo. During acquisition and digitization of the signal, with each such step, one row of data space (k-space) is filled. To fill the entire data space for one image, this process has to be repeated as many times as the number of phase encoding steps needed to obtain the image. To express this time in seconds, the number of phase encoding steps are multiplied by the TR. Distinct from the conventional spin echo technique, in fast (turbo) spin echo imaging (FSE), within each TR period, multiple echoes at various TE values are obtained, and a new phase encoding step is applied before each of these echoes. The number of echoes obtained for the encoding of each line of k-space in the FSE technique is referred to as the echo train length. Each echo will fill a new line within the k-space data set. Therefore, instead of filling just one line with each TR, multiple lines are filled, and the data space acquisition is completed much more quickly. It is important to realize that even though only a single TE is typically displayed on the MRI technician’s imaging console (this is sometimes referred to as effective TE) during acquisition of FSE images, multiple TE times are actually used. The obvious advantage of fast spin echo imaging is that by filling up k-space much more quickly, the scan time is significantly reduced. This improves image quality by increasing the signal-to-noise ratio. The increased signal, however, may at times be a disadvantage (e.g., identifying a periventricular [PV] hyperintense lesion adjacent to brighter cerebrospinal fluid [CSF]).

Gradient-Recalled Echo Sequences, Partial Flip Angle As described earlier, in spin echo imaging, the 90-degree pulse flips the longitudinal magnetization vector into the horizontal plane. After this pulse, the transverse magnetization starts to decay as a result of dephasing, resulting in a decrease of signal by the time (TE) the signal is read by the receiver coils. To prevent this, at a time point equal to one half of the echo time (TE/2), a 180-degree refocusing pulse is applied to reverse the directions in which the individual precessing protons are dephasing, so that at a time point equal to TE they will once again be in phase, maximizing the signal acquired by the receiver coils. Thus a signal can be collected that is close in strength to the original. This method only compensates for the dephasing caused by magnetic field inhomogeneities, not for the loss of signal caused by spin-spin interactions, so the recorded signal will not be as large as the original. In GRE, or gradient echo imaging, instead of “letting” the transverse magnetization dephase and then using the 180-degree refocusing pulse to rephase, a dephasing-refocusing gradient is applied. This gradient will initially dephase the spins of the transverse magnetization. This is followed by the refocusing component of the gradient, which will rephase them at time TE as a readable echo at the receiver coils. Because of greater spin dephasing, GRE is more susceptible to local magnetic field inhomogeneities. This may cause increased artifacts within and near interfaces between tissues with significantly different degrees of magnetic susceptibility, such as at bone/soft tissue or air/ bone/brain interfaces near the ethmoid sinuses and medial temporal lobes. However, it is very useful when looking specifically for pathology involving tissue components or deposits exhibiting significant paramagnetism. For example, in the case of chronic hemorrhage, the iron in hemosiderin causes magnetic susceptibility artifact by distorting the magnetic field, resulting in very dark signal voids with an apparent size greater than the spatial extent of the iron deposition, thereby increasing sensitivity for such lesions on the specific pulse sequences designed

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to maximize this effect. Such pulse sequences include 3D spoiled gradient echo, T2* (pronounced T2-star), and SWI techniques. T2* imaging, in which signal is obtained from transversely magnetized precessing protons without a preceding echo, allows for the detection of hemorrhage as well as deoxyhemoglobin, as in the blood oxygen level dependent (BOLD) effect used to assess relative brain perfusion levels in functional MRI. Another term that should be explained in conjunction with gradient echo imaging is the partial flip angle. Instead of applying a 90-degree pulse to flip the entire magnetization vector into the horizontal plane, a pulse is used that only partially flips the vector, at a smaller angle. As a result, only a component of the magnetization vector will be in the horizontal plane after application of the excitation pulse. Utilizing a smaller flip angle allows use of a shorter TR, since there will already be a significant longitudinal component of the net magnetization vector after excitation, requiring less time for sufficient recovery of longitudinal magnetization prior to the next excitation pulse. The T1-weighted signal generated by a tissue in a GRE sequence can be optimized for any given TR by varying the flip angle according to a mathematical relationship known as the Ernst equation. The optimal flip angle for a given tissue at a particular TR is thus known as the Ernst angle. Use of shorter longitudinal relaxation times in gradient echo imaging has the obvious advantage of decreasing scan time. By changing the flip angle (which, just like TR and TE is an operator-controlled parameter), the tissue contrast may be manipulated. Selecting a small flip angle in conjunction with a sufficiently long TR will decrease the T1 weighting of the image, as the longitudinal magnetization will be nearly maximized for all tissues. This effect is similar to that for a conventional spin echo sequence, when selecting a long TR allows the longitudinal magnetization to recover more, thereby reducing or eliminating T1 weighting from the resulting image. The generation of image contrast in GRE imaging is similar to that in spin-echo imaging. One important difference is that T2-weighted images cannot be generated, owing to lack of a refocusing pulse in the GRE technique. Instead, the shorter T2* decay is used to generate T2-like image contrast while minimizing T1 effects. Therefore, T2*weighted images are obtained using a small flip angle, a long TR, and long TE. A small flip angle in conjunction with a long TR and a short TE will result in PD weighting, because the T1 and T2* effects upon image contrast are minimized. Selecting a large flip angle together with a short TR and a short TE will result in T1 weighting. Advantages of GRE imaging include speed, less contamination of signal in the slice to be imaged by signal from adjacent slices, and higher spatial resolution. Disadvantages include greater susceptibility to inhomogeneities in the magnetic field such as magnetic susceptibility artifact (although, in some situations, this may also be an advantage, as outlined earlier) and the requirement for higher gradient field strengths. One very useful application of GRE imaging is in volumetric analysis of imaged tissues; the shorter TR and resultant speed allow for rapid data acquisition in three dimensions, which can be used to format and display images in any plane.

Inversion Recovery Sequences (FLAIR, STIR) For better detection and visualization of abnormalities on MR images, it is often useful to suppress the signal from certain tissues, thereby increasing the contrast between the region of pathology and the background tissue. Examples of this include visualization of hyperintense lesions adjacent to bright CSF spaces on T2-weighted images, or whenever there is a need to eliminate the hyperintense signal coming from fatty background.

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Inversion recovery techniques use a unique pulse sequence to avoid signal detection from the selected tissues (fat or CSF). Initially, the application of a 180-degree radiofrequency pulse flips the longitudinal magnetization vectors of all tissues by 180 degrees, so that the vectors will point downward (south). Next, the flipped vectors are allowed to start recovering according to their respective T1 times. As the downward-pointing vectors recover, they become progressively smaller, eventually reaching zero magnitude, and from that point they start growing and pointing upward (north). Without interference, they recover the original longitudinal magnetization. However, during the process of recovery, after a time period referred to as inversion time (TI), a 90-degree pulse is applied to flip the longitudinal vectors to the transverse plane, where signal detection occurs. The amount of magnetization flipped by this pulse depends on how far the longitudinal recovery has been allowed to proceed. If the 90-degree pulse is applied when a given tissue’s vector happens to be zero (this is the so-called null point), no magnetization will be flipped from that tissue to the transverse plane, and therefore no signal will be detected from that tissue. Different tissues recover their longitudinal magnetization at different rates according to their specific T1 times. Knowing a given tissue’s T1 time, we can calculate when it will reach the null point (when its longitudinal magnetization is zero), and if we apply the 90-degree pulse at that point, we will not detect any signal from that particular tissue. The TI is linearly dependent upon a given tissue’s T1 value, being calculated as 0.69 multiplied by the T1 value. In the FLAIR (fluid-attenuated inversion recovery) sequence, the TI (when the 90-degree pulse is applied) occurs when the magnetization vector for CSF is at the null point, so no signal will be detected from the CSF (eFig. 40.13). In FLAIR images, the dark CSF is in sharp contrast with the hyperintensity of PV lesions, allowing their better identification. In STIR (short TI, or tau inversion, recovery) imaging, which is a fat-suppression technique, the methodology is essentially the same as for FLAIR. However, instead of CSF, the signal from fat is nulled. The TI for the STIR technique is set to 0.69 times the T1 of fat, which results in application of the final 90-degree pulse when the fat tissue’s magnetization is at the null point, so no signal from fat will be detected.

eFig. 40.13 Axial FLAIR Image of a Normal Subject, Obtained With a 3-T Scanner.

Fat Saturation Fat saturation is a pulse sequence used to suppress the bright signal of adipose tissue and thereby allow better visualization of hyperintense abnormalities or, upon gadolinium administration, abnormal enhancement that otherwise may be obscured by fatty tissue in areas such as the orbits or spinal epidural space. In the same external magnetic field, the protons in fat versus water experience slightly different local magnetic fields because of differences in molecular structure. As a consequence, the protons in the fat will have a slightly different precession frequency from that of the water protons and will therefore resonate with a slightly different externally applied pulse frequency. Thus it is possible to apply a radiofrequency pulse (presaturation pulse) that will resonate selectively with the fat-based protons only. This pulse will flip the magnetization vector of fat to the transverse plane, where it will be destroyed or “spoiled” by a gradient pulse. Next, the planned pulse sequence is applied, and at that point the obtained transverse magnetization will not have the component from fat, as it was destroyed (eFig. 40.14). Therefore, by the time of TE, no signal will be detected from the fat tissue, and areas of fat will be dark in the image, allowing hyperintense enhancement to stand out.

Echoplanar Imaging Echoplanar imaging is one of the fastest MR imaging techniques. With this technique, the data space (k-space) is filled very rapidly in one shot (during a single TR period) or in multiple shots. In single-shot

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eFig. 40.14 Axial Fat-Suppressed Image of the Neck of a Normal Subject Obtained With a 3-T Scanner.

echoplanar imaging, multiple echoes are generated, each of which is phase encoded separately by a rapidly changing magnetic field gradient. The readout gradient is also varied rapidly from positive to negative as k-space is filled line by line. This technique allows for the acquisition of all information encoding a single slice within a single TR or “in one shot.” Digital processing of these rapidly obtained signals requires very powerful computer hardware. In the multishot version of the echoplanar imaging technique, the phase encoding and the readout process is divided into multiple segments of length TR, which increases the scan time but lessens the burden on the gradient-generating components of the MRI device. In echoplanar imaging, the collection of data generally takes less than 100 ms per slice. This drastically reduced scan time is ideal for scanning poorly cooperative, moving patients and eliminating artifacts due to cardiac pulsation and respiratory motions. It

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also serves as the basis for DWI, DTI, and dynamic contrast-enhanced brain perfusion studies, as well as BOLD imaging.

Diffusion-Weighted Magnetic Resonance Imaging Diffusion of water molecules within tissues has a random molecular (Brownian) motion, which varies in a tissue- and pathology-dependent manner. It may have a directional preference in some tissues; for instance, there is greater diffusion in the longitudinal than in the transverse plane of an axon. Water diffusion may occur more rapidly in aqueous compartments such as CSF, relative to water that is largely intracellular, as in regions of cytotoxic edema secondary to brain ischemia or water present in fluid compartments with high viscosity, such as abscesses or epidermoid cysts. DWI is an imaging technique that is able to differentiate areas of low from high diffusion. The imaging sequence used for this purpose is a T2-weighted sequence, usually a single-shot, spin-echo, echoplanar, imaging sequence, with the addition of transient gradients applied before TE. The purpose of the gradients is to sensitize the pulse sequence to diffusion occurring during the time interval between their application. In tissues where more diffusion occurred during application of the gradient (such as in normal tissues), the diffusion causes dephasing of transverse magnetization, resulting in signal loss, and therefore, a darker appearance on the image. In areas with less diffusion (for example, in acutely ischemic brain areas), no significant dephasing or signal change occurs. Therefore, the detected signal is higher, and these areas appear bright on the image. The degree of the applied diffusion-encoding gradient is referred to as the B value. In a regular conventional T2 or FLAIR image, the B value is zero (i.e., no gradient). As the B value is increased by the gradient being stronger, the diffusion of the water molecules will cause more and more dephasing and signal loss. As a result, if the B value is high enough, as in DWI, the areas of higher diffusion rates, such as CSF and normal brain tissue, will be dark due to the dephasing and signal loss related to water diffusion. In contrast, ischemic areas with little or no water molecule diffusion will appear bright because they lack dephasing and signal loss. In imaging protocols where more T2 weighting (longer TE values) and smaller B values are used, areas with long T2 values may appear relatively bright in the diffusion-weighted images, despite their considerable diffusion. This phenomenon is referred to as T2 shine-through, and it is due to the low applied B value, which means a weaker diffusion gradient and less diffusion weighting. This shinethrough can be decreased by applying a stronger diffusion gradient, leading to higher B values and more diffusion weighting. Based on the differences in the change of signal intensity in different areas at different applied B values, it is possible to calculate the apparent diffusion coefficient (ADC) in various areas/tissues in the image. The term apparent is used because in a tissue there are other factors besides this coefficient that contribute to signal loss, including patient motion and blood flow. The higher the diffusion rate, the higher the ADC value of the given tissue, and the brighter it will appear on the ADC image or map. As an example, CSF, where the diffusion is highest, will be bright on the ADC map, whereas areas of little (restricted) diffusion, such as ischemic areas, will be dark. One of the most obvious practical uses of DWI is the delineation of acutely ischemic areas, which appear bright against a dark background in diffusion-weighted images and dark on the corresponding ADC maps. According to the most appealing theory, the reason for restricted diffusion in acutely ischemic brain tissue is the evolving cytotoxic edema (cellular swelling), which decreases the relative size of the extracellular space, thereby limiting water diffusion. Although in neurological practice, the term restricted diffusion usually refers to cerebral ischemia, and this imaging modality remains most important for acute stroke imaging, there are other abnormalities

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that also restrict diffusion and appear bright on diffusion-weighted images. Examples include abscesses, hypercellular tumors such as lymphoma, some meningiomas, epidermoid cysts, aggressive demyelinating disease, and proteinaceous material, such as produced in sinusitis.

Perfusion-Weighted Magnetic Resonance Imaging Perfusion-weighted imaging utilizes MRI sequences that generate signal intensities proportional to tissue perfusion. Although there are techniques (like spin-labeled perfusion imaging) that provide information about tissue perfusion without injecting contrast material, the most common technique uses a rapid bolus of paramagnetic contrast agent (gadolinium), which while passing through the tissues, causes distortion of the magnetic field and signal loss in the applied gradient echo or echo planar image. This signal loss only occurs in tissues that are perfused, whereas nonperfused regions do not have such signal loss, or in cases of decreased but not absent perfusion, the signal loss is not as prominent as seen in the healthy tissue. When the selected slice is imaged repeatedly in rapid succession, parameters related to perfusion (e.g., relative cerebral blood volume [rCBV], time to peak signal loss [TTP], mean transit time of the contrast bolus [MTT]) can be calculated for each voxel within the slice being imaged. Estimates of cerebral blood flow (CBF) can be calculated for each voxel as well. The main clinical application of PWI is in the setting of acute stroke, primarily for visualization of tissue at risk, the ischemic penumbra. When used in conjunction with diffusion-weighted images, which delineate the acutely infarcting area, it is frequently seen that perfusion-weighted images reveal a more extensive area, beyond the extent of the zone of infarction, that exhibits decreased or absent perfusion. This is the ischemic penumbra, tissue at risk that is potentially salvageable, prompting use of thrombolytic therapy. If the perfusion deficit appears the same as the zone of restricted diffusion (area in the process of infarction), the chance for saving tissue is likely to be lower than that for an ischemic infarction exhibiting a significant perfusion-diffusion mismatch.

Susceptibility-Weighted Imaging As described earlier, factors that distort magnetic field homogeneity, such as paramagnetic or ferromagnetic substances, cause local signal loss. Signal loss occurs because in the altered local magnetic field, protons will precess with different frequencies, resulting in dephasing and thus decreasing the net magnetization vector that translates into a detectable signal. Gradient echo images are especially sensitive to magnetic field distortions, which appear as areas of decreased signal due to the magnetic susceptibility artifact. SWI (Haacke et al., 2009; Mittal et al., 2009) uses a high spatial resolution 3D gradient echo imaging sequence. The contrast achieved by this sequence distinguishes the magnetic susceptibility difference between oxygenated and deoxygenated hemoglobin. Since the applied phase postprocessing sequence accentuates the paramagnetic properties of deoxyhemoglobin and blood degradation products such as intracellular methemoglobin and hemosiderin, this technique is very sensitive for intravascular venous deoxygenated blood as well as extravascular blood products. It has been used for evaluation of venous structures—hence the earlier name high-resolution blood oxygen level-dependent venography—but the clinical application is now much broader. Its exquisite sensitivity for blood degradation products makes this technique very useful when evaluating any lesion (e.g., stroke, arteriovenous malformation [AVM], cavernoma, or neoplasm) for associated hemorrhage (eFig. 40.15). It is also used for imaging microbleeds associated with traumatic brain injury, diffuse axonal injury, or cerebral amyloid angiopathy.

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eFig. 40.15 Susceptibility-Weighted Image Obtained With a 3-T Scanner. Note numerous hypointense lesions in this patient with a history of multiple cavernomas.

Diffusion Tensor Imaging DTI is a more advanced type of diffusion imaging capable of quantifying anisotropy of diffusion in white matter. Diffusion is isotropic when it occurs with the same intensity in all directions. It is anisotropic when it occurs preferentially in one direction, as along the longitudinal axis of axons. For this reason, DTI finds its greatest current application in MRI examinations of the white matter. As opposed to characterizing diffusion within each voxel with just a single ADC, as in DWI, in DTI intravoxel diffusion is measured along three, six, or more gradient directions. The measured values and their directions are called eigenvectors. The vector that corresponds to the principal direction of diffusion (the direction in which diffusion is greatest in magnitude) is called the principal eigenvector. In normal white matter, diffusion anisotropy is high because diffusion is greatest parallel to the course of the nerve fiber tracts. Therefore, the principal eigenvector delineates the course of a given nerve fiber pathway. Diffusion tensor images can be displayed as maps of the principal eigenvectors, which will show the direction/course of the given white matter tract (tractography). These images can also be color coded, allowing for more spectacular visualization of nerve fiber tracts (eFig. 40.16). Any disruption of a given nerve fiber tract by diseases such as multiple sclerosis (MS), trauma, or gliosis, will reduce anisotropy, highlighting the disruption of the white matter tract. Tensor imaging/tractography shows degenerating white matter tracts that appear normal on conventional MRI. It is also useful in surgical resection planning to show the anatomical relationship of the resectable lesion to the adjacent fiber tracts, thus avoiding or reducing surgical injury to critical pathways. For further information on the topic of surgical planning, see the section “Advanced structural neuroimaging for planning of brain tumor surgery.”

Magnetization Transfer Contrast Imaging As the name indicates, magnetization transfer contrast imaging is a technique that produces increased contrast within an MR image, specifically on T1-weighted gadolinium-enhanced images and in

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eFig. 40.16 Diffusion Tensor Image Obtained With a 3-T Scanner.

magnetic resonance angiography (Henkelman et al., 2001). In water, hydrogen atoms are relatively loosely bound to oxygen atoms, and they move frequently between them, binding to one oxygen atom then switching to another. In other tissues (e.g., lipids, proteins), the hydrogen atoms are more tightly bound and tend to stay in one place for longer periods of time. Nevertheless, it does happen that a “bound” hydrogen in lipid or protein is exchanged with a “more free” hydrogen from water. In magnetization transfer imaging, at the beginning of the sequence a radiofrequency pulse is applied that saturates the bound protons in lipids and proteins but does not affect the free protons in water. In regions where magnetization transfer (i.e., exchange of saturated protons with free protons) occurs, the saturated protons will decrease the signal obtained from the imaged free protons. The more frequently this magnetization transfer occurs, the less signal is obtained from the region and the darker the region will be in the image. Magnetization transfer happens more frequently in the white matter, resulting in signal loss, and therefore on magnetization transfer images, the white matter appears darker. The CSF on the other hand, where magnetization transfer does not occur, does not lose signal. Magnetization transfer is minimal in blood because of the high amount of free water protons. This technique is useful when gadolinium-enhanced T1-weighted images are obtained, because enhancing lesions stand out better against the darker background of the more hypointense white matter. In fact, applying a magnetization transfer sequence to single-dose gadolinium-enhanced T1-weighted images results in contrast enhancement intensity comparable to giving a double dose of gadolinium. This sequence is also used in time-of-flight magnetic resonance angiography. There is no signal change in the blood, but the background tissue becomes darker, so the imaged blood vessels stand out better, and smaller branches are better visualized. This benefit comes at the expense of a significantly prolonged scan time, because it takes additional time to apply the magnetization transfer pulse. Another application of magnetization transfer imaging is in the assessment of “normal-appearing” tissues that in fact contain abnormalities, albeit not visible on conventional MR pulse

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sequences. By selecting a ROI (essentially a quadrilateral that is selected to enclose the tissue of interest within an image) corresponding to the “normal-appearing” tissue and calculating the degree to which magnetization transfer occurs within each voxel of the ROI, a histogram plot can be generated. On such magnetization transfer ratio (MTR) histograms, tissues with no apparent lesional

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signal on conventional images, such as the “normal-appearing white matter” of MS, may exhibit a decreased peak height. Such histograms in MS patients may also exhibit a larger proportion of voxels with low MTR values than normal tissues, reflecting a microscopic and macroscopic lesion load that is otherwise undetectable by conventional imaging techniques.

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Magnetic Resonance Imaging Characteristics of Brain Tumors

Tumor

Typical Location, Appearance

Typical T1 Signal Characteristics

Typical T2 Signal Characteristics

Typical Enhancement Pattern

Ventricular Region Central neurocytoma

Intraventricular, at foramen of Monro

Isointense

Iso- to hyperintense

Intraventricular, at foramen of Monro

Hypo- to isointense

Iso- to hypointense

Hyperintense with possible hypointense foci due to calcium Iso- to hyperintense

Variable, usually moderate and heterogeneous Intense

Iso- to hypointense

Hyperintense

Mild or absent

Solid portion isointense, cyst hypointense

Solid portion hypo- to hyperintense, cyst hyperintense Hyperintense or mixed intensity Hyperintense Hyperintense Hyperintense; also typically hyperintense on DWI

From none to heterogeneous or rim

Subependymal giant cell astrocytoma

Choroid plexus papilloma Intraventricular (lateral ventricle in children, fourth ventricle in adults) Calcification and hemorrhage may be present Subependymoma Mostly fourth ventricle but can be third and lateral ventricles Intra-axial, Mostly Supratentorial Ganglioglioma, ganglio- Supratentorial, mostly temporal lobe. cytoma Solid and cystic Pleomorphic xanthoastrocytoma Diffuse astrocytomas Anaplastic astrocytoma Oligodendroglioma

Cerebral cortex and adjacent meninges Has cystic portions Supratentorial in two-thirds of cases Frequently in frontal lobes Supratentorial white matter and cortical mantle May exhibit cyst or calcification

Glioblastoma

Frontal and temporal lobes, spreads along pathways such as corpus callosum Supratentorial or infratentorial In immunocompetent host, usually solitary at ventricular border; in immunocompromised, multiple in white matter

Mixed (edema, necrosis, hemorrhage) Iso- to hypointense

Mixed (edema, necrosis, hemorrhage) Iso- to hyperintense

Intense, inhomogeneous, nodular or ringlike Intense Typically ringlike in immunocompromised host

Posterior fossa, sellar region Usually large cyst with mural nodule Fourth ventricle Cystic component Infratentorial Vascular nodule and cystic cavity

Iso- to hypointense

Iso- to hyperintense

Iso- to hypointense

Iso- to hyperintense

Hypo- to isointense, but can be mixed due to hemorrhage

Arises from roof of fourth ventricle

Iso- to hypointense

Hyperintense, but can be mixed due to hemorrhage Iso-, hypo-, or hyperintense

Solid component enhances intensely Intense in solid portion, rim around cyst Solid component enhances

Cribriform plate, anterior fossa Falx, convexity, sphenoid wing, petrous ridge, olfactory groove, parasellar region, and the posterior fossa Calcification may be present Cerebellopontine angle, vestibular portion of cranial nerve VIII Cyst or calcification may be present Arises from peripheral nerve sheath, any location

Isointense Iso- to slightly hypointense

Iso- to hyperintense Can be hypo-, iso-, or hyperintense

Heterogeneous Intense, homogeneous

Iso- to hypointense

Iso- to hyperintense

Homogeneous

Iso- to hypointense

Hyperintense

Homogeneous

Primary CNS lymphoma

Intra-axial, Posterior Fossa Pilocytic astrocytoma Ependymoma Hemangioblastoma

Medulloblastoma

Extra-axial Esthesioneuroblastoma Meningioma

Schwannoma

Neurofibroma

Hypointense or mixed intensity

Intense

Iso- to hypointense Iso- to hypointense Hypo- to isointense

Solid portion and adjacent meninges enhance Grade II may enhance Diffuse or ringlike Variable, patchy

Heterogeneous

(Continued)

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Magnetic Resonance Imaging Characteristics of Brain Tumors—cont’d Typical T1 Signal Characteristics

Typical T2 Signal Characteristics

Typical Enhancement Pattern

Sella, with potential supra- and parasellar extension

Hypo- or isointense

Hyperintense

Craniopharyngioma

Suprasellar cistern, sometimes intrasellar Solid and cystic components

Iso- to hypointense Cyst has variable signal intensity

Homogeneous, enhances in a delayed fashion (initially hypointense relative to the normally enhancing gland; on delayed images, hyperintense relative to the gland due to delayed contrast accumulation) Solid component enhances homogeneously

Pineoblastoma Pineocytoma

Tectal area Tectal area Well defined, noninvasive Tectal region

Isointense Isointense

Solid and cystic component both hyperintense Calcification may be hypointense Iso- to hypo- to hyperintense Moderate heterogeneous May be hypointense Intense with variable pattern (central, nodular) Variable, hypo- and Intense hyperintense

Tumor

Typical Location, Appearance

Sella and Pineal Regions Pituitary adenoma

Germinoma

Variable, hypo- and hyperintense

CNS, Central nervous system; DWI, diffusion-weighted imaging.

On MRI (Provenzale et al., 2000), the solid component is usually isointense on T1 and hypo- to hyperintense on T2-weighted images. The cystic component, if present, exhibits CSF signal characteristics. The associated mass effect is variable. With contrast, various enhancement patterns are seen—homogeneous or rim pattern—but no enhancement is also possible. Pilocytic astrocytomas. Pilocytic astrocytomas have two major groups: juvenile and adult. These tumors are classified as WHO grade I. Juvenile pilocytic astrocytomas are the most common posterior fossa tumors in children. The most common locations are the cerebellum, at the fourth ventricle, third ventricle, temporal lobe, optic chiasm, and hypothalamus (Koeller and Rushing, 2004). The appearance is often lobulated, and the lesion appears well demarcated on MRI. Hemorrhage and necrosis are uncommon. Areas of calcification may be present. The tumor usually exhibits solid as well as cystic components, with or without a mural nodule. The adult form is usually well circumscribed, often calcified, and typically exhibits a large cyst with a mural nodule. On MRI, the solid portions of the tumor are iso- to hypointense on T1- and iso- to hyperintense on T2-weighted images (Arai et al., 2006). The cystic component usually exhibits CSF signal characteristics. The associated edema and mass effect is usually mild, sometimes moderate. With gadolinium, the solid components (including the mural nodule) enhance intensely, but not the cyst, which rarely may show rim enhancement. Pleomorphic xanthoastrocytoma. Pleomorphic xanthoastrocytoma is a rare variant of astrocytic tumors. It is thought to arise from the subpial astrocytes and typically affects the cerebral cortex and adjacent meninges and may cause erosion of the skull. The most common location is the temporal lobe. It is classified as WHO grade II. It usually occurs in the second and third decades of life, and patients often present with seizures. On MRI (Tien et al., 1992) usually a well-circumscribed cystic mass appears in a superficial cortical location. A solid portion or mural nodule is often seen, and the differential diagnosis includes pilocytic astrocytoma and ganglioglioma. The signal characteristics are hypointense or mixed on T1-, and hyperintense or mixed on T2-weighted images. With contrast, the solid portions and sometimes F ECF

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the adjacent meninges enhance. Calcification may be present. There is mild or no mass effect associated with this tumor. Diffuse astrocytomas. Diffuse astrocytomas are well-differentiated tumors (WHO grade II), usually arising from the fibrillary astrocytes of the white matter. Even though imaging may show a fairly well-defined boundary, these tumors are infiltrative and usually spread beyond their macroscopic border. In 2016 update to the WHO classification of central nervous system (CNS) tumors, astrocytoma is subdivided by the presence of isocitrate dehydrogenase (IDH) mutations, with IDH-mutant tumors carrying better prognoses. Although grade II astrocytoma is a relatively slow-growing tumor, they have a relatively high recurrence rate and an inherent malignant potential to transform into high-grade astrocytoma (Lind-Landström et al., 2012). Two-thirds of cases are supratentorial (Fig. 40.17). A subgroup of these astrocytomas involves specific regions such as the optic nerves/tracts or the brainstem (Fig. 40.18). Diffuse astrocytomas are iso- or hypointense on T1-weighted images and hyperintense on T2-weighted images. Expansion of the adjacent cortex may be seen, and mass effect (if present) is generally modest. There is little to no surrounding edema. Diffuse astrocytoma usually do not enhance, however, small ill-defined areas of enhancement are not rare. The appearance of enhancement in a previously nonenhancing tumor is a worrisome sign of progression to higher grades. Anaplastic astrocytoma. Anaplastic astrocytoma is classified as grade III by the WHO grading system. It represents 25%–30% of gliomas, usually appears between 40 and 60 years of age, and is more common in men. Anaplastic astrocytoma is a diffuse infiltrating tumor that often evolves from a well-differentiated astrocytoma as a result of chromosomal and gene alterations. It is most frequently found in the frontal lobes. On MRI, anaplastic astrocytomas appear as poorly circumscribed heterogeneous tumors, which are iso- to hypointense on T1-weighted and hyperintense on T2-weighted images, with associated hyperintensity in the surrounding white matter representing vasogenic edema. Foci of hemorrhage may be present but not too commonly. There is moderate mass effect associated with the lesions, and, with contrast, a variable degree and pattern of enhancement is noted (diffuse or ringlike). This tumor is 02 .4.(1( 4 (

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Fig. 40.17 Low-Grade Glioma. A, On FLAIR image, a faint hyperintense lesion is seen (arrowheads) with somewhat blurred margins in the right corona radiata at the border of the lateral ventricle, extending minimally toward the corpus callosum (arrow). B, On T1-weighted postcontrast image, this lesion does not enhance.

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Fig. 40.18 Tectal Glioma. A, B, On axial and sagittal T2-weighted images, a faintly hyperintense mass lesion is seen involving the tectum of the midbrain (arrows). There appears to be at least partial obstruction of the aqueduct, resulting in enlargement of the third and lateral ventricles. C, Following gadolinium administration, the tumor does not enhance (arrows).

highly infiltrative, usually cannot be fully removed by surgery, and the median survival is 3–4 years. Gliomatosis cerebri was previously considered a distinct entity, but since the 2016 update to the WHO classification of CNS tumors, it is now being considered a growth pattern of many gliomas, most commonly, anaplastic astrocytoma. The glial tumor cells are disseminated throughout the parenchyma and infiltrate large portions of the neuraxis. Macroscopically it appears homogeneous and is seen as enlargement/expansion of the parenchyma; the gray/white matter interface may become blurred, but the architecture is otherwise not altered. Unilateral hemispheric white matter is generally involved first; then the pathology spreads to the contralateral hemisphere

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through the corpus callosum. Later, the deep gray matter (basal ganglia, thalamus, massa intermedia) may be affected as well. Diffuse tumor infiltration often extends into the brainstem, cerebellum, and even the spinal cord. Histologically, most cases of gliomatosis cerebri are WHO grade III. The MRI appearance is iso- to hypointense on T1 and hyperintense on T2. Hemorrhage is uncommon, and enhancement is also rare, at least in the early stages (Fig. 40.19). Later, multiple foci of enhancement may appear, signaling more malignant transformation. The imaging appearance is similar to that of autoimmune or infectious encephalitis, including subacute sclerosing panencephalitis, but in these disorders, clinical findings are more pronounced.

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B Fig. 40.19 Gliomatosis Cerebri. A, Axial T2-weighted magnetic resonance (MR) image of the brain shows bilateral patchy areas of increased signal intensity in periventricular white matter. B, Axial T2-weighted MR image of brain obtained at the level of the upper pons shows diffuse thickening and hyperintensity of the left optic nerve (white arrow) and increased signal intensity in the posterior aspect of pons and in the cerebellum (black arrows). A focus of very high signal intensity is present in posterior left cerebellar hemisphere (asterisk). (From Yip, M., Fisch, C., Lamarche, J.B., 2003. AFIP archives: gliomatosis cerebri affecting the entire neuraxis. Radiographics 23, 247–253.)

Oligodendroglioma. Oligodendroglioma, made up by IDH mutant and 1p/19q codeleted cells, accounts for 5%–10% of all gliomas. It arises from the oligodendroglia that form the myelin sheath of the CNS pathways. Oligodendroglioma occurs most commonly in young and middle-aged adults, with a median age of onset within the fourth to fifth decades and a male predominance of up to 2:1. Seizure is often the presenting symptom. The most common location is the supratentorial hemispheric white matter, and it also involves the cortical mantle. The tumor often has cystic components and at least, microscopically, in 90% of cases also shows calcification. Hemorrhage and necrosis are rare, and the mass effect is not impressive. On MRI (Koeller and Rushing, 2005) the appearance is heterogeneous, and the tumor is hypo- and isointense on T1 and hyperintense on T2. With gadolinium, the enhancement is variable, usually patchy, and the periphery of the lesion tends to enhance more intensely. Oligodendrogliomas are hypercellular and have been noted to appear hyperintense on diffusion-weighted images (Fig. 40.20). Glioblastoma. Glioblastoma (GBM), previously known as glioblastoma multiforme, is a highly malignant tumor classified as grade IV by the WHO. It is most common in older adults, usually appearing in the fifth and sixth decades and represents 40%–50% of all primary neoplasms and up to 20% of all intracranial tumors. It is subdivided into two types on the basis of the presence or absence of IDH mutation. It is likely that most of the previously recognized primary GBMs were IDH wild-type, and most of the secondary GBMs (from progression of a previous lower-grade tumor) were IDH mutant. Methylation of the promoter for O[6]-methylguanine-DNA methyltransferase (MGMT), the gene for methylguanine methyltransferase, is well recognized as a favorable prognostic factor in GBM (Binabaj et al., 2018). Glioblastoma forms a heterogeneous mass exhibiting cystic and necrotic areas and often a hemorrhagic component as well. The most common locations are the frontal and temporal lobes. The tumor is highly infiltrative and has a tendency to spread along larger pathways

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such as the corpus callosum and invade the other hemisphere, resulting in a characteristic “butterfly” appearance. GBM has also been described to spread along the ventricular surface in the subarachnoid space and may also invade the meninges. There are reported cases of extracranial glioblastoma metastases. Structural neuroimaging distinguishes between multifocal and multicentric glioblastomas. The term multifocal glioblastoma refers to multiple tumor islands in the brain that arose from a common source via continuous parenchymal spread or meningeal/CSF seeding; therefore, they are all connected, at least microscopically. Multicentric glioblastoma refers to multiple tumors that are present independently, and physical connection between them cannot be proven, implying they are separate de novo occurrences. This is less common, having been noted in 6% of cases. On MRI (Fig. 40.21) glioblastomas usually exhibit mixed signal intensities on T1- and T2-weighted images. Cystic and necrotic areas are present, appearing as markedly decreased signal on T1-weighted and hyperintensity on T2-weighted images. Mixed hypo- and hyperintense signal changes due to hemorrhage are also seen. The hemorrhagic component can also be well demonstrated by gradient echo sequences or by SWI. The core of the lesion is surrounded by prominent edema, which appears hypointense on T1-weighted and hyperintense on T2-weighted images. Besides edema, the signal changes around the core of the tumor reflect the presence of infiltrating tumor cells and, in treated cases, postsurgical reactive gliosis and/or postirradiation changes. Following administration of gadolinium, intense enhancement is noted, which is inhomogeneous and often ringlike, also including multiple nodular areas of enhancement. The surrounding edema and ringlike enhancement at times makes it difficult to distinguish glioblastoma from cerebral abscess. DWI is helpful in these cases; glioblastomas are hypointense with this technique, whereas abscesses exhibit remarkable hyperintensity on diffusion-weighted images.

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D Fig. 40.20 Oligodendroglioma. A mass lesion is seen in the left medial frontal lobe, involving the cortical mantle and underlying white matter. A, B, On T2 and FLAIR images, the tumor is hyperintense. C, On diffusion-weighted image, faint hyperintensity due to the hypercellular nature of this tumor is noted (arrowheads). D, With contrast, a few areas of enhancement are seen that tend to involve the periphery of the lesion (arrows).

Owing to its aggressive growth (the tumor size may double every 10 days) and infiltrative nature, the prognosis for patients with glioblastoma is very poor. Despite surgery, irradiation, and chemotherapy the median survival is 1 year. Ependymoma. Although ependymomas are primarily extra-axial tumors (within the fourth ventricle), intraparenchymal ependymomas arising from ependymal cell remnants of the hemispheric parenchyma are also well known, so this tumor type is discussed here. Ependymomas comprise 5%–6% of all primary brain tumors; 70% of cases occur in childhood and the first and second decades, and ependymoma is the third most common posterior fossa tumor in children. Ependymomas arise from differentiated ependymal cells, and the most common location (70%) is the fourth ventricle. The tumor is usually well demarcated and

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is separated from the vermis by a CSF interface. The tumor may be cystic and may contain calcification and hemorrhage but these features are more common in supratentorial ependymomas. It may extrude from the cavity of the fourth ventricle through the foramina of Luschka and Magendie. Spreading via CSF to the spinal canal (drop-metastases) may occur, but on spine imaging ependymoma is more commonly noted to arise from the ependymal lining of the central canal, presenting as an intramedullary spinal cord tumor. A subtype, myxopapillary ependymoma, is almost always restricted to the filum terminale. Ependymomas are hypo- to isointense on T1-weighted images and iso- to hyperintense on T2-weighted images. With gadolinium, intense enhancement is seen, mostly involving the solid components of the tumor, whereas the cystic components tend to exhibit rim enhancement.

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Fig. 40.21 Glioblastoma Multiforme. A, Axial FLAIR image demonstrates a mass lesion spreading across the corpus callosum to involve both frontal lobes in a symmetrical fashion (“butterfly” appearance). The tumor is isointense, exerts mass effect on the sulci and the lateral ventricles, and is surrounded by vasogenic edema. B, On axial T1 postcontrast imaging, the tumor exhibits heterogeneous irregular enhancement, most marked at its periphery.

The differential diagnosis for infratentorial ependymoma includes medulloblastoma, pilocytic astrocytoma, and choroid plexus papilloma. Lymphoma. Primary CNS lymphoma (PCNSL) is a non-Hodgkin lymphoma, which in 98% of cases is a B-cell lymphoma. It once accounted for only 1%–2% of all primary brain tumors, but this percentage has been increasing, mostly because of the growing acquired immunodeficiency syndrome (AIDS) population. The peak age of onset is 60 in the immunocompetent population and age 30 in immunocompromised patients. Lesions may occur anywhere within the neuraxis, including the cerebral hemispheres, brainstem, cerebellum, and spinal cord, although the most common location (90% of cases) is supratentorial. PCNSL lesions are highly infiltrative and exhibit a predilection for sites that contact subarachnoid and ependymal surfaces as well as the deep gray nuclei. The imaging appearance of PCNSL depends on the patient’s immune status. The tumor is hypo- to isointense on T1-weighted and hypo- to slightly hyperintense on T2-weighted images. Contrast enhancement is usually intense. In immunocompetent patients (Zhang et al., 2010) the lesion is often single and tends to abut the ventricular border (Costa et al., 2006), and ring enhancement is uncommon (Fig. 40.22). In immunocompromised patients, usually multiple, often ring-enhancing lesions are seen, which are most commonly located in the PV white matter and the gray/white junction of the lobes of the hemispheres, but the deep central gray matter structures and the posterior fossa may be involved as well. Overall, the imaging appearance appears more malignant in the immunocompromised cases and may be difficult to differentiate from toxoplasmosis. Other components of the differential diagnosis in patients with multiple PCNSL lesions include demyelination, abscesses, neurosarcoidosis, and metastatic disease. Hemangioblastoma. Hemangioblastomas represent only 1%–2% of all primary brain tumors, but in adults they are the most common type of primary intra-axial tumor of the posterior fossa (cerebellum and medulla). These tumors are WHO grade I, well circumscribed, and exhibit a vascular nodule with a usually larger cystic cavity. On

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MRI the solid portion is hypo- to isointense on T1 and hyperintense on T2-weighted images. Sometimes hyperintense foci are noted on T1; this is due to occasional lipid deposition or hemorrhage within the tumor. The cystic component is usually hypointense on T1 (but may be hyperintense relative to CSF due to high protein content) and markedly hyperintense on T2. On FLAIR images, the cyst fluid is not completely nulled, resulting in a bright signal, and the nodule is also hyperintense. There is usually mild surrounding edema. With gadolinium, the solid component exhibits intense enhancement. Hemangioblastomas are seen in 50% of patients with von Hippel-Lindau disease, and approximately one-fourth of all hemangioblastomas occur in these patients (Neumann et al., 1989).

Extra-axial Primary Brain Tumors Descriptions of schwannomas and the more rare extra-axial primary brain tumor types—esthesioneuroblastoma, central neurocytoma, and subependymoma—are available in the online version of this chapter (http://www.expertconsult.com).

Meningiomas. Meningiomas are the most common primary brain tumors of nonglial origin and make up 15% of all intracranial tumors. The peak age of onset is the fifth decade, and there is a striking female predominance that may be related to the fact that some meningiomas contain estrogen and progesterone receptors. These tumors arise from meningothelial cells. In 1%–9% of cases, multiple tumors are seen. The most common locations are the falx (25%), convexity (20%), sphenoid wing, petrous ridge (15%–20%), olfactory groove (5%–10%), parasellar region (5%–10%), and the posterior fossa (10%). Rarely, an intraventricular location has been reported. Meningiomas often appear as smooth hemispherical or lobular dural-based masses (Fig. 40.23). Calcification is common, seen in at least 20% of these tumors. Meningiomas also often exhibit vascularity. The extra-axial location of the tumor is usually well appreciated owing to a visible CSF interface between tumor and adjacent brain parenchyma. Meningiomas may become malignant, invading the brain and eroding the skull. In such cases, prominent

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Schwannoma. Schwannomas arise from the Schwann cells of the nerve sheath, and the most commonly affected nerve is the vestibular portion of the vestibulocochlear nerve. They are typically bilateral in neurofibromatosis (NF) type 2. The unilateral form sporadically occurs in non-NF patients, with slight female predominance. Schwannomas typically arise in the intracanalicular segment of the eighth cranial nerve where myelin transitions from central (oligodendroglia) to peripheral (Schwann cell) type. If untreated, the tumor grows toward the internal auditory meatus and eventually bulges into the cerebellopontine

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angle, where it may deform and displace the brainstem. The intra- and extracanalicular parts of the tumor together result in a mushroom- or ice cream cone–like appearance. The tumor is iso- to hypointense on T1-weighted images and iso- to hyperintense on T2-weighted images. This pattern may be modified by the presence of cystic changes or calcification. Gadolinium administration causes homogeneous enhancement that, together with the performance of axial and coronal thin-slice T2-weighted images, allows for the visualization of even very small intracanalicular schwannomas. For images, refer to the section “Neurofibromatosis.”

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B Fig. 40.22 Central Nervous System Lymphoma in an Immunocompetent Individual. A, FLAIR sequence depicts a single hyperintense lesion with spread along the ventricular border. B, After contrast administration, multiple areas of enhancement are seen within the lesion, without a ringlike enhancement pattern.

edema may be present in the brain parenchyma, to the extent that the extra-axial nature of the tumor is no longer obvious. On T1-weighted images, meningiomas are usually iso- to slightly hypointense. The appearance on T2 can be iso-, hypo-, or hyperintense to the gray matter. Although MRI does not reveal the histological subtypes of meningiomas with absolute certainty, there have been observations according to which fibroblastic and transitional meningiomas tend to be iso- to hypointense on T2-weighted images, whereas the meningothelial or angioblastic type is iso- or more hyperintense. Not uncommonly, the skull adjacent to a meningioma will exhibit subtle thickening—a useful diagnostic clue in some cases. After gadolinium administration, meningiomas typically exhibit intense homogeneous enhancement. A quite typical imaging finding on postcontrast images is the dural tail sign, which refers to the linear extension of enhancement along the dura, beyond the segment on which the tumor is based. Earlier this had been attributed to en plaque extension of the meningioma along these dural segments and was thought to be specific for this type of tumor. However, recently it has been recognized that this imaging appearance is not specific to this situation and may be seen in other tumors, secondary to increased vascularity/hyperperfusion or congestion of the dural vessels after irradiation and as a postsurgical change. Primitive neuroectodermal tumor. Primitive neuroectodermal tumor (PNET) is a collective term that includes several tumors arising from cells that are derived from the neuroectoderm and are in an undifferentiated state. The main tumors that belong to the PNET group are medulloblastomas, esthesioneuroblastomas, and pinealoblastomas. The tumors belonging to the PNET group are fast growing and highly malignant. The most common mode of metastatic spread for PNETs is via CSF pathways, an indication for imaging surveillance of the entire neuraxis when these tumors are suspected. Medulloblastoma. Medulloblastomas arise from the undifferentiated neuroectodermal cells of the roof of the fourth ventricle (superior or inferior medullary velum, vermis). They represent 25% of all cerebral tumors in children, usually presenting in the first and second decade. The tumor fills the fourth ventricle, extending

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rostrally toward the aqueduct and caudally to the cisterna magna, frequently resulting in obstructive hydrocephalus. Leptomeningeal and CSF spread may also occur, resulting in spinal drop metastases. Cystic components and necrosis may be present. Calcification is possible. On CT, medulloblastoma typically appears as a heterogeneous, generally hyperdense midline tumor occupying the fourth ventricle, with mass effect and variable contrast enhancement. The MRI signal (Koeller and Rushing, 2003) is heterogeneous; the tumor is iso- or hypointense on T1 and hypo-, iso-, or hyperintense on T2. Contrast administration induces heterogeneous enhancement (Fig. 40.24). Restricted diffusion may be seen on DWI/ADC (Gauvain et al., 2001). Consistent with its site of origin, indistinct borders between the tumor and the roof of the fourth ventricle may be observed, aiding in the differential diagnosis, which in children includes atypical, rhabdoid-teratoid tumor, brainstem glioma, pilocytic astrocytoma, choroid plexus papilloma, and ependymoma. The adult differential diagnosis includes the latter two entities in addition to metastasis and hemangioblastoma. Medulloblastoma does not tend to extrude via the foramina outside of the fourth ventricle, facilitating differentiation from ependymoma. In children, choroid plexus papilloma is more likely to occur within the lateral ventricle. Pineoblastoma. Pineoblastomas are highly cellular tumors that are similar in MRI appearance to pineocytomas. However, they tend to be larger (>3 cm), more heterogeneous, frequently cause hydrocephalus, and also may spread via the CSF. This tumor is isointense to gray matter on T1, with moderate heterogeneous enhancement following administration of gadolinium. Like other PNETs, the hypercellularity of pineoblastoma results in T2-weighted signal that tends to be iso- or hypointense relative to gray matter, and restricted diffusion may also be seen. Cysts within the tumor may appear markedly hyperintense on T2, peripheral edema less so. In cases accompanied by hydrocephalus, FLAIR imaging may reveal uniform hyperintensity in a planar distribution along the margins of the lateral ventricles due to transependymal flow of CSF. Peripheral calcifications or intratumoral hemorrhage will exhibit markedly hypointense signal with blooming artifact on T2* (pronounced T2-star) images. Differential diagnostic considerations include germ cell tumor, pineocytoma, and (uncommonly) metastases.

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D Fig. 40.23 Two Cases of Meningioma. In the first (A, B) two extra-axial mass lesions are seen, one arising from the tentorium and the other from the sphenoid wing in the left middle cranial fossa (arrows). These compress the right cerebellar hemisphere and the left temporal lobe, respectively. A, On T2-weighted image, the masses are mostly isointense with foci of hypointensity. B, After gadolinium administration, the masses enhance homogeneously. Note the small dural tail along the tentorium. In the second case (C, D) a large olfactory groove meningioma that exerts significant mass effect on the frontal lobes, corpus callosum, and lateral ventricles is presented. C, On FLAIR image, hyperintense vasogenic edema is seen in the compressed brain parenchyma. D, Tumor enhances homogeneously with gadolinium.

Other pineal region tumors. Besides pineoblastomas, which histologically belong to the group of PNETs, the pineal gland may also develop tumors of pinealocyte origin (pineocytoma) and germ cell tumors. Pineocytoma. Pineocytomas are homogeneous masses containing more solid components, but cysts may also be present. These tumors have a round, well-defined, noninvasive appearance. Calcification is commonly seen, but hemorrhage is uncommon. These tumors may be hypointense on T2 and exhibit a variable (central, nodular) pattern of

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intense enhancement after gadolinium administration (Fakhran and Escott, 2008). Germ cell tumors (germinoma). Masses in the pineal region are most often germ cell tumors, usually germinomas. Less common types include teratoma, choriocarcinoma, and embryonal carcinoma. Germinomas are well-circumscribed round or lobulated lesions. Hemorrhage and calcification are rare. Metastases may spread via CSF, so the entire neuraxis should be imaged if these tumors are suspected.

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Fig. 40.24 Medulloblastoma. A large mass lesion is seen (asterisk) filling and expanding the fourth ventricle. A, On T1-weighted image, tumor is partially iso- but mostly hypointense. B, On T2-weighted image, tumor shows iso- and hyperintense signal change; it compresses/displaces the brainstem and cerebellum. On sagittal images, note the secondary Chiari malformation (caudal displacement of cerebellar tonsils) due to mass effect (arrow). C, On T1 postcontrast image, there is a heterogeneous enhancement pattern.

MRI signal characteristics are variable, with iso- to hyperintense signal relative to gray matter on both T1 and T2. With gadolinium, intense contrast enhancement is seen. Subependymal giant cell astrocytoma. Subependymal giant cell astrocytoma (SEGA), a WHO grade I tumor, arises from astrocytes in the subependymal zone of the lateral ventricles and develops into an intraventricular tumor in the region of the foramen of Monro. It is seen almost exclusively in patients with tuberous sclerosis. Just like central neurocytoma, this tumor is also prone to cause obstructive hydrocephalus. The tumor is heterogeneously hypo- to isointense on T1 and heterogeneously hyperintense on T2-weighted images, with possible foci of hypointensity due to calcification. On FLAIR, an isointense to hyperintense solid tumor background may be punctuated by hypointense cysts. FLAIR is also useful to assess for the possible presence of hyperintense cortical tubers, which if present aid in the differential diagnosis. With gadolinium, intense enhancement is seen. Choroid plexus papilloma. Choroid plexus papilloma is a wellcircumscribed, highly vascular, intraventricular WHO grade I tumor derived from choroid plexus epithelium. In children it is usually seen in the lateral ventricle, while in adults it tends to involve the fourth ventricle. General imaging characteristics include a villiform or bosselated “cauliflower-like” appearance. Hemorrhage and calcification are noted occasionally in the tumor bed. The tumor’s location frequently causes obstructive hydrocephalus. On MRI, the appearance is hypo- or isointense to normal brain on T1 and iso- to hyperintense on T2-weighted images. The latter may also show punctate or linear/ serpiginous signal flow voids within the tumor. Calcification (25%) or hemorrhage manifests as a markedly hypointense blooming artifact on T2* gradient echo images. With gadolinium, intense enhancement is seen. Choroid plexus carcinomas are malignant tumors that may invade the brain parenchyma and may also spread via CSF.

Tumors in the Sellar and Parasellar Region The sellar and parasellar group of extra-axial masses include pituitary micro- and macroadenomas and craniopharyngiomas. Meningiomas, arachnoid cysts, dermoid and epidermoid cysts, optic pathway gliomas, hamartomas, metastases, and aneurysms are also encountered in the para- and suprasellar region.

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Pituitary adenomas. The distinction between micro- and macroadenomas is based on their size: tumors less than 10 mm are microadenomas; the larger tumors are macroadenomas. These tumors may arise from hormone-producing cells, such as prolactinomas or growth hormone–producing adenomas, resulting in characteristic clinical syndromes. Pituitary adenomas are typically hypointense on T1-weighted and hyperintense on T2-weighted images, relative to the surrounding parenchyma. This signal change, however, is not always conspicuous, especially in the case of small microadenomas. Gadolinium administration helps in these cases, when the microadenoma is visualized as relative hypointensity against the background of the normally enhancing gland (Fig. 40.26). Following a delay, this difference in enhancement is often no longer apparent, and if the postcontrast images are obtained in a later phase, a reversal of contrast may be noted. The adenoma takes up contrast in a delayed fashion and is seen as hyperintense against the more hypointense gland from where the contrast has washed out. Sometimes when the signal characteristics are not conspicuous, only alteration of the size and shape of the pituitary gland or shifting of the infundibulum may indicate the presence of a microadenoma. Because of this, it is important to be familiar with the normal range of pituitary gland sizes, which depend on age and gender. In adults, a gland height of more than 9 mm is worrisome. In the younger population, however, different normal values have been established. Before puberty, the normal height is 3–5 mm. At puberty in girls, the gland height may be 10–11 mm and may exhibit an upward convex morphology. In boys at puberty, the height is 6–8 mm, and the upward convex morphology can be normal. The size and shape of the gland may also change during pregnancy: convex morphology may appear, and a gland height of 10 mm is considered normal. While microadenomas are localized to the sellar region, macroadenomas may become invasive and extend to the suprasellar region and may displace/compress the optic chiasm or even the hypothalamus. Extension to the cavernous sinus is also possible (see eFig. 40.27). Craniopharyngioma. Craniopharyngiomas are believed to originate from the epithelial remnants of the Rathke pouch. This WHO grade I tumor may be encountered in children, and a second peak incidence is in the fifth decade (Eldevik et al., 1996). The most common location is the suprasellar cistern (Fig. 40.28), but intrasellar

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eFig. 40.25 Esthesioneuroblastoma. A 41-year-old patient, diagnosed 19 years ago. A, Axial FLAIR image demonstrates a destructive mass lesion, which is mostly isointense. It involves the ethmoid region (asterisk), invades both orbits, left more than right (arrows), causing marked left proptosis. The tumor also spreads to the sellar and cavernous sinus area, encases the carotid arteries (arrowheads), invades the middle cranial fossa (double arrows) and the prepontine cistern (double arrowheads). B, Axial T1 postcontrast image reveals the same mass lesion, which demonstrates intense gadolinium enhancement.

Esthesioneuroblastoma. The cells of an esthesioneuroblastoma are derived from olfactory neuroepithelium neurosensory cells: hence its other name, olfactory neuroblastoma. This tumor characteristically extends through the cribriform plate to the anterior cranial fossa, orbit, and paranasal sinuses. Invasion of other intracranial compartments and even of the brain is possible, and spreading via CSF has been described.

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The signal intensity of the tumor is variable. On MRI, T1-weighted signal is usually isointense relative to gray matter, while the T2-weighted signal varies from iso- to hyperintense (Schuster et al., 1994). With gadolinium administration, intense, sometimes inhomogeneous enhancement is seen. See eFig. 40.25 for a very advanced case of esthesioneuroblastoma that spread to multiple cranial compartments.

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Central neurocytoma. This neuron-derived tumor accounts for less than 1% of all primary brain tumors. It tends to appear in the fourth decade. The tumor is intraventricular, most commonly in the lateral ventricles anteriorly at the foramen of Monro, close to the septum and the columns of the fornix. Even though the tumor is relatively benign histologically, this location frequently leads to

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obstructive hydrocephalus. The MRI signal is heterogeneous (Chang et al., 1993); the signal is isointense on T1 and iso- or hyperintense on T2 relative to the cortical gray matter. Calcification is possible, and the tumor may contain cystic regions. Sometimes multiple cysts are noted, resulting in a “bubbly” appearance. The enhancement pattern is variable, but usually moderate and heterogeneous.

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Subependymoma. Subependymoma is a rare, benign (WHO grade I) intraventricular tumor thought to originate from subependymal neuroglial cells. It most commonly presents in middle age (peak incidence during the fifth and sixth decades). Typically asymptomatic, it may be seen incidentally at autopsy. General imaging characteristics include a tendency to be small in size, round or lobular, well delineated, and homogeneous. Larger tumors are more likely to exhibit cysts, calcifications, or hemorrhage. The majority present within the fourth ventricle, but subependymomas are also seen in the third and lateral ventricles. Subependymomas of the lateral ventricle may be attached to the septum pellucidum, a location characteristic

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of central neurocytoma. Fourth-ventricular subependymomas, like ependymoma, may be seen to extrude posteroinferiorly via the foramen of Magendie. Of note, hydrocephalus is uncommon with subependymomas. On CT, subependymoma is iso- to hypodense. MRI features include T1 hypo- to isointensity, T2 hyperintensity, and hyperintense signal on FLAIR. Following gadolinium administration, enhancement is usually either absent or mild. Differential diagnostic considerations include central neurocytoma (more intensely enhancing), ependymoma (the adult peak is at a lower age than subependymoma), and intraventricular meningioma as well as metastasis.

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eFig. 40.27 Pituitary Macroadenoma. A, Coronal T2-weighted image demonstrates a prominent mass (asterisk) in the sella turcica. This is mostly isointense, with small hyperintense foci. The mass also invades the right cavernous sinus (arrow). B, Coronal T1-weighted postcontrast image reveals intense, fairly homogeneous enhancement of the mass (asterisk). C, Sagittal T1-weighted postcontrast image reveals the enhancing macroadenoma (asterisk) that expands the sella, emerges into the suprasellar cistern (arrowhead). Infiltration of the pituitary stalk is also seen (arrow).

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Fig. 40.26 Pituitary Microadenoma. A, Axial T2-weighted image demonstrates a round area of hyperintensity on right side of pituitary gland (arrow). B, On coronal noncontrast T1-weighted image, the gland has an upward convex morphology, and there is a vague hypointensity in its right side (arrow). C, On coronal T1-weighted postcontrast image, the microadenoma is well seen as an area of hypointensity (arrow) against the background of the normally enhancing gland parenchyma.

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Fig. 40.28 Craniopharyngioma. A, On sagittal T1-weighted image, a suprasellar mass lesion has a prominent T1 hypointense cystic component (arrows). B, On sagittal T2-weighted image, the cyst is hyperintense. C, With gadolinium, both the rim of the cyst and the solid portion of the mass exhibit enhancement (arrows).

tumors are also possible. The tumor may cause expansion of the sella or erosion of the dorsum sellae. In the suprasellar region, displacement of the chiasm, the anterior cerebral arteries, or even the hypothalamus is possible. Craniopharyngiomas have both solid and cystic components. Histologically, the more common adamantinomatous and the less common papillary forms are distinguished. The adamantinomatous type frequently exhibits calcification. The MRI signal is heterogeneous. Solid portions are iso- or hypointense on T1, whereas cystic components exhibit variable signal characteristics depending on the amount of protein or the presence of blood products. On T2, the solid and cystic components are sometimes hard to distinguish, as they are both usually hyperintense. Areas of calcification may appear hypointense on T2. In contrast, the solid portions of the tumor exhibit intense enhancement.

Metastatic Tumors Intracranial metastases are detected in approximately 25% of patients who die of cancer. Cerebral metastases comprise over half of brain tumors (Vogelbaum and Suh, 2006) and are the most common type of brain tumor in adults (Klos and O’Neill, 2004). Most (80%) metastases involve the cerebral hemispheres, and 20% are seen in the posterior fossa. Pelvic and colon cancer have a tendency to involve the posterior fossa. Intracranial metastases, depending on the type of tumor, may involve the skull and the dura, the brain, and also the meninges in the form of meningeal carcinomatosis. Among all tumors that metastasize to the bone, breast and prostate cancer and multiple myeloma are especially prone to spread to the skull and dura. Most often, carcinomas involve the brain and get there by hematogenous spread. Systemic tumors with F ECF

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the greatest tendency to metastasize to brain are lung (as many as 30% of lung cancers give rise to brain metastases), breast (Fig. 40.29), and melanoma (Fig. 40.30). Cancers of the gastrointestinal tract (especially colon and rectum) and the kidney are the next most common sources. Other possibilities include gallbladder, liver, thyroid gland, pancreas, ovary, and testicles. Tumors of the prostate, esophagus, and skin (other than melanoma) hardly ever form brain parenchymal metastases. It is important to highlight the potential imaging differences between primary and metastatic brain tumors, since a significant percentage of patients found to have brain metastasis have no prior diagnosis of cancer. Cerebral parenchymal metastases can be single (usually with kidney, breast, thyroid, and lung adenocarcinoma) or (more commonly) multiple (in small cell carcinomas and melanoma) and tend to involve the gray/white matter junction. Seeing multiple tumors at the corticomedullary junction favors the diagnosis of metastatic lesions over a primary brain tumor. The size of metastatic lesions is variable, and the mass effect and peritumoral edema is usually prominent and, contrary to that seen with primary brain tumors, frequently out of proportion to the size of the tumor itself. The edema is vasogenic, persistent, and involves the white matter, highlighting the intact cortical sulci as characteristic fingerlike projections. It is hypointense on T1 and hyperintense on T2 and FLAIR. The tumor itself exhibits variable, often heterogeneous signal intensity, especially if the metastasis is hemorrhagic (15% of brain metastases). Tumors that tend to cause hemorrhagic metastases include melanoma; choriocarcinoma; and lung, thyroid, and kidney cancer. The tumor signal characteristic can be unique in mucin-producing colon adenocarcinoma metastases, where the mucin and protein content cause a hyperintense signal on T1-weighted images. 02 .4.(1( 4 (

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B Fig. 40.29 Brain Metastases from Breast Cancer. A, On axial FLAIR image, multiple areas of vasogenic edema extend into subcortical white matter with fingerlike projections. B, On axial T1-weighted postcontrast image, numerous small enhancing mass lesions are scattered in both hemispheres at the gray/white junction. Both homogeneous and ringlike enhancement patterns are present.

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Fig. 40.30 Hemorrhagic Melanoma Metastases. A, Coronal T2-weighted image demonstrates a large hyperintense mass in the right frontal lobe, with associated hyperintense vasogenic edema and mass effect. A smaller mass lesion with similar signal characteristics is present at the gray/white junction in the left frontal lobe. Note surrounding rim of hypointensity, indicating hemosiderin deposition within these hemorrhagic metastases. B, On gradient echo, hypointense blood degradation products are well seen within the metastases. C, Following gadolinium administration, intense enhancement is noted.

Detection of intracerebral metastases is facilitated by administration of gadolinium, and every patient with neurological symptoms and a history of cancer needs to have a gadolinium-enhanced MRI study. The enhancement pattern of metastatic tumors can be solid or ringlike. To improve the diagnostic yield, triple-dose gadolinium or magnetization transfer techniques have been used, which improve detection of smaller metastases that are not so conspicuous with single-dose contrast administration. A triple dose of gadolinium improves metastasis detection by as much as 43% (van Dijk et al., 1997). Meningeal carcinomatosis can also be detected by contrast administration, which can

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reveal thickening of the meninges and/or meningeal deposits of the metastatic tumor.

For demonstration of the role of advanced structural neuroimaging in brain tumor surgery planning, see the online version of this chapter, available at http://www.expertconsult.com.○ Ischemic Stroke Acute ischemic stroke. With the introduction of intravenous tissue plasminogen activator (IV tPA) and, later, mechanical thrombectomy in the treatment of acute ischemic stroke, timely diagnosis of an ischemic

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eFig. 40.31 Diffusion Tensor Imaging, for Surgical Planning. A 34-year-old patient with anaplastic astrocytoma. A–C, Axial FLAIR images reveal a prominent, partially solid, partially cystic mass lesion (asterisk) in the left frontal lobe parenchyma. There is midline shift and distortion of the ventricles. Corpus callosum involvement is also seen (arrow). Surrounding vasogenic edema is noted (arrowheads). With gadolinium, intense enhancement was seen (not shown). D–F, Diffusion tensor images, corresponding to the axial FLAIR images. (D, E) Due to the mass, there is altered fractional anisotropy, disruption of the signal from the fiber system of the corpus callosum (arrowheads) and corona radiata (arrow), indicating the infiltrative nature of this neoplasm. F, Disruption of signal from the internal capsule and frontal lobe projection fibers due to the infiltrative tumor (arrowheads). Note the corresponding intact fiber system in the contralateral hemisphere (arrows).

Advanced structural neuroimaging for planning of brain tumor surgery. Besides functional MRI, advanced structural MRI techniques are also indispensable tools for brain tumor surgery planning. The goal is to maximize the amount of neoplastic tissue removal and to avoid injury to eloquent cortical structures and neural pathways. DTI is an excellent tool for visualization of the nerve fiber systems within and around neoplasms, helping define the boundaries of the planned surgical procedure. The imaging appearance helps decide whether the signal from a certain

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fiber system is just displaced or disrupted by the neoplasm. Disruption of the fractional anisotropy and signal of a neural pathway indicates the infiltrative nature of the tumor and predicts injury to the fibers if that particular portion of the tumor is removed. eFig. 40.31 demonstrates a case of an infiltrative anaplastic astrocytoma that infiltrates/disrupts multiple fiber systems. On the other hand, extra-axial/compressive tumors and certain, noninfiltrative intra-axial tumors only displace the adjacent pathways—hence those can be preserved during removal of the lesion.

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lesion, determining its location and extent, and demonstrating the amount of tissue at risk has become essential (see Chapters 65 and 68). CT imaging remains of great value in the evaluation of acute stroke; it is readily available, and newer CT modalities including CTA and CT perfusion imaging are coming into greater use. The applicability of CT to acute stroke continues to be enhanced by the ever-increasing

rapidity with which scans can be acquired, allowing for greater coverage of tissues with thinner slices. The technological advances allowing for rapid acquisition of data have led to 4D imaging, where complete 3D data sets of the brain are serially obtained over very short time intervals, allowing for higher temporal and spatial resolutions in brain perfusion studies of acute ischemic stroke patients. CT is very useful in detecting hyperdense hemorrhagic lesions as the cause of stroke. Early ischemic stroke, however, may not cause any change on unenhanced CT, making it difficult to determine the extent of the ischemic lesion and the amount of tissue at risk. CT is especially limited in evaluating ischemia in the posterior fossa, owing to streak artifacts at the skull base. Despite these limitations, early signs of acute ischemia on unenhanced CT may be helpful in the first few hours after stroke. CT signs of acute ischemia include blurring of the gray/white junction and effacement of the sulci due to ischemic swelling of the tissues. Blurring of the contours of the deep gray matter structures is of similar significance. In cases of internal carotid artery occlusion, middle cerebral artery main segment (M1) occlusion, or more distal occlusions, intraluminal clot may be seen as a focal hyperdensity, sometimes referred to as a hyperdense middle cerebral artery (MCA), or hyperdense dot sign (Fig. 40.32). Several MRI modalities, as well as CT perfusion studies, are capable of providing data regarding cerebral ischemia and perfusion to assist in the evaluation for possible thrombolytic therapy very early after symptom onset. DWI with ADC mapping is considered to be the most sensitive method for imaging acute ischemia (Figs. 40.33–40.36). In humans, the hyperintense signal indicating restriction of diffusion is detected within minutes after onset (Hossmann and Hoehn-Berlage, 1995).

Temporal evolution of ischemic stroke on magnetic resonance imaging

Fig. 40.32 Evolving Ischemic Stroke in the Territory of the Left Middle Cerebral Artery. On this noncontrast CT scan, a hyperdense signal is seen in the distal left internal carotid artery and in the M1 segment of the left middle cerebral artery, indicating the presence of a blood clot (arrowheads). There is hypodensity in the corresponding area of the left hemisphere, demonstrating the evolving ischemic infarct.

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Acute stroke. Initially, the hyperintense signal on DWI is caused by decreased water diffusivity due to swelling of the ischemic nerve cells (for the first 5–7 days); then it increasingly results from the abnormal T2 properties of the infarcted tissue (T2 shine-through). For this reason, a reliable estimation of the age of the ischemic lesion is not possible by looking at DWI images alone. Imaging protocols for acute ischemic

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Fig. 40.33 Acute Ischemic Stroke in the Territory of the Middle Cerebral Artery. A, On diffusion-weighted imaging, a hyperintense area of restricted diffusion is seen in the territory of the left middle cerebral artery. Note evolving mass effect on the sulci and left lateral ventricle and the mild midline shift. B, On apparent diffusion coefficient map, corresponding hypointensity is seen in the same area.

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Fig. 40.34 Acute Ischemic Stroke in the Territory of the Anterior Cerebral Artery. A, On diffusion-weighted imaging, a hyperintense area of restricted diffusion is seen in the right medial frontal lobe, involving the territory of the anterior cerebral artery. B, On apparent diffusion coefficient map, corresponding hypointensity is seen in the same area.

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Fig. 40.35 Acute Ischemic Stroke in the Territory of the Posterior Cerebral Artery. A, On diffusion-weighted imaging, a hyperintense area of restricted diffusion is seen in the left medial occipital lobe, involving the territory of the posterior cerebral artery. B, On apparent diffusion coefficient map, corresponding hypointensity is seen in the same area.

stroke usually include T1- and T2-weighted fast spin echo images, FLAIR sequences, and DWI with ADC maps. These sequences together confirm the diagnosis of ischemia, determine its extent, and allow for an approximate estimation of the time of onset (Srinivasan et al., 2006). On ADC maps, the values decrease initially after the onset of ischemia (i.e., the signal from the affected area becomes progressively more hypointense). This reaches a nadir at 3–5 days but remains significantly low until the seventh day after onset. After this time, the values increase (the signal

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gets more and more hyperintense) and return to the baseline values in 1–4 weeks (usually in 7–10 days). Therefore, ADC maps are quite useful for the estimation of the age of the lesion: If the signal of the area is hypointense on an ADC map, the lesion is likely less than 7–10 days old. If the area is isointense or hyperintense on the ADC map, the onset was likely more than 7–10 days ago. As already noted, although these signal changes take place on ADC maps, the DWI images remain hyperintense, without noticeable changes of intensity by visual inspection.

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On T2-weighted (including FLAIR) images, the signal intensity of the ischemic area is normal in the initial hyperacute stage, increases markedly over the first 4 days, then becomes stable. In a research setting, computing the numerical values of hyperintensity in infarcted tissue on serial T2-weighted scans can demonstrate a consistent sharp signal increase after 36 hours, distinguishing lesions younger or older than 36 hours. This is certainly not possible by visual inspection used in clinical practice.

One purpose of MRI in the evaluation of acute stroke is to determine the extent of irreversible tissue damage and to identify tissue that is at risk but potentially salvageable. The combination of DWI and PWI is frequently used for this purpose (Fig. 40.37). Evaluation is based on the premise that diffusion-weighted images delineate the tissue that suffered permanent damage (although in some cases, restricted diffusion is reversible, corresponding to ischemia without infarction), whereas areas without signal change on DWI but abnormal signal on perfusion-weighted images represent tissue at risk, the so-called ischemic penumbra. If there is a mismatch between the extent of DWI changes and perfusion deficits, the latter being larger, reperfusion treatment with mechanical thrombectomy is justified to salvage the brain tissue at risk up to 24 hours of last known normal (Powers et al., 2018). If the extent of diffusion and perfusion abnormalities is similar or the same, the tissue is thought to be irreversibly injured, with no penumbra, and therefore the potential benefit from reperfusion treatment may not be high enough to justify the risk of hemorrhage associated with thrombolytic treatment.

Subacute ischemic stroke (1 day to 1 week after onset).

Fig. 40.36 Acute Ischemic Stroke in the Left Anterior Watershed Area. On diffusion-weighted imaging, a hyperintense area of restricted diffusion is seen in the left frontal lobe, involving the watershed zone between the anterior and middle cerebral artery.

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In this stage, there is an ongoing increase of cytotoxic edema due to swelling of the ischemic neurons. Parallel with this, the involved tissue becomes more and more hypointense on T1 and also gradually more hyperintense on T2 and FLAIR sequences. Cytotoxic edema is usually maximal 2–3 days after onset, but in the case of malignant middle cerebral artery strokes, it may keep increasing until day 5. Arterial wall enhancement is seen during this stage, whereas parenchymal enhancement usually begins at the end of the first week. Reperfusion usually occurs at this stage and may be associated with petechial hemorrhages or even frank hemorrhage within the infarcted tissue. Petechial hemorrhages are very common; microbleeds (not always visible with CT or MRI) occur in as much as 65% of ischemic stroke patients (Werring, 2007). Frank hemorrhagic transformation, however, is much less common. Late subacute ischemic stroke (1–3 weeks after onset). In this stage, gradual resolution of the edema is seen. As the infarcted

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Fig. 40.37 Ischemic Penumbra in Acute Right Middle Cerebral Artery Stroke. A, Diffusion-weighted image reveals a small, circumscribed area of restricted diffusion in the paraventricular region of the right centrum semiovale (arrow). B, Magnetic resonance perfusion-weighted image demonstrates a much larger perfusion deficit, as revealed by increased mean transit time, indicated in red. The perfusion deficit (red) outside the small area of restricted diffusion (arrow, A) represents the ischemic penumbra.

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Fig. 40.38 Chronic Ischemic Stroke. A, On FLAIR image, a large area of encephalomalacia is seen in the territory of the left middle cerebral artery. Hypointense cerebrospinal fluid (CSF)-like cavity is surrounded by hyperintense signal change in adjacent parenchyma, indicating gliosis. Note ex vacuo enlargement of adjacent segment of left lateral ventricle. B, On noncontrast T1-weighted image, the cavity of encephalomalacia appears as CSF-like hypointensity. Areas of gliosis appear as faint zones of hypointensity.

tissue is disintegrating and resorbed, the T1 hypointensity and T2 hyperintensity of the lesion become more marked. Gray matter enhancement (which in the case of infarcted cortex has a gyriform pattern) is intense throughout this stage. Chronic ischemic stroke (3 weeks and older). Areas of complete tissue destruction with death not only of neurons but of glia and necrosis of other supporting tissues as well, will eventually appear as cavitary lesions filled with fluid that have signal characteristics identical to CSF: hyperintensity on T2-weighted images and marked hypointensity on T1 images and FLAIR sequences. The region of encephalomalacia is bordered by a glial scar (reactive gliosis) that is hyperintense on T2 and FLAIR images (Fig. 40.38). Although the initial signal changes on DWI frequently predict the final extent of tissue destruction, changes on DWI can also disappear, and the final size of tissue cavitation can be best determined on T1-weighted images, which should be part of every stroke follow-up imaging protocol. Tissue in the margins of the cavitary lesion, and often in other areas of the brain as well, may have undergone extensive neuronal loss resulting only in atrophy but not in signal intensity changes, even on T2-weighted images (partial infarction). Besides signal changes, chronic ischemic infarcts lead to secondary changes in the brain. Owing to the loss of tissue, ex vacuo enlargement of the adjacent CSF spaces (sulci and adjacent ventricular segments) occurs. Pathways that originate from or pass through the infarcted area undergo wallerian degeneration, which is seen as T2 hyperintense signal change along the course of these pathways (Fig. 40.39). Later, the hyperintensity may resolve, but the loss of pathways may result in volume loss of the structures they pass through (e.g., cerebral peduncle, pons, medullary pyramid), noted as decreased cross-sectional area.

Stroke Etiology Structural imaging provides data on the morphology and location of ischemic cerebral lesions, which can be very helpful to

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determine stroke etiology: lacunar, atherothrombotic, embolic, hypoperfusion-related, or venous. Diagnostic evaluation and treatment of a patient with stroke, as well as secondary stroke prevention, is often dependent upon structural imaging. A discussion of the neuroimaging aspects of the various stroke etiologies is available at http://www.expertconsult.com. Other Cerebrovascular Occlusive Disease Arteriolosclerosis (white matter hyperintensity of presumed vascular origin). Diffuse or patchy T2 hyperintense signal changes in the deep hemispheric and subcortical white matter are probably the most common abnormal findings on MRI in the adult and elderly patient population. The terms microvascular ischemic changes, chronic small vessel disease, or leukoaraiosis are alternatively used to describe these lesions on imaging studies. Their etiology and clinical significance have been debated extensively. Certain hyperintense signal changes are considered normal incidental findings, with no clinical relevance. A uniformly thin, linear, T2 hyperintensity that has a smooth outer border along the border of the body of the lateral ventricles is often seen in the elderly population and likely represents fluid or gliotic changes in the subependymal zone. It tends to be more pronounced at the tips of the frontal horns (ependymitis granularis). This finding is thought potentially to be due to focal loss of the ependymal lining with gliosis and/or influx of interstitial fluid into these regions. Patchy signal changes within the white matter of the cerebral hemispheres beyond a relatively low threshold (generally, one white matter hyperintensity per decade of life is felt to fall within the normal range) are pathological and are most commonly of ischemic origin. According to the most accepted hypothesis, these hyperintensities are the result of gradual narrowing or occlusion of the small vessels of the white matter, the diameters of which are less than 200 µm (hence the terms microvascular lesions or small vessel disease). Pathologically, these

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Fig. 40.39 Wallerian Degeneration. A, Coronal T2-weighted image demonstrates a chronic lacunar ischemic lesion in the right internal capsule (arrow). From here, a linear hyperintense signal change is seen extending caudally along the course of the degenerating corticospinal tract fibers, through the right cerebral peduncle into the pons (arrowheads). B–D, Serial T2-weighted axial images of the brainstem demonstrate the hyperintense signal of the degenerating fibers (arrows) in the right cerebral peduncle (B), right pontine tegmentum (C), and in the right medullary pyramid (D).

lesions are composed of focal demyelination and gliosis. The lumen of the involved vessels is narrow or occluded; their walls may exhibit arteriosclerotic changes and commonly amyloid deposits. On imaging studies, they have a chronic appearance, with diffuse borders and no surrounding edema or evidence of mass effect. They are generally associated with some degree of central atrophy, which tends to worsen with higher lesion loads. The distribution of these lesions changes only very gradually on serial scans, often showing minimal to no significant difference on studies spaced several years apart. While age by itself can cause such changes, and the incidence of these lesions increases with age in people 40 years or older, there are several other risk factors that can make them more numerous. These include hypertension, diabetes, hypercholesterolemia, and smoking. Indeed, patients with these medical problems are more likely to have an elevated number of ischemic white matter lesions. Chronic ischemic white matter lesions are hypodense on CT, but MRI is much more sensitive and reveals more extensive lesions (Fig.

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40.41, A). On MRI, the lesions are hyperintense on T2 and FLAIR sequences. They may or may not be visible as T1 hypointensities. It is possible that only lesions visible on T1-weighted images may be clinically significant. Common locations are the PV and, more commonly, the deep white matter, but subcortical lesions are also common, with sparing of the U-fibers. The lesions can be isolated, scattered, or more confluent, especially in the PV zone. Morphologically, individual lesions generally exhibit indistinct borders with a diffuse “cotton-wool” appearance and range in size from punctate to small. Regions of confluent lesions may appear large and more commonly affect the deep white matter anterior and posterior to the bodies of the lateral ventricles, symmetrically within the parietal and frontal lobes. Deep white matter lesions also often occur in a distribution parallel to the bodies of the lateral ventricles on axial views, with an irregular band-like or “beads-on-string” appearance often separated from the PV lesions by an intervening band of relatively unaffected white matter. Involvement of the external capsules is also characteristic. These patterns of lesion

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Watershed ischemic stroke. Watershed ischemic stroke involves the border zones between the vascular territories of the major cerebral arteries. Infarcts may be superficial, between the territories of the major branches of the circle of Willis, such as anterior watershed infarcts between the proximal territories of the anterior and middle cerebral arteries (see Fig. 40.36) and posterior watershed infarcts between those of the middle and posterior cerebral arteries. Deep border zone infarcts develop between the superficial and deep branches of a cerebral artery. Bilateral, roughly symmetrical watershed infarcts result from global cerebral hypoperfusion caused by heart failure, hypoxia, or hypoglycemia that tends to damage the border zone regions. In unilateral cases, one of these factors is usually coupled with arterial stenosis or occlusion, which can be evaluated with Magnetic Resonance Angiography (MRA) or CTA of the carotid and vertebral arteries. Ischemic stroke of thromboembolic origin. Thromboembolic stroke results from occlusion of one or more major cerebral arteries or their branches by a blood clot. The occlusion may be due to in situ thrombus formation or embolization from a distant source. Emboli can be of cardiac origin, but they may also be the result of arteryto-artery embolization, commonly due to carotid or aortic arch atherosclerotic disease. The location of infarctions on CT or MRI can orient as to the source of emboli. Unilateral anterior strokes are often due to embolization from the proximal internal carotid artery, a preferential site for atherosclerotic plaque formation. Likewise, unilateral embolic stroke in the posterior circulation necessitates evaluation of the vertebrobasilar system. It should be kept in mind that in case of the quite common anatomical variant of fetal origin

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of the posterior cerebral arteries (termed fetal PCA when they are predominantly fed by large posterior communicating arteries, which are variably present and arise from the internal carotids), posterior circulation stroke may result from embolization from the anterior circulation. Multiple, especially bilateral, cortical ischemic strokes almost always suggest an embolic origin. If the strokes are bilateral and/or involve both the anterior and posterior circulation, a more proximal embolic source such as the aortic arch or heart can be suspected. Reperfusion injury is a common phenomenon in embolism, and in this stroke type, hemorrhagic transformation of varying degree is often seen. Lacunar ischemic stroke. Lacunar ischemic strokes constitute 20%–25% of all strokes and are typically seen in patients with hypertension and diabetes. This stroke type is thought to be due to narrowing and in situ thrombosis of the small, deep-penetrating arteries such as the lenticulostriate arteries. The most common locations include basal ganglia, internal capsule, and thalamus. According to structural imaging criteria, their size is usually less than 15 mm in diameter. Acutely, lacunar infarctions may exhibit restricted diffusion if the resolution of the ADC map is high enough to differentiate such from background signal variation. Chronic lacunes have a smoothly rounded, well-defined appearance. The encephalomalacic core of chronic lacunar infarctions follows CSF signal on all pulse sequences, appearing markedly hyperintense on T2 and hypointense on both T1 and FLAIR. There is often a thin rim of hyperintense signal on FLAIR due to gliosis, which helps differentiate lacunes from large VirchowRobin spaces (eFig. 40.40).

B eFig. 40.40 Chronic Lacunar Ischemic Stroke and Microvascular Ischemic Changes in the Hemispheric White Matter. A, On axial FLAIR image, a small lacunar area of encephalomalacia is seen in the left corona radiate (arrow). It has hypointense cerebrospinal fluid (CSF)-like signal in its center and is surrounded by a rim of hyperintensity, indicating gliosis. In addition, there are extensive hyperintense signal changes in the hemispheric white matter. Some of these are confluent, close to the ventricular borders, others involve the external capsules or are scattered in other regions of the white matter. These lesions have the imaging appearance of microvascular ischemic changes. B, On noncontrast T1-weighted image, the lacunar stroke appears as a hypointense CSF-like cavity. Faint hypointense signal change appears in the zones of microvascular ischemia.

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C Fig. 40.41 Microvascular Ischemic White Matter Changes. A, Axial FLAIR image reveals extensive hyperintense areas in the hemispheric white matter bilaterally. Some are confluent at the borders of the ventricles, others are scattered in other regions. Note the “band” of hyperintensity in the left hemisphere parallel to the border of the lateral ventricle. (B, C) On axial FLAIR and T2-weighted images, faint hyperintense signal changes are seen in the pontine tegmentum bilaterally, exhibiting the typical imaging appearance of microvascular ischemia (arrows).

distribution and morphology are often best seen on FLAIR. Contrary to the lesions of multiple sclerosis (MS), microvascular ischemia tends not to involve the temporal lobes or the corpus callosum. Besides the hemispheric white matter, microvascular ischemic lesions often also involve the basis pontis (see Fig. 40.41, B and C, available online). The clinical significance of ischemic white matter lesions depends on their extent and location. The presence of a few small, scattered, ischemic white matter lesions on T2-weighted images is clinically meaningless, and these are usually considered a normal imaging manifestation of aging. Patients may feel more comfortable with descriptions such as “age spots of the brain” to convey their benign nature when verbally discussing results. More extensive lesions also visible on T1-weighted sequences, however, are more likely to be associated with neurological abnormalities such as abnormal gait, dementia, and incontinence. In ischemic arteriolar encephalopathy or Binswanger disease, there is pronounced, widely distributed, and confluent PV and deep white matter signal change. In more severe cases, the confluent hyperintensity also involves the internal and external capsules or subcortical white matter. Besides confluent lesions, coexisting multiple scattered T2 hyperintensities are also very common. Ischemic white

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matter lesions are often intermixed with lacunar ischemic strokes and generalized cerebral volume loss is also frequently noted. eFig. 40.42 illustrates a case where the combination of various vascular pathologies, including large vessel stroke, and multiple lacunar infarcts led to vascular dementia. Scattered small, nonspecific-appearing, seemingly microvascular white matter hyperintensities have a broader differential diagnosis in the younger patient population. Multiple small T2 hyperintense lesions in the hemispheric white matter can be caused by migraine, trauma, inborn errors of metabolism, vasculitis (including Sjögren syndrome, lupus, Behçet disease, and primary CNS vasculitis), Lyme disease, and MS. Since the MRI appearance of these is nonspecific, clinical correlation is always warranted. In many instances, these white matter lesions are idiopathic, and future serial imaging studies are needed for follow-up.

Hippocampal sclerosis. Although ischemia may not be the only pathological mechanism underlying hippocampal sclerosis, this entity is discussed in conjunction with other ischemic lesions of the CNS, in the online version of this chapter available at http://www.expertconsult.com.

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eFig. 40.42 Vascular Dementia. An 85-year-old patient with gradual, stepwise cognitive decline. A, Encephalomalacia (arrow), on axial FLAIR image, due to chronic ischemic infarct in the right temporal lobe. Both temporal lobes also exhibit diffuse microvascular ischemic changes. B, Axial FLAIR image demonstrates extensive, confluent hyperintense signal abnormality in the hemispheric white matter, including periventricular and subcortical areas, the corona radiate, and conspicuously the external capsules as well. Microvascular ischemia is the most likely etiology. This imaging finding can be seen in Binswanger disease. C, A more rostral axial FLAIR image demonstrates multiple chronic lacunar ischemic infarcts (arrows), within the confluent hyperintense microvascular ischemic white matter changes.

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CADASIL. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominant inherited vascular disease. Pathologically there is destruction of the smooth muscle cells in the small and medium-sized penetrating arteries, with deposition of osmiophilic material and fibrosis leading to progressive thickening of the arterial wall and narrowing of the lumen. As a result, leukoencephalopathy and multiple ischemic strokes occur. Over 90% of patients have detectable mutations of the NOTCH3 gene, which encodes a

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transmembrane receptor primarily expressed in arterial smooth muscle cells. On MRI, multiple focal infarcts and T2 hyperintense white matter lesions are seen. The white matter lesions may involve the external capsules and, very characteristically, the anterior temporal lobe white matter in a confluent fashion that includes the subcortical arcuate fibers (eFig. 40.43). This latter finding is helpful for the structural imaging diagnosis and also helps distinguish CADASIL from “sporadic” ischemic arteriosclerotic vascular disease.

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C eFig. 40.43 CADASIL. A–C, Axial FLAIR images demonstrate diffuse, confluent hyperintense signal changes in the deep and subcortical white matter. Multiple chronic lacunar infarcts are also seen bilaterally (arrowheads). Note characteristic confluent hyperintensity (arrows) in the anterior temporal lobe white matter (C), involving the subcortical fibers as well.

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Hippocampal sclerosis is a potential typical imaging finding in patients with seizures of temporal lobe origin. Previous history of febrile seizures is quite common. On the affected side, the hippocampus exhibits decreased size and often also abnormal T2 hyperintense signal, which is best appreciated on coronal T2 as well as coronal and axial FLAIR images (eFig. 40.44). The underlying pathology is

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neuronal loss and gliosis involving the CA1 and CA3 regions of the hippocampus. Ex vacuo enlargement of the adjacent segment of the lateral ventricle temporal horn is also seen. There may be involvement of the hippocampus only, but at times other structures of the mesial temporal lobe are also affected and exhibit T2 hyperintensity. In these cases, mesial temporal sclerosis is a more appropriate term.

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eFig. 40.44 Hippocampal Sclerosis. Past history of ischemic stroke as well as long-standing history of temporal lobe epilepsy. A, Coronal FLAIR image demonstrates significant reduction of the size of the left hippocampus (arrow), when compared with the right. The left hippocampus also exhibits T2 hyperintense signal abnormality. There is ex vacuo expansion of the temporal horn of the left lateral ventricle. B, Axial FLAIR image reveals reduced size and abnormal T2 hyperintense signal of the left hippocampus (arrow) and expansion of the left lateral ventricle temporal horn.

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D eFig. 40.45 Venous Stroke. A 57-year-old patient with new-onset seizure, followed by prolonged altered mental status. A, Axial FLAIR image demonstrates hyperintense signal change in the left transverse sinus, due to thrombosis (arrows). B, Axial T1 postcontrast image reveals filling defect in the sinus, due to the presence of blood clot (arrow). C, Diffusion-weighted image shows restricted diffusion in the left temporal lobe, involving cortical and subcortical areas, in a nonarterial distribution. The change is due to venous ischemia (arrowheads). D, Three days later, axial FLAIR image reveals hyperintense signal in the left temporal lobe (arrow), again in a nonarterial pattern. This is subacute venous ischemia, but the extent is less than seen previously on the diffusion-weighted image (patient was treated with anticoagulation).

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eFig. 40.45—cont’d E, One year later, FLAIR image reveals the chronic stage of the venous stroke, as revealed by hypointense signal change in the temporal lobe, due to hemosiderin deposition (arrow). F, Axial T2-weighted image demonstrates the hypointense hemosiderin deposition even better (arrow).

Venous occlusion/infarction. Venous infarction may follow the thrombosis of cerebral veins (cortical draining veins and the cerebral deep venous system) or of one or more intracranial venous sinuses. The pathogenesis of venous ischemia/stroke is fundamentally different from arterial strokes. Thrombosis of the efferent channels (veins or sinuses) causes elevation of venous pressure, leading to congestion/ dilatation of upstream capillaries and venules. This results in interstitial edema, which makes the area of venous infarction/ischemia hyperintense on T2-weighted and FLAIR pulse sequences. Rupture of the vessels may occur, leading to the frequently observed hemorrhagic component of these lesions, best visualized on susceptibility sensitive sequences. Further changes depend on the severity and duration of venous occlusion. Often the congestion is brief or transient, and the ischemic tissue recovers. In these cases, the sometimes very prominent signal changes can resolve, and no residual deficits will remain. In more severe cases that progress to infarction, restriction of diffusion (hyperintense signal on DWI and hypointense signal on ADC maps) is a common finding due to cytotoxic edema. Cytotoxic and vasogenic edema also results in hypointense signal on T1-weighted images. The venous etiology of the stroke is suggested by the morphological appearance of the lesion. Its distribution does not follow an arterial branch pattern. The appearance of the hyperintense signal changes on

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T2-weighted images and FLAIR sequences is also different; oftentimes heterogeneous signal changes are noted within the venous infarction, consisting of a “curly cue” or “fudge-swirl” pattern. Tumor-like appearances are also possible. In cases of ischemia/stroke that are suspected to be of venous origin, it is important to carefully evaluate the draining veins in the area, and the sinuses as well, to look for thrombosis. The normal flow voids on MRI may be absent, replaced in some cases by hyperintense signal changes on FLAIR or hyperdensities on CT that exhibit a tubular or curvilinear string-like morphology. However, the pattern and distribution of cortical draining veins is very variable, which makes it difficult to pinpoint abnormalities of individual veins. Sometimes there is a striking absence of visualizable draining veins. Conversely, in cases of sinus thrombosis, massive engorgement of the veins may be seen. Venous thrombosis frequently starts at the level of a draining vein. In these cases, magnetic resonance venography (MRV) may be initially unremarkable. MRV will become abnormal only later when the thrombosis progresses to the venous sinuses. Suspected cases of venous infarction are often best evaluated with two modalities: conventional MRI or CT in conjunction with MRV or a CT venogram. eFig. 40.45 demonstrates the evolution of a venous infarct, due to left transverse sinus thrombosis, from the acute to chronic stages.

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Fig. 40.46 Left transverse and sigmoid sinus thrombosis with a small left temporal lobe area of venous ischemia. This 48-year-old patient presented with a new-onset seizure and right visual field deficit that resolved later. A, Axial FLAIR image reveals abnormal hyperintense signal in the left transverse and sigmoid sinus, indicating thrombosis. Compare with the right transverse sinus, with the normal hypointense flow void. This FLAIR image also shows a small but noticeable area of hyperintensity due to venous ischemia in the left temporal lobe. B, Noncontrast T1-weighted image also reveals abnormal hyperintense signal in the involved venous sinuses. Again, compare with the contralateral sinus. C, Postcontrast T1-weighted image reveals normal filling in the sinus on the right, but there is no filling along the visualized segment of the left transverse sinus (arrowheads).

Cerebral venous sinus thrombosis. Acute cerebral venous sinus thrombosis results in diminished or absent flow in the involved sinuses. Cerebral venous sinus thrombosis usually causes typical signal changes on MRI (Fig. 40.46) and severely attenuated or absent flow signal on MRV. MRV techniques include flow-sensitive modalities such as 2D time-of-flight and phase contrast imaging, as well as postcontrast highresolution three-dimensional spoiled gradient-recalled (3D SPGR), which offers excellent visualization of the sinuses with a very high spatial resolution and contrast-to-noise ratio. In the appropriate clinical context, a useful sign of venous sinus thrombosis is the absence of a normal hypointense flow void in the involved sinuses on T1- and T2-weighted images and absent flow in the involved sinus on MRV. Nonflowing blood generally results in increased signal intensity on T1 and T2. In the early acute stage, however, the sinuses may still be hypointense. This is followed by signal that is isointense to the gray matter. The typical hyperintense signal on T1- and T2-weighted images appears when methemoglobin is present in the clot. At all stages, therefore, simultaneous review of the MRV or CT angiogram for lack of flow signal and lack of contrast filling in conjunction with conventional MRI may be particularly useful to increase the sensitivity and specificity of detection of sinus thrombosis while also adding information regarding the age of the clot. Following administration of gadolinium, there may be enhancement of the dural wall of the sinus and along the periphery of the clot, but not within the clot itself, resulting in an “empty delta” appearance. This is classically a CT finding, but the same concept also applies to MRI in the context of the T1-weighted clot signal that varies with clot age. MR demonstrates lack of flow, appearing as absence of contrast-related signal in the involved sinuses. CT angiogram reveals no contrast filling in the thrombosed sinuses. The cortical veins that drain into the involved sinuses may appear engorged on MRV. However, if the thrombosis also involves these draining veins, they too may exhibit lack of signal on MRV, lack of filling on CT angiogram, and lack of flow voids in conjunction with iso- or hyperintense signal on T1- and T2-weighted images.

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Variations in the speed of blood flow and anatomical variants of the venous sinuses may change their usual signal characteristics, leading to a false diagnosis of venous sinus thrombosis. Slow flow in a venous sinus may cause increased signal on T1- and T2-weighted images, potentially leading to a false assumption of thrombosis. Gadoliniumenhanced images help in these cases, demonstrating contrast filling/ enhancement in the sinuses and confirming the absence of thrombosis. A normal variant of venous sinus hypoplasia/aplasia may result in decreased/absent flow signal on MRV, falsely interpreted as thrombosis. T1- and T2-weighted images, however, are usually able to demonstrate the absence of thrombus in the sinus. These examples highlight the importance of reviewing all necessary image modalities (MRV, T2-weighted images, T1-weighted images with and without contrast) to make or reject a diagnosis of venous sinus thrombosis.

Hemorrhagic Cerebrovascular Disease Structural neuroimaging is crucial in the evaluation of hemorrhagic cerebrovascular disease. Besides detection of the hematoma itself, its location can provide useful information regarding its etiology. Lobar hematomas, especially along with small, scattered, parenchymal microbleeds, raise the possibility of cerebral amyloid angiopathy, whereas putaminal, thalamic, or cerebellar hemorrhages are more likely to be of hypertensive origin. Other underlying lesions such as brain tumors causing hemorrhages can be detected by structural imaging. This section discusses hemorrhagic cerebrovascular disease and cerebral intraparenchymal hematoma, whereas other causes of hemorrhage such as trauma or malignancy are discussed in other sections. Refer to Chapters 66 and 67 for a clinical neurological review of intracerebral hemorrhages. For decades, noncontrast CT scanning has been (and in most emergency settings still is) the essential tool for initial evaluation of intracerebral hemorrhage. In hyperacute (95% of cases) cortical tubers do not enhance after gadolinium administration. Subependymal nodules. Subependymal nodules are usually bilateral in PV regions such as the caudate nucleus, thalamus, or caudothalamic groove. They often bulge into the ventricles and appear along the ventricular surface as “candle-guttering.” Their signal characteristics are variable. They may appear iso- to hyperintense on T1 and hypo- to hyperintense on T2-weighted images. Calcification, easily seen on CT, may be present. Contrary

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to cortical tubers, subependymal nodules commonly exhibit enhancement with gadolinium. They may progress to become SEGAs. White matter lesions. In tuberous sclerosis, MRI may reveal several patterns of white matter lesions: (1) radially oriented cerebral or cerebellar bands, which are thought to represent bands of unmyelinated cells and fibers with disturbed migration, (2) wedge-shaped lesions, or (3) patchy signal changes. These are isointense or hypointense on T1and hyperintense on T2-weighted images. Von Hippel-Lindau disease. Von Hippel-Lindau disease is a neurocutaneous syndrome that presents with visceral tumors (pheochromocytoma, renal cancer), cysts (renal, pancreatic, hepatic), and retinal and CNS hemangioblastomas. Hemangioblastomas are described in the brain tumor section. The most common locations include the cerebellum and medulla; supratentorial tumors are rare. In the cerebellum, hemangioblastomas tend to involve the hemispheres. When associated with von Hippel-Lindau disease, hemangioblastomas tend to occur earlier, in the fourth decade. Sturge-Weber syndrome. Sturge-Weber syndrome is characterized by cutaneous and leptomeningeal angiomatosis. Prominent leptomeningeal enhancement is seen on MRI after gadolinium administration. The ipsilateral choroid plexus commonly exhibits angiomatous transformation with intense enhancement. The cortical superficial veins are often absent, and to enable venous drainage, the medullary and subependymal veins are often enlarged. On the involved side, there is cerebral atrophy with enlargement of the ipsilateral central and superficial CSF spaces. Thickening of the overlying calvarium and enlargement of the adjacent paranasal sinuses are typical findings. Cortical calcification is another diagnostic finding in Sturge-Weber syndrome. This is usually better seen on CT scan but may appear as hyperintense signal on T1-weighted images, and in advanced cases exhibits a “tram-track” pattern. T2 hyperintense signal changes are also seen in the subcortical white matter of the involved areas, reflecting gliosis and disturbed myelination.

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eFig. 40.85 Tuberous Sclerosis. A, Axial T2-weighted image demonstrates multiple subependymal nodules (arrows) and a left frontal (arrowhead) tuber. They contain hypointense areas suggestive of calcification. B, Axial FLAIR image shows, besides the cortical tubers (arrowheads), linear hyperintense areas in the right hemisphere, extending from cortical regions toward the subependymal zones (arrows). These represent bands of unmyelinated fibers and cells with disturbed migration. C, This axial FLAIR image, besides revealing hyperintense and partially calcified hamartomas (arrowheads), also demonstrates a hyperintense mass lesion near the left foramen of Monro, most consistent with a subependymal giant cell astrocytoma (arrow). D, Axial T1 postcontrast image shows homogeneous enhancement within this tumor (arrow).

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eFig. 40.86 Agenesis of the Corpus Callosum. Mid-sagittal FLAIR image shows absence of the corpus callosum.

In this section, we discuss the MRI findings resulting from abnormal development of the brain and meninges. These include (1) disorders of formation and diverticulation of the neural tube, especially that of the prosencephalon (e.g., holoprosencephaly, septo-optic dysplasia); (2) absence or abnormal development of neural pathways (e.g., agenesis of the corpus callosum due to anomalous neural tube closure); (3) disorders of neuronal migration causing various types of gray matter heterotopia, schizencephaly, lissencephaly, pachygyria, and polymicrogyria; (4) developmental abnormalities of the meninges resulting in lipoma and arachnoid cyst formation; (5) abnormal folding of the neuroepithelium, such as with colloid cysts; (6) entrapment of epidermal and dermal elements during neural tube closure leading to formation of epidermoid and dermoid cysts; and (7) vascular malformations. Developmental abnormalities that result in abnormalities of CSF circulation (e.g., Chiari malformations) are discussed in a different section. Disorders of histogenesis are discussed in the section on neurocutaneous syndromes. Developmental anomalies are often not isolated findings and may occur in combination. For instance, pericallosal lipomas are frequently associated with corpus callosum dysgenesis, frontal lobe abnormalities, or even craniofacial maldevelopment. For a review of developmental disorders of the nervous system, see Chapter 89. Holoprosencephaly. During development of the forebrain, cleavage of the prosencephalon vesicle generates the symmetrical telencephalic vesicles which later develop into the cerebral hemispheres. As the walls of these vesicles thicken (due to neuronal migration) and the telencephalic vesicles fold into the shape of the future hemispheres, the initially larger openings that connected the cavities of the forming ventricles narrow down to become the interventricular foramina of Monro. Occasionally, cleavage of the forebrain does not occur or does so only partially, resulting in the various forms of holoprosencephaly (alobar, semilobar, lobar). In the alobar form, a single prosencephalic cavity is lined by neural tissue of variable thickness. Septo-optic dysplasia. Septo-optic dysplasia is a complex maldevelopment of the anterior midline structures. On MRI, the ventricles are enlarged, the septum pellucidum is absent, and, especially well seen on dedicated thin-slice images of the orbit, the optic nerves are atrophic. Dandy-Walker malformation. Dandy-Walker malformation is a developmental anomaly that consists of hypoplasia of the cerebellar vermis, with absent inferior lobules, an enlarged fourth ventricle communicating with a ventricular cyst occupying a large posterior fossa, and superior displacement of the tentorium cerebelli, in addition to the torcular herophili and transverse sinuses. Other potential associated anomalies include callosal agenesis, encephalocele, heterotopias, or

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hydrocephalus. Sometimes a forme fruste of this malformation is found, seen as some degree of vermian hypoplasia with an enlarged fourth ventricle or sometimes just an enlarged cisterna magna. These findings are referred to as Dandy-Walker variants. Agenesis of the corpus callosum. Abnormal closure of the neural tube may lead to total or partial agenesis of the corpus callosum due to lack of a neural substrate the fibers can grow into. The callosal fibers that fail to cross the midline are arranged into parasagittal axon bundles called Probst bundles. The absence or abnormal shape of the corpus callosum is well seen on MR images (eFig. 40.86). Callosal dysgenesis is frequently coupled with other developmental anomalies such as colpocephaly (enlargement of the occipital horns), heterotopias, lipoma, and Dandy-Walker malformation. Gray matter heterotopia. During development of the CNS, the wall of the neural tube is a site of neurogenesis and a starting point for neuronal migration. Development of the cerebral cortex requires migration of neurons from the ventricular zone toward the surface where the cortical mantle is being formed. Neurons migrate along the “scaffolding” fibers of the radial glia toward their final cortical position. Formation of the layers of the cerebral cortex follows an inside-to-outside pattern (i.e., the deeper layers are formed first and neurons destined for the more superficial layers migrate through the established deeper layers). The process of migration along the radial glial fibers can be disturbed by various insults, and the migration may be arrested anywhere along its course. Neurons whose migration is arrested “get stuck” in a given part of the wall of the neural mantle and form nodules or bands of ectopic nerve cells, referred to as neuronal heterotopia. These heterotopic bands or nodules may appear in PV locations, often bulging into the ventricular cavity (eFig. 40.87) but also anywhere in the white matter. Sometimes they have a more superficial location or even bulge into the subarachnoid space. In cases of cryptogenic epilepsy, high-resolution MRI scans may detect such heterotopias, which can be missed on conventional T1, T2, or FLAIR images but are relatively conspicuous on 3D-SPGR and T1 inversion recovery pulse sequences. Pachygyria, polymicrogyria, lissencephaly. The terms pachygyria, polymicrogyria, and lissencephaly refer to disturbed development and subsequent abnormal morphology of the cerebral cortex, usually as a result of disturbed migration of cortical neurons. In pachygyria, the gyri are abnormally thick and reduced in number. In polymicrogyria, multiple abnormally small gyri are seen (eFig. 40.88). In lissencephaly, the brain surface appears smooth due to lack of proper differentiation of the cortex, resulting in absent sulci and gyri. In these conditions, not only is the outer morphology abnormal but also there is significant disorganization of the cortical layers. Schizencephaly. In schizencephaly, an abnormal cleft connecting the lateral ventricles with the subarachnoid space is seen in one or both cerebral hemispheres. The cleft is entirely lined by dysplastic gray matter that is continuous with the gray matter at the surface of the cerebral hemisphere, giving it an infolded appearance. The walls of the cleft may be fused or separated, referred to as closed-lip and openlip schizencephaly, respectively. Schizencephaly is caused by disturbed neuronal migration during development of the affected region. Porencephaly. Porencephaly consists of a CSF-filled cavity within a cerebral hemisphere (eFig. 40.89). It may or may not communicate with the ventricular system. The cavity may be the result of disturbed development, such as arrested migration of neurons, but it is usually due to destructive lesions such as trauma, ischemic stroke, or hemorrhage that results in loss of brain tissue. In these cases, depending on the stage of development during which the insult occurred, the wall of the porencephalic cyst may be bordered by reactive gliosis that is seen as hyperintense signal change in the adjacent parenchyma on T2

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eFig. 40.87 Heterotopia. A, B, Axial T1- and T2-weighted images demonstrate multiple bilateral heterotopic neuronal nodules bulging into the cavity of the lateral ventricles (arrowheads). Their signal characteristics, accordingly, are identical to that of the cortical gray matter.

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eFig. 40.89 Porencephaly. Sagittal FLAIR image demonstrates a prominent porencephalic cyst in the cerebrum, with cerebrospinal fluid signal characteristics. Note thinning of the overlying calvarium (arrowheads).

eFig. 40.88 Polymicrogyria. Axial T2-weighted image shows an extensive cortical folding anomaly, with abnormally small cortical gyri bilaterally (arrowheads). Note the incidental finding of a cavum septi pellucidi (asterisk).

and FLAIR sequences. In porencephaly, gray matter, if present, does not line the entirety of the cleft, which aids in distinguishing it from schizencephaly. Hydranencephaly. In hydranencephaly, the most profound form of cerebral maldevelopment, almost all of the cerebrum is absent and replaced by a CSF-filled sac. It is thought that hydranencephaly is the result of a destructive process in utero, usually occurring during the second trimester. Possible etiologies include vascular insults, infections,

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placental abnormalities, and toxic drug effects. Maternal smoking has been implicated as a possible cause as well. In hydranencephaly, the tissues supplied by the internal carotid arteries are lost, which explains why the structures supplied by the posterior circulation are usually present (portions of the occipital and temporal lobes, the thalami, basal ganglia, brainstem, and cerebellum). These structures, however, may be atrophic. MRI provides an accurate diagnosis and helps differentiate this condition from severe hydrocephalus, porencephaly, or holoprosencephaly. Lipomas. Lipomas are not tumors but rather congenital malformations due to abnormal differentiation of the primitive meninx. They are composed of mature adipose tissue and considered asymptomatic incidental findings. Most commonly, lipomas are at the

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eFig. 40.90 Pericallosal Lipoma. A, Sagittal FLAIR image shows a curvilinear hyperintensity around the contour of the corpus callosum, consistent with lipoma. Note that there is also dysgenesis of the corpus callosum, mostly affecting the genu and the splenium. B, On an axial T1-weighted image, the lipoma is also hyperintense. C, On an axial T1-weighted fat-suppressed image obtained at the same level as B, the signal from the lipoma is eliminated, now appearing dark (arrows).

midline. A typical location is pericallosal (eFig. 40.90). Other locations include the quadrigeminal plate cistern, cerebellopontine angle, sylvian fissure, basal cisterns, adjacent to the tuber cinereum or optic chiasm, and choroid plexus. Pericallosal lipomas can be curvilinear; with these, some hypoplasia of the corpus callosum may be noted. Tubulonodular lipomas are frequently associated with corpus callosum dysgenesis or other congenital malformations. Since lipomas represent welldifferentiated adipose tissue, they follow the MRI signal characteristics

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of fat: with T1, T2, and FLAIR fast spin echo techniques, they exhibit prominent hyperintensity. They may be missed on T2-weighted images owing to the hyperintensity of adjacent CSF. The hyperintense signal of lipomas is completely suppressed with fat saturation techniques, and this can be helpful to differentiate from hemorrhage on MRI. Because of the radiolucent characteristics of fat, on CT, lipomas are profoundly hypodense.

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eFig. 40.91 Epidermoid Cyst. A, Sagittal T1-weighted postcontrast image reveals a prominent hypointense, nonenhancing cyst (arrow) in the suprasellar area, with local mass effect. B, On the coronal T2-weighted image the cyst is hyperintense (arrow). C, Typical hyperintense signal of the epidermoid cyst (arrows) on the diffusion-weighted image.

Epidermoid. These lesions, also known as squamous epithelial cysts, congenital keratin cysts, or ectodermal inclusion cysts, are formed by epidermal cells. Most epidermoids are congenital and due to the inclusion of epidermal cells of the ectoderm during neural tube closure, but rarely they are acquired secondary to traumatic inoculation of epidermal cells by skin sutures or spinal tap. The most common locations of the congenital type are the basal cisterns, cerebellopontine angle (40%–50%), parasellar region, third or fourth ventricle, temporal horn, and sometimes within the hemispheres. Epidermoids are generally hypointense to brain on T1-weighted images but in 75% of cases are slightly hyperintense to CSF. Sometimes triglyceride and fatty acid deposition in the cyst yield a T1 appearance that is hyperintense to brain, referred to as a white epidermoid. On T2 they are isointense or slightly hyperintense to CSF. On FLAIR, the signal of the cystic contents is not suppressed completely. Importantly, on diffusion-weighted images, epidermoids appear bright because diffusion is restricted. This may be the only imaging feature that reliably distinguishes them from arachnoid cysts (eFig. 40.91). Epidermoids do not enhance with gadolinium. Dermoid. Like epidermoids, dermoids are also ectodermal inclusion cysts. However, in addition to epidermal cells, dermoid cysts also contain derivatives of the dermis, such as cells of sebaceous and sweat glands, hair follicles, and adipocytes. The most common locations are in the midline: sellar, parasellar, frontonasal regions, midline vermis, and fourth ventricle. Dermoids are hyperintense on T1 because of their lipid content, and as a result their signal is diminished with fat suppression sequences. On T2-weighted images, they appear heterogeneous, from hypo- to iso- to hyperintense. Hair content may appear as curvilinear hypointensity. Dermoid cysts do not enhance with gadolinium. At times, dermoid cysts rupture and their hyperintense fat content may be seen scattered in the subarachnoid space on noncontrast T1-weighted images. This may cause chemical meningitis, with associated abnormal enhancement of the meninges. Colloid cyst. Colloid cysts originate from the infolding neuroepithelium of the tela choroidea and are located almost exclusively in the anterior third of the third ventricle at the level of the foramen of Monro. Although histologically benign, colloid cysts represent a potential life-threatening emergency owing to their location. Sudden obstruction of the interventricular foramina of Monro by a colloid

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cyst may even cause acute hydrocephalus, coma, and death due to herniation or neurogenic cardiac dysfunction with subsequent cardiac arrest. The homogeneous signal characteristics of colloid cysts vary depending on the content of the cyst. Most often it is hyperintense on T1- and hypointense on T2-weighted images; this is due to mucus or protein content. If close attention is paid to the anterior third ventricle, the usually hyperintense colloid cyst on T1-weighted images is readily recognizable (eFig. 40.92). A potential problem can arise if the protein content of a colloid cyst is low and results in an isointense rather than hyperintense signal; such a cyst may escape detection. This emphasizes the importance of reviewing all available pulse sequences. Another potential problem is small cyst size. If a colloid cyst is less than 5 mm in diameter, it may be missed if the 5-mm thick slices of a conventional MRI study happen to skip it. The epithelial lining of colloid cysts may appear as a thin rim of enhancement after gadolinium administration. Arachnoid cyst. Arachnoid cysts are extra-axial CSF-filled cysts lined by arachnoid membrane. Considering their structure, the term intra-arachnoid cyst would be more appropriate, as these cysts are formed between the layers of the arachnoid membrane. Arachnoid cysts are frequent incidental findings on MRI. The most common locations are the middle and posterior fossa, the suprasellar region, and at the vertex. In general, arachnoid cysts exhibit CSF signal characteristics, being hypointense on T1 and FLAIR and hyperintense on T2-weighted images (eFig. 40.93). However, the composition of the fluid inside the arachnoid cyst may be different from that of CSF. The fluid secreted by the cyst wall may have higher protein content and therefore appear slightly more hyperintense on T1-weighted images than the CSF. Pulsation, flow turbulence, or (rarely) intracystic hemorrhage may also result in alteration of the signal within the cyst. When evaluating a suspected arachnoid cyst, the pulse sequences should include DWI to distinguish it from an epidermoid cyst. Epidermoid cysts, unlike arachnoid cysts, are hyperintense on DWI. Arachnoid cysts do not enhance with gadolinium. Dilated Virchow-Robin spaces. Enlarged periarteriolar spaces with CSF signal characteristics may be confused with infarction. They are most often seen in the basal ganglia region (type I Virchow-Robin spaces) at the level of the anterior commissure, within the anterior or posterior perforated subspaces. They are also commonly present in the deep white matter of the cerebral hemispheres (type II), most

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eFig. 40.92 Colloid Cyst. A, Axial T1-weighted image reveals a round hyperintense mass in the rostral third ventricle at the level of the interventricular foramen of Monro (arrow). B, Axial T2-weighted image shows the cyst in the same location; hypointensity is due to protein or mucus content (arrow).

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eFig. 40.93 Arachnoid Cyst. A, Axial T1-weighted image shows an extra-axial cyst in the left middle cranial fossa that exhibits cerebrospinal fluid (CSF)-like hypointense signal. There is mass effect with resultant compression and posterior displacement of the left temporal lobe. B, Axial T2-weighted image demonstrates the same arachnoid cyst with CSF-like hyperintense signal.

prominently within the centrum semiovale. Another common location is within the midbrain (type III) at the mesencephalic-diencephalic and ponto-mesencephalic junctions. Enlarged perivascular spaces can usually be distinguished from chronic lacunar infarctions based on their morphological appearance and, on FLAIR images, by absence of a surrounding thin rim of gliotic hyperintensity, which is characteristic of infarction. Occasionally, however, even enlarged perivascular spaces may exhibit a thin T2 hyperintense rim. eFig. 40.94 provides

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examples of enlarged perivascular spaces, including typical as well as less common appearances. Choroid fissure cyst. Choroid fissure cysts are well-demarcated cysts that are seen along the choroid fissure, dorsal to the hippocampus. On axial images they are typically seen alongside the midbrain. Depending on their size, they may exert mild local mass effect, but do not cause any clinical symptoms. They exhibit CSF signal characteristics, being T1 and FLAIR hypointense and T2 hyperintense (eFig. 40.95).

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C eFig. 40.94 Perivascular (Virchow-Robin) Spaces. A, Axial T2-weighted image demonstrates elongated, hyperintense areas in the white matter, representing perivascular spaces (arrowheads). B, Axial FLAIR image reveals extreme enlargement of multiple perivascular spaces (arrows) in the hemispheres. The thin rim of hyperintense signal along the periphery of enlarged perivascular spaces is a potential imaging finding. C, Axial T2-weighted image shows typical location of an enlarged perivascular space (arrow) in the left basal ganglia region, at the level of the anterior commissure. D, Axial T2-weighted image reveals prominence of some of the perivascular spaces in the cerebral peduncles (arrows). This is a very common location for enlarged perivascular spaces. E, Diffuse prominence of the perivascular spaces in the basal ganglia bilaterally (arrows). This imaging appearance, especially when more widespread, is referred to as état criblé.

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eFig. 40.96 Choroid Plexus Cyst. A, Axial FLAIR image demonstrates cystic formations (arrows), in the atria of the lateral ventricles. B, On the diffusion-weighted image the cysts are characteristically hyperintense (arrows).

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Choroid plexus cyst. These benign cysts tend to arise from the glomus of the choroid plexus; hence they are most commonly found in the atria of the lateral ventricles. They are T1 hypointense and T2 hyperintense and at times multiple cysts are seen. They typically exhibit hyperintense signal on diffusion-weighted images (eFig. 40.96). Ependymal cyst. The typical location for these cysts is the body of the lateral ventricle. They exhibit CSF-like signal and are surrounded by a thin wall. These cysts are benign, not invasive, but may reach a considerable size, causing expansion of the involved ventricle segment (eFig. 40.97). Neuroglial cyst. These are well-demarcated intraparenchymal cysts, exhibiting CSF-like signal and no contrast enhancement. Microscopically the wall is composed by glial elements, glial processes/ end feet. Typical locations include the frontal and temporal lobe white matter. They are usually small, but in extreme cases they may be very large, with mass effect. See eFig. 40.98 for examples.

B eFig. 40.95 Choroid Fissure Epithelial Cyst. A, Coronal T2-weighted image reveals a hyperintense, well-demarcated, cyst (arrow) dorsal to the hippocampus. B, Axial FLAIR image demonstrates the cystic formation, which is hypointense (arrow), at the level of the midbrain.

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eFig. 40.97 Ependymal Cyst. A thin-walled cyst (asterisk) in the lateral ventricle, exhibiting cerebrospinal fluid signal characteristics, being hyperintense on (A) T2-weighted and hypointense on (B) T1-weighted images. There is focal expansion of the ventricle due to the cyst.

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eFig. 40.98 Neuroglial Cyst. Two examples are shown. A, Axial FLAIR image demonstrates a small, welldemarcated hypointense cyst in the left anterior temporal lobe white matter (arrow). B, Axial T1-weighted image reveals a large, well-demarcated hypointense cyst in the left hemisphere, which, due to its size, causes sulcal effacement and distortion of the left lateral ventricle.

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Fig. 40.99 Obstructive Hydrocephalus. A–C, In this case of congenital obstructive hydrocephalus, the cerebral aqueduct appears stenotic (small arrow). There is extreme dilatation of the third and lateral ventricles, with the cerebral tissue being extremely thinned. The fourth ventricle is normal in size.

Vascular Malformations The various vascular malformations (AVMs, cavernous malformations, developmental venous anomaly [DVA], and capillary telangiectasia) are discussed in the online version of this chapter, available at http://www.expertconsult.com. See Chapters 66 and 67 for further review. Cerebrospinal Fluid Circulation Disorders Abnormalities in CSF and intraspinal cord flow cause changes in the brain or spinal cord that are readily identifiable by CT or MRI. Hydrocephalus is an abnormal intracranial accumulation of CSF that interferes with normal brain function (see Chapter 88). It should be distinguished from dilation of the ventricles and subarachnoid space due to decreased brain volume, which can be normal or pathological and has been called hydrocephalus ex vacuo. We will avoid using this term, because true hydrocephalus often requires treatment by shunting. Hydrocephalus may follow increased CSF production or impaired resorption. Resorption occurs not only via the pacchionian granulations in the venous sinuses but also through the brain lymphatic system. Traditionally, two main types of hydrocephalus are distinguished: obstructive and nonobstructive. Nonobstructive hydrocephalus is due to increased CSF production, as with choroid plexus papillomas in children. Depending on whether CSF flow from the ventricular system to the subarachnoid space is intact or impeded, we can distinguish between communicating and noncommunicating types of obstructive hydrocephalus. Some processes increase CSF ICP but not the volume of intracranial CSF, causing the syndrome of idiopathic intracranial hypertension (known as pseudotumor cerebri). Interruption of CSF circulation can also happen at the craniocervical junction, where pathologies that interfere with the return of CSF from the spinal subarachnoid space to the intracranial compartment, as happens in the Chiari malformations, can arise. Finally, CSF intracranial volume may be abnormally reduced, causing the syndrome of intracranial hypotension. Obstructive, noncommunicating hydrocephalus. Depending on the site of obstruction, various segments of the ventricular system will enlarge. Obstruction at the foramen of Monro causes unilateral or bilateral enlargement of the lateral ventricles. Aqueductal stenosis,

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which may be congenital, leads to enlargement of the third and lateral ventricles, but the fourth ventricle is normal in size (Fig. 40.99). Obstruction of the foramina of Luschka and Magendie results in enlargement of the third, fourth, and lateral ventricles. Other possible imaging findings include thinning and upward bowing of the corpus callosum. In third ventricle enlargement, the optic and infundibular recesses are widened. When the evolution of the hydrocephalus is rapid, transependymal CSF flow induces a T2 hyperintense signal (best seen on FLAIR sequences) along the walls of the involved ventricular segments, and in the case of the lateral ventricles, most pronounced at the frontal horns. Normal-pressure hydrocephalus. In this type of hydrocephalus, there is enlargement of the ventricles, most pronounced for the third and lateral ventricles (Fig. 40.100). The subarachnoid spaces at the top of the convexity are typically compressed, but the larger sulci, such as the interhemispheric sulcus and the sylvian fissure, may be dilated as well as the ventricles (Kitagaki et al., 1998). In this case, the cross-sections of the dilated sulci often have the appearance of a “U” rather than the appearance of a “V” characteristic of atrophy. These morphological findings are more helpful than flow studies. Increased CSF flow in the cerebral aqueduct may cause a hypointense “jet-flow” sign on all sequences. Quantitative CSF flow studies (cine phasecontrast MR imaging) are frequently used for evaluation of patients with suspected normal-pressure hydrocephalus. However, the distinction between using MRI to diagnose normal-pressure hydrocephalus versus determining the probability of clinical improvement from shunt placement should be kept in mind, as studies seem to show that MRI may be better at the former than the latter. Although CSF flow studies had been thought to help to predict shunt responsiveness (Bradley et al., 1996), later studies have challenged this view (Dixon et al., 2002; Kahlon et al., 2007). Traditionally it has been hypothesized that in this condition there is a problem with CSF absorption at the level of the arachnoid granulations, since normal-pressure hydrocephalus has been observed as a late complication after meningitis or subarachnoid hemorrhage that caused meningeal involvement/scarring. But this syndrome, often associated with vascular disease in older people, may also be the result of decreased superficial venous compliance and a

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Arteriovenous malformations. AVMs are congenital lesions consisting of direct arteriovenous shunts with no intervening capillary network (see Chapters 54, 66, 67). Usually seen within the cerebral hemispheres, AVMs may involve the white matter, the cortical gray matter, or the deep gray nuclei alone or in combination. AVMs of smaller average size may also occur within the cerebellum, brainstem, and spinal cord. Although hemorrhage secondary to AVM is readily detected on noncontrast CT, only large AVMs can usually be detected when hemorrhage is not present. On postcontrast CT, however, AVMs brightly enhance. The classic MRI appearance of AVM consists of an irregular or globoid mass resembling a “bag of worms” with minimal to no mass effect. On T2-weighted images, flow voids are markedly hypointense (black) and correspond to vessels within the nidus, as well as the supplying arteries and draining veins. If present, hemorrhage may vary in signal based on the age of the blood products. On T1, prominent flow voids are also apparent and on postcontrast images, AVMs exhibit bright enhancement. On FLAIR, flow voids may be surrounded by hyperintense signal due to gliosis. The T2* gradient echo technique is highly sensitive for hemorrhage, which will exhibit markedly hypointense “blooming” when present. MRA may detect AVMs greater than 1 cm in size, but even for larger lesions, the detailed angioarchitecture is not visible. CTA is useful to define large supplying arteries and draining veins. Conventional digital subtraction angiography (DSA) remains the gold standard for accurate delineation of feeding arteries and draining veins. DSA is also the most sensitive modality for detecting aneurysms, which are present within the AVM nidus in greater than 50% of cases and often also arise from feeding arteries. Cavernous malformation. Also known as cavernomas or cavernous hemangiomas, these vascular lesions are composed of a compact mass of thin-walled sinusoidal vessels with no neural tissue between them (see Chapters 66 and 67). Cavernomas may occur anywhere within the neuraxis, most commonly the cerebral hemispheres but also the brainstem, cerebellum, and spinal cord. Chronic microhemorrhage within the lesion is a characteristic feature, which may result in slow enlargement over time. A cavernoma may be an incidental asymptomatic finding, but patients can also present with headaches or seizures. Large hemorrhages are rare. Usually seen in isolation, multiple lesions may occur in familial cases, and coexistent DVAs may be seen. On CT, cavernous malformations appear as round, heterogeneous hyperdensities, with the central portion more hyperdense than the periphery. This hyperattenuation is due to calcification, hemosiderin deposition, and increased blood within the vascular portion of the lesion. In cases of acute to subacute hemorrhage within a cavernoma, perilesional edema and mass effect may be seen. On MRI, the signal changes are heterogeneous, generally with two concentric zones of mixed intensity on T1- and T2-weighted images. Both hypo- and hyperintense signal findings are seen, depending on the age of blood products. The most typical MR imaging finding is a “popcorn-ball”

appearance on T2, with a heterogeneously hyperintense core of blood products surrounded by a rim of characteristically dark hypointensity due to hemosiderin deposition. With T2* and other gradient echo techniques, cavernomas appear as more prominent areas of hypointensity, appearing larger than they actually are (“blooming” artifact) owing to the sensitivity of these pulse sequences to magnetic field distortion by blood products. With gadolinium, enhancement varies from minimal to prominent and is largely due to accumulation of contrast within the vascular component of the lesion. Their slow flow may make cavernomas angiographically silent. Developmental venous anomaly. DVAs (also termed venous angiomas) appear as brightly enhancing draining veins in abnormal locations, usually within the white matter of a cerebral hemisphere or the cerebellum. The basic structure consists of a straight or curvilinear parent or “collector” vein with multiple smaller, radially oriented tributary veins at one end. The characteristic appearance of this “spoke-wheel” structure has been termed caput medusa. When present within a cerebral hemisphere, the DVA is often prominently seen coursing through the intervening white matter from a ventricle to the ipsilateral cortical surface. The parent vein may be contiguous with a dural venous sinus or drain into a deep ependymal vein at its ventricular end. Venous angiomas are often invisible on T1 and T2 but may be seen as a faint flow void, depending on the size of the lesion and the spatial resolution of the image. Their characteristic structure usually can be easily appreciated on volumetric gradient echo pulse sequences, on which the luminal signal appears markedly hypointense. DVAs are rarely associated with symptomatic hemorrhage (0.34% per year) and are incidental asymptomatic findings in the majority of cases. Their presence may coincide with that of cavernoma in the same patient and in unusual instances when the two are contiguous, the finding is termed a mixed vascular malformation. Capillary telangiectasia. Capillary telangiectasias are usually subcentimeter in size and are not associated with mass effect, edema, or surrounding gliosis. Rarely they may exhibit symptoms or signs referable to their location (Beukers and Roos, 2009; Morinaka et al., 2002). Given the typical pontine location, which tends to be somewhat obscured by beam-hardening artifact on CT, capillary telangiectasias are usually not detected with this modality despite their tendency to occasionally calcify. On MRI, capillary telangiectasias are also generally not detectable using T1-weighted images. On T2-weighted pulse sequences, a capillary telangiectasia may be visible as a faint, diffusely round patch of hyperintense signal, but equally as often, it is not discernible from normal brain parenchyma. The modalities of choice for the detection of capillary telangiectasias are T2* (T2-star) gradient echo (Lee et al., 1997) and SWI (Yoshida et al., 2006), on which the lesions appear moderately to prominently hypointense due to the slow-flowing deoxygenated blood, which is paramagnetic. On postcontrast images, a capillary telangiectasia will often appear as a small patch of faint enhancement.

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Fig. 40.100 Two Cases of Normal-Pressure Hydrocephalus. In the first case (A) axial noncontrast T1-weighted images demonstrate significant enlargement of the ventricles, which is clearly out of proportion to the size of the superficial cerebrospinal fluid (CSF) spaces. The parietal sulci appear somewhat effaced. B, Coronal T2-weighted image also exhibits prominent ventricular enlargement. Note intraventricular artifact due to CSF pulsation (arrowheads), indicating hyperdynamic flow. The second case demonstrates communicating hydrocephalus. Images C–F are axial sections of the MRI from a 71-year-old woman with progressive gait and cognitive impairment, as well as urinary incontinence. Note the low signal in the sylvian aqueduct, owing to a flow void from high-velocity CSF flow through this structure (C, arrow). Although basal cisterns (C) and interhemispheric and sylvian fissures (D, E) are dilated, sulci in the high convexity (F) are compressed. Trans-ependymal reabsorption of CSF, suggested by the homogeneous high signal in the periventricular white matter (E), need not occur in all cases of symptomatic hydrocephalus. In addition to the compressed sulci in the convexity, the U-shape of some of the dilated sulci (E, white arrows) is helpful to make the diagnosis.

reduction in the blood flow returning via the sagittal sinus (Bateman, 2008). The term normal pressure is a misnomer because long-term monitoring of ventricular pressure has shown recurrent episodes of transient pressure elevation. Chiari malformation. Depending on associated structural abnormalities, different types of Chiari malformation are distinguished. In the most common, type 1 Chiari, there is caudal displacement of the tip of the cerebellar tonsils 5 mm or more below the level of the foramen magnum. Most often this malformation is accompanied by a congenitally small posterior fossa. However, acquired forms of tonsillar descent also exist, either due to space-occupying intracranial pathology or to a low-pressure environment in the spinal canal, such as after lumboperitoneal shunt placement. In typical Chiari 1, the

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ectopic cerebellar tonsils are frequently peg shaped, but otherwise the cerebellum is of normal morphology. There is usually crowding of the structures at the level of the foramen magnum. The 5-mm diagnostic cutoff value has been selected in adults, as this condition tends to be symptomatic and clinically significant at this or higher measured values. If the tonsils are caudal to the level of the foramen magnum by less than 5 mm, the term low-lying cerebellar tonsils is used; this is frequently an asymptomatic incidental finding. When evaluating younger patients or children, it is to be remembered that the considered “normal” position of the cerebellar tonsils is different in the various age groups. In the first decade, 6 mm below the foramen magnum is considered the upper limit of normal, and with increasing age, there is an “ascent” of the tonsils, with a 5-mm cutoff value in the second and

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Fig. 40.101 Chiari Type 1 Malformation. Sagittal T2-weighted image demonstrates caudal displacement of the cerebellar tonsil through the foramen magnum into the cervical spinal canal (arrowhead). The tonsil is characteristically peg-shaped. There is a prominent longitudinal hyperintense cavity in the visualized cervical spinal cord segment, consistent with a syrinx (arrows).

third decades, 4 mm up to the eighth decade, and 3 mm in the ninth decade of life (for review see Nash et al., 2002). Tonsillar ectopia and crowding at the foramen magnum interfere with return of CSF from the spinal to the intracranial subarachnoid space. This may lead, by still-disputed mechanisms, to syrinx formation in the spinal cord (Fig. 40.101). If there is imaging evidence of a Chiari malformation on brain MRI, it is essential to image the cervical and thoracic cord to rule out a syrinx. In Chiari type 2 malformation, there is a developmental abnormality of the hindbrain and caudal displacement not only of the cerebellar tonsils but also the cerebellum, medulla, and fourth ventricle. The cervical spinal nerve roots are stretched/compressed, and there is often a spinal cord syrinx present. Other abnormalities include lumbar or thoracic myelomeningocele; hydrocephalus is often present as well. Chiari type 3 malformation is an even more severe developmental abnormality, with cervical myelomeningocele or encephalocele.

For a description of idiopathic intracranial hypertension (pseudotumor cerebri) and of the imaging sequelae of intracranial hypotension, see the online version of this chapter at http:// www.expertconsult.com. Orbital Lesions The structural neuroimaging of orbital lesions is discussed online at http://www.expertconsult.com.

Spinal Diseases Spinal Tumors Tumors affecting the spinal region can be classified according to their predominant location, intrinsic to the vertebral column itself or within the spinal canal. Spinal canal tumors may be intramedullary or extramedullary. Intramedullary tumors involve the spinal cord parenchyma, whereas extramedullary tumors are outside the spinal cord

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but within the spinal canal. Depending on their relation to the dura, extramedullary tumors may be classified as intradural or extradural. As tumors grow, they can spread to other compartments. For example, metastases in the vertebral bodies often extend to the epidural space and cause spinal cord compression. Tumors in pre- and paravertebral locations may also extend to the extradural space, either through the vertebral bodies, as happens with metastatic lung cancer, or through the neural foramina, as in lymphoma. Vertebral metastases, extradural tumors. In the majority of cases, tumors involving the vertebrae are metastatic in origin. Half of all vertebral metastatic tumors are from lung, breast (Fig. 40.106), and prostate cancer. Kidney and gastrointestinal tumors, melanoma, and those arising from the female reproductive organs are other common sources. Of all structural neuroimaging techniques, MRI is the imaging modality of choice to evaluate vertebral metastases, with sensitivity equal to and specificity better than bone scan (Mechtler and Cohen, 2000). MR imaging protocols for the evaluation of vertebral metastases typically include T1-weighted images with and without gadolinium, T2-weighted images, and STIR sequences. Typically, osteolytic metastases appear as hypointense foci on noncontrast T1-weighted images, hyperintense signal on T2 and STIR sequences, and enhance on postcontrast images. The enhancement may render the previously T1 hypointense metastatic foci isointense, interfering with their detection. Therefore, precontrast T1-weighted images should always be obtained as well. Osteoblastic metastases, such as seen in prostate cancer, are hypointense on T2-weighted images. Besides the vertebral bodies, metastases preferentially involve the pedicles. With marked involvement, the vertebral body may collapse. Extradural tumors most commonly result from spread of metastatic tumors to the epidural space, directly from the vertebral body or from the prevertebral/paravertebral space. These mass lesions in the epidural space initially indent the thecal sac, and, as they grow, they displace and eventually compress the spinal cord or cauda equina. If spinal cord compression is long-standing and severe enough, T2 hyperintense signal change may appear in the involved cord segment as a result of edema and/or ischemia secondary to compromised local circulation. An example of tumor spread from a paravertebral focus is lymphoma, which may extend into the spinal canal through the neural foramen. When intraspinal extension is suspected in a patient with lymphoma, MRI is the study of choice (Fig. 40.107). In cases of epithelial tumors, by the time of presentation, plain radiographs reveal the intraspinal extension with more than 80% sensitivity, but in patients with lymphoma, plain radiographs are still normal in almost 70% of cases (Mechtler and Cohen, 2000). In the smaller group of extradural primary spinal tumors, multiple myeloma is the most common in adults. Involvement of the vertebral bone marrow may occur in multiple small foci, but diffuse involvement of an entire vertebral body is also possible. Myelomatous lesions are hypointense on T1-, hyperintense on T2-weighted images, and highly hyperintense on STIR sequences. There is marked enhancement after gadolinium administration. Extramedullary intradural spinal tumors. This group of tumors includes leptomeningeal metastases, meningiomas, nerve sheath tumors, embryonal tumors (teratoma), congenital cysts (epidermoid, dermoid), and lipoma. Leptomeningeal metastases. Leptomeningeal metastases result from tumor cell infiltration of the leptomeningeal layers (pia and arachnoid). Non-Hodgkin lymphoma, leukemia, breast and lung cancer, melanoma, and gastrointestinal cancers are the most common sources of metastases. Leptomeningeal seeding also occurs from primary CNS tumors such as malignant gliomas, ependymoma,

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Idiopathic intracranial hypertension (pseudotumor cerebri). In idiopathic intracranial hypertension, or pseudotumor cerebri, there is elevated ICP of unknown origin. The diagnosis is made by history, examination findings of raised ICP (papilledema), and after an imaging study has ruled out a mass, a lumbar puncture (LP) to demonstrate the elevated opening pressure. Imaging findings in this condition are nonspecific, such as small, “slitlike” ventricles, enlargement of the optic nerve sheaths (well seen on thin-slice T2-weighted images) and an “empty sella,” which is due to flattening of the pituitary gland at the floor of the sella turcica, presumably due to the raised ICP that also involves the suprasellar cistern. A flattened shape of the pituitary gland is not rare, and in the absence of the appropriate clinical context, the diagnosis of an empty sella syndrome should be avoided. In the “true” empty sella syndrome, seen in intracranial hypertension, the flattening of the gland may be reversible after decreasing the ICP. In a number of intracranial hypertension cases, structural CT or MRI or MRV will disclose a sinus thrombosis as the cause of the syndrome. Intracranial hypotension. Various conditions may lead to decreased ICP. The most common cause is CSF leakage, which can be present after an LP but may also be seen after skull base trauma, neurosurgical procedures, overdraining shunts, or as the consequence of arachnoid ruptures caused by forceful Valsalva maneuvers such as coughing. Often there is no obvious cause. Decreased CSF volume may cause caudal displacement of various structures, including the cerebellar tonsils and optic chiasm. There may be effacement of the basal (prepontine) cistern due to ventral displacement of the pons. After gadolinium administration, there is striking diffuse enhancement of the pachymeninges and supra- and infratentorial dura, but not of the leptomeninges (eFig. 40.102). This finding is thought to be due to compensatory dural venous dilatation. In more severe cases with displacement of the brain, subdural hygromas may also develop.

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eFig. 40.102 Intracranial Hypotension. Axial T1-weighted postcontrast image reveals intense gadolinium enhancement of the pachymeninges, presumably due to venous dilatation. Note that the leptomeninges are normal in appearance.

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eFig. 40.103 Retinoblastoma. A, On axial T2-weighted image, the tumor is well seen as a relative hypointensity against the hyperintense background in the right globe. B, The mass enhances on the coronal fat-suppressed, contrast-enhanced T1-weighted image. C, Axial noncontrast computed tomography scan demonstrates hyperdense areas of calcification within the tumor.

For evaluation of intraorbital pathology, MRI is generally superior to CT; however, bone window CT images are excellent for assessment of traumatic changes such as fracture of the orbital walls or air entrapment after injury. For assessment of soft-tissue pathology within the orbits, specific MRI protocols have been developed. These typically include thin-slice sagittal, coronal, and axial T2-weighted images and T1-weighted images with and without gadolinium. These sequences are often combined with fat suppression techniques, because the elimination of signal from the extra- and intraconal fat increases contrast and helps delineate pathology. Ocular tumors. Melanoma and retinoblastoma are the most common ocular tumors. Melanomas may arise from various structures of the globe including the choroidea, iris, ciliary body, conjunctiva, or the lacrimal sac. The signal intensity of the tumor depends on the amount of melanin and the associated hemorrhage, if any. Typically, melanin causes hyperintense signal change on T1 and hypointensity on T2-weighted images. The tumor enhances after gadolinium administration. Fat suppression techniques are very useful in these cases; the T1 hyperintense signal and gadolinium enhancement stand out well against the suppressed background signal. Retinoblastoma is a common malignancy of early childhood (eFig. 40.103). The signal intensity is variable. The tumor may not be conspicuous on T1-weighted images, where the vitreous signal is also hypointense, but on T2-weighted images, the hypointense signal of the tumor is in sharp contrast to the hyperintense vitreous body. The signal of the tumor may change if hemorrhage or calcification occurs. Calcification is well seen on CT. Optic nerve tumors. In the group of optic nerve tumors, we distinguish those arising from the optic nerve itself, such as optic nerve glioma, and those arising from its covering, such as optic nerve sheath meningioma. Optic nerve gliomas are common findings in NF type 1. They cause expansion of the nerve to a variable degree, and often the arachnoid covering also shows hyperplasia. Optic nerve gliomas are low-grade astrocytomas, appearing isointense on T1-weighted images. On T2,

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intraorbital gliomas are usually hypointense, whereas retro-orbital segment tumors are hyperintense. Optic gliomas typically enhance after gadolinium administration. Optic nerve sheath meningiomas, like other meningiomas, enhance intensely and homogeneously with gadolinium and can be very well visualized on T1 postcontrast fat-suppressed images. This technique confirms its origin from the optic nerve sheath and reveals its extent. Thyroid ophthalmopathy. The most characteristic structural imaging finding in thyroid ophthalmopathy is thickening of the extraocular muscles, most often involving the inferior and medial rectus muscles. It is usually bilateral, and the tendon of the muscles is typically spared. Isolated lateral rectus involvement is against this diagnosis and suggests myositis of other cause. Owing to enlargement of the muscles, there is crowding around the optic nerve, which may be compressed. Enlargement of the superior ophthalmic vein is also frequently seen. When the globes are proptotic, the optic nerves appear unusually straight (eFig. 40.104). Optic neuritis. MRI can be very helpful in confirming the clinically suspected diagnosis of optic neuritis (see Chapters 16 and 80) by revealing the signal change caused by inflammation of the nerve. This is best appreciated on fat-suppressed thin-slice T2-weighted and T1 postcontrast images. On T2-weighted images, the inflamed nerve segment is hyperintense, and, after gadolinium, focal enhancement is seen (eFig. 40.105). If the disease occurs as part of MS, the characteristic white matter lesions are seen on the brain images. Orbital pseudotumor. Orbital pseudotumor is a diffuse inflammatory process that may involve the sclera and uvea, but a retrobulbar mass and myositis/thickening of the extraocular muscles is common. As opposed to lymphoma, which is often a differential diagnostic consideration, the inflammatory tissue is hyperintense on T2-weighted images. The myositis caused by this condition should be differentiated from thyroid ophthalmopathy in Graves disease. Contrary to Graves disease, in orbital pseudotumor the bulbar insertion of the muscles is involved.

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eFig. 40.104 Thyroid Ophthalmopathy. A, Axial T1-weighted image of the orbit demonstrates enlargement of the medial rectus muscle but sparing of its tendon. B, C, Axial and coronal T2-weighted images demonstrate enlargement and hyperintense signal of the medial rectus and superior rectus muscles. D, Axial T1-weighted postcontrast image shows enhancement of the enlarged medial rectus muscle. Note proptosis of the globe on axial images.

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D eFig. 40.105 Optic Neuritis. MRI from a 36-year-old woman with multiple sclerosis, complaining of left eye visual loss and pain when moving the eye. A, B, Axial and coronal T2-weighted images demonstrate hyperintense signal in intraforaminal and prechiasmatic segments of left optic nerve (arrowheads). C, D, On axial and coronal T1-weighted postcontrast images, involved optic nerve segments exhibit intense enhancement (arrows).

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Fig. 40.106 Spinal Metastasis. MRI from a 52-year-old woman with breast cancer. A, Sagittal T1-weighted image reveals hypointense signal in two adjacent vertebral bodies (arrowheads). Metastatic mass extends beyond the vertebral bodies into the epidural space (arrow). B, Sagittal T1-weighted, fat-suppressed postcontrast image better delineates the extent of the tumor. C, Axial postcontrast image demonstrates tumor spread toward the pre- and paravertebral space (arrowheads), into the epidural space (small arrows) and into the pedicle (double arrowheads).

Fig. 40.107 Lymphoma. A left paravertebral tumor (arrow) extends through the left neural foramen into the cervical spinal canal (arrowheads).

and neuroblastomas. The optimal imaging modality to detect leptomeningeal seeding is gadolinium-enhanced MRI, which reveals linear or multifocal nodular enhancing lesions along the surface of the spinal cord or nerve roots. The diagnostic yield can be improved by using higher doses of gadolinium. Spinal meningiomas. Most (90%) spinal meningiomas are intradural, but extradural extension also occurs. The tumors displace/ compress the spinal cord or nerve roots. MRI signal characteristics can be variable: they often exhibit isointense signal to the spinal cord on both T1- and T2-weighted images, but T2 hypointensity may also be seen. Similar to intracranial meningiomas, these tumors enhance in an intense homogeneous fashion (Fig. 40.108). In patients with NF type 2, the entire spine should be imaged because multiple meningiomas may be present. Nerve sheath tumors and embryonal tumors that belong to this group of spinal tumors are described in the online version of this chapter, available at http://www.expertconsult.com. Intramedullary tumors. The most common primary spinal cord tumors are astrocytomas and ependymomas, representing 80%– 90% of all primary malignancies. For best structural assessment of

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intramedullary tumors (primary and metastatic), MR imaging with and without gadolinium should be obtained. Ependymoma. Ependymomas are more common in males and in about 50% of cases involve the lower spinal cord in the region of the conus medullaris and cauda equina. The myxopapillary type arises from the ependymal remnants of the filum terminale. Ependymomas are usually well demarcated and may exhibit a T1 and T2 hypointense pseudocapsule. This is important from a surgical standpoint, because these tumors may usually be removed with minimal injury to the surrounding cord parenchyma. The involved cord is expanded. On T1-weighted images, ependymomas are usually isointense to the spinal cord or, rarely, hypointense. On T2-weighted images, they are usually hyperintense relative to the spinal cord. The tumor may have a hemorrhagic component as well, in which case the signal characteristic is usually heterogeneous, depending on the stage of the hemorrhage. Ependymomas are often associated with a rostral or caudal cyst, which is hypointense on T1- and hyperintense on T2-weighted images. With gadolinium, intense homogeneous enhancement is seen within the solid portion of the tumor. Astrocytoma. Astrocytomas occur in both the pediatric and adult populations. Their peak incidence is in the third to fifth decades of life. They have a preference for the thoracic cord segments. Up to three quarters are low grade. They exhibit T1 hypointensity and appear hyperintense on T2-weighted images. Although the tumor margin is usually poorly defined, subtotal resection is often possible. A cyst or syringomyelic cavity is associated with spinal cord astrocytoma in up to 50% of cases. Contrary to intracranial low-grade gliomas, spinal astrocytomas typically enhance, often in a heterogeneous fashion (Fig. 40.110). Intramedullary metastases. Lung and breast cancer are the most common sources of intramedullary metastases, but lymphoma, colorectal cancer, and renal cell cancer may also metastasize to the cord. Metastases have some preference for the conus medullaris but may be multiple in 10% of cases and involve other cord segments as well. Their signal intensity varies; mucus-containing breast or colon cancer metastases can be hyperintense on noncontrast T1-weighted images. On postcontrast images, intense enhancement is seen, which may be homogeneous or ringlike. Associated edema is frequently seen as surrounding T1 hypointensity and T2 hyperintensity. The cord may be expanded to variable degrees.

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Neurological Investigations and Interventions inferior to the cartilage endplate. Infection of the subchondral region of a vertebral body results in subsequent perforation of the vertebral endplate, leading to infection of the intervertebral disk, or diskitis. The infected disk decreases in height and in conjunction with spread of infection through the disk, the adjacent vertebral body is infected. In children, a direct hematogenous route to the disk can cause diskitis to occur before the development of osteomyelitis. Diskitis and osteomyelitis are typically hypointense relative to normal disks and vertebrae on T1-weighted images and hyperintense on T2-weighted images, indicating edema. On STIR, markedly hyperintense signal correlates with the signal changes on T1 and T2. There is destruction of the endplates and, therefore, the endplate/disk margin is poorly seen. With gadolinium, there is enhancement of the infected marrow and irregular peripheral enhancement at the periphery of the involved disk (Fig. 40.112). Pathological fractures of the infected vertebrae may also be seen. Epidural abscess, paravertebral phlegmon. The pathologies of epidural abscess and paravertebral phlegmon are most commonly seen as complications of diskitis and osteomyelitis. Since epidural abscess and resultant spinal cord compression represent a neurological emergency, besides the affected vertebral bodies and disks, it is important to always evaluate the epidural space for abscess and the paraspinal tissues for phlegmon (purulent inflammation and diffuse infiltration of soft or connective tissue) if diskitis and/or osteomyelitis are seen. Epidural abscess may be missed on conventional T1- and T2-weighted images because its signal characteristics may blend in with its surroundings. The central portion of the abscess may exhibit hyperintensity similar to CSF on T2-weighted images while exhibiting iso- to hypointense signal relative to the spinal cord on T1-weighted images. With gadolinium administration, however, intense enhancement is noted (Fig. 40.113). Just as may occur with compression due to epidural tumors, the compressed spinal cord segment may exhibit T2 hyperintense signal alteration. Phlegmon in the paravertebral tissues also enhances peripherally with gadolinium. This paravertebral infectious process is also well seen on STIR sequences as hyperintensity against the hypointense signal of the fat-suppressed bone marrow background.

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B Fig. 40.108 Two Cases of Meningioma. A, Sagittal T2-weighted image demonstrates a hypointense extramedullary dural-based mass lesion that causes marked spinal cord compression (arrow). B, Sagittal T1-weighted postcontrast image reveals an extramedullary dural-based mass lesion in a similar location. The mass enhances homogeneously (arrow).

Vascular Disease This section is available online at http://www.expertconsult. com. Refer to Chapter 69. Infection Infections of the spine may involve the disk spaces as well as the vertebral bodies. Neurological emergency occurs when the infection proceeds to the epidural space, leading to abscess formation that can result in spinal cord compression. Diskitis and osteomyelitis. The most common pathogen responsible for diskitis and osteomyelitis is Staphylococcus aureus. The most common route of transmission is hematogenous, and in these cases the lumbar spine is involved most frequently, usually at the L3/4 or L4/5 levels. Contiguous spread of infection may also occur, and postoperative causes (such as after instrumentation) have been documented as well. In adults the diskitis/osteomyelitis complex generally begins with infection of the subchondral bone marrow

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Noninfectious Inflammatory Disorders Multiple sclerosis. MS (see Chapter 80) commonly affects the spinal cord. Simultaneous cerebral demyelinating lesions are usually seen in the same patient (Matsushita et al., 2010). On MRI studies of the spinal cord in MS patients, the cervical segments are most commonly involved (Fig. 40.114). The lesions are hyperintense on T2-weighted images and are seen even more conspicuously on sagittal STIR sequences. The lower signal-to-noise ratio of STIR makes this sequence less specific than T2-weighted images for cord lesions, but it is more sensitive. STIR is generally useful only in the sagittal plane, and findings on this sequence should always be correlated with T2 images. Lesional signal changes with either technique are patchy and segmental, often discretely overlapping with the dorsal, anterior, or lateral columns of the spinal cord. The lateral and dorsal columns are affected most frequently. The signal changes are usually in the peripheral regions of the cord, but individual lesions may intersect with the central cord gray matter as well. In MS, the lesions typically do not span more than two vertebral lengths rostrocaudally and tend to involve less than half of the cross-section of the cord. Following administration of gadolinium, active cord lesions may exhibit homogeneous or open-ring enhancement. Large active MS lesions may cause swelling, with local expansion of the cord. In patients with a severe clinical picture or a long-standing history of MS, varying degrees of spinal cord atrophy may be seen. In less severe cases, volumetric analysis may reveal atrophy not detectable by visual inspection.

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Nerve sheath tumors. Nerve sheath tumors include schwannomas and neurofibromas. Neurofibromas are characteristic for NF type 1 and are often multiple, whereas schwannomas are unusual in NF type 1 and are usually solitary. Two-thirds of these tumors are intradural, others also extend to the extradural space through the neural foramina in a dumbbell-shaped fashion, and there is another group that is entirely extradural. The tumor may cause enlargement of the neural foramen, and the intraspinal portion may displace/compress the spinal cord. On MRI, the signal is isointense to the spinal cord on T1- and hyperintense on T2-weighted images. Contrast enhancement is homogeneous (eFig. 40.109). Neurofibromas and schwannomas have similar signal characteristics but are typically different in shape: schwannomas result in eccentric enlargement of the nerve root,

whereas neurofibromas cause diffuse thickening. Schwannomas may undergo cystic degeneration, resulting in a T1 hypointense center that does not enhance. Hemorrhagic transformation and calcification may also be present. Embryonal tumors. Epidermoid and dermoid cysts, teratomas, and lipomas represent 1%–2% of all primary spinal tumors. Their presence warrants evaluation for other possible developmental abnormalities such as spina bifida or diastematomyelia. Teratomas are of mixed and variable signal intensity depending on their tissue contents. Lipomas are hyperintense on noncontrast T1-weighted images, and their signal is fully suppressed on STIR sequences. Cervical and thoracic lipomas may be intramedullary as well. Lumbosacral lipomas are often seen in the setting of a tethered cord.

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eFig. 40.109 Neurofibromatosis. A, Sagittal postcontrast image demonstrates prominent enlargement of two neural foramina due to neurofibromatous enlargement of the exiting nerve roots (arrows). B, Axial T1-weighted image reveals enlarged nerve root due to neurofibroma (arrow). Note the plexiform neurofibroma (arrowheads) in the left paraspinal muscle, which is easy to miss in this noncontrast image. C, Axial T1-weighted postcontrast image better shows the enhancing enlarged nerve root (arrow) and the plexiform neurofibroma (arrowheads).

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Spinal cord infarction. The spinal cord is supplied by three longitudinally oriented arteries: one anterior spinal artery (ASA) and two posterior spinal arteries (PSAs). Superiorly, these arteries originate from the vertebral arteries. Their blood supply to the cord is supplemented by segmental anterior and posterior radicular feeder arteries that, originating in posterior intercostal arteries from the aorta, pass through the neural foramina alongside the nerve roots. Additional medullary feeder arteries arising from segmental spinal arteries supplement the spinal cord circulation, the largest of which is the great radicular artery of Adamkiewicz, entering approximately at the level of T11. Radicular and medullary feeder arteries to the ASA are not present at all thoracic spinal cord levels; thereby a watershed zone is present between these arteries, which can be in either the upper or the midthoracic region of the cord. Severe hypotension or occlusion of these key feeding branches can result in watershed infarctions in these regions. In ASA occlusion, the infarct is longitudinal and involves the anterior two-thirds of the cord. In the acute stage, the involved cord segment may be slightly expanded. The ischemic area appears hyperintense at this stage on T2-weighted images. In the subacute phase, areas of gadolinium enhancement may be seen within the ischemic lesion. In the chronic stage, cord atrophy may be noted. Arteriovenous malformation. Different subtypes of AVMs are distinguished depending on their location within the spinal canal. Intramedullary AVMs have an intramedullary nidus, sometimes with extension to the subpial zone. In the case of mixed (intraand extramedullary) AVMs, the nidus has extramedullary or even extraspinal extension (eFig. 40.111). Another type of spinal AVM is also intradural, but the nidus is extramedullary. MRI is more helpful than CT in depicting AVMs. In the case of intramedullary AVMs, T1-weighted images reveal an enlarged cord with flow voids and usually mixed signal intensity due to blood degradation products. On T2-weighted images, hyperintense signal is seen that may represent

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edema, ischemia, gliosis, or a combination of these, but hypointense signal zones due to flow voids and blood degradation products may also be encountered. After gadolinium administration, the nidus and vessels enhance, and sometimes cord parenchymal enhancement is also seen. In pure extramedullary AVMs, the large flow voids may displace the cord. On T2-weighted images, cord hyperintensity may be present, and with gadolinium enhancing, pial and epidural vessels are seen. Manufacturer-specific MRI pulse sequences exist to improve visualization of these vessels. Dural arteriovenous fistula. Dural arteriovenous fistula is the most common spinal AVM. In this malformation, the arterial blood is drained via a dilated intradural vein. The pial vessels are often enlarged. CT usually reveals cord enlargement and enhancing pial veins. On MRI, the cord is enlarged, with areas that are hypointense on T1- and hyperintense on T2-weighted images. Sometimes T2 hyperintense signal change within the cord is the only finding. T2-weighted images may also reveal hypointense flow voids corresponding to dilated pial veins. These enhance with gadolinium. A hypointense flow void corresponding to the fistula may also be visualized, but the best imaging modality remains spinal angiography. Cavernous malformation. Cavernous malformations may present as intramedullary lesions within the spinal cord as well as intra-axial lesions of the brain. They are composed of thin-walled sinusoidal vessels with no neural tissue between them. They are usually not visualized by CT scan. On MRI, the signal changes are mixed; T1 and T2 hypo- and hyperintensities are seen, depending on the age of blood products. The most typical MR imaging finding is the “popcorn ball” appearance, with a heterogeneous/hyperintense core of blood products surrounded by a rim of marked hypointensity on T2-weighted images; this is due to hemosiderin deposition. With gradient echo techniques, cavernomas appear as more prominent areas of hypointensity (“blooming”), owing to the sensitivity of this pulse sequence to magnetic field distortion by paramagnetic blood products. With gadolinium, very faint if any enhancement is seen. Cavernomas are not visualized by angiography.

B eFig. 40.111 Mixed (Extra- and Intramedullary) Spinal Arteriovenous Malformation. A, Sagittal T2-weighted image demonstrates a lesion with mixed signal intensity, containing multiple hypointense flow voids of various sizes, consistent with a vascular malformation (arrows). B, Axial T2-weighted image reveals that this malformation has a prominent intramedullary component as well (small arrows).

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Fig. 40.110 Astrocytoma. A, Sagittal T1-weighted image reveals prominent expansion of the cervical and upper thoracic cord due to a T1 hypointense intramedullary tumor. B, Sagittal T2-weighted image demonstrates the hyperintense mass. C, Sagittal T1-weighted postcontrast image reveals a patchy heterogeneous pattern of enhancement.

Fig. 40.112 Diskitis and Osteomyelitis. Two levels are involved (arrows). Sagittal T1-weighted postcontrast image demonstrates decreased disk height and destruction of the adjacent endplates. With gadolinium, there is irregular enhancement of the infected marrow.

Neuromyelitis optica. Acute spinal cord involvement presents with bright spotty T2 lesions with corresponding T1 prolongation, spanning at least three vertebral segments, known as longitudinally extensive transverse myelitis (LETM; Fig. 40.115). The central gray matter along the central canal of the spinal cord is the preferred area of involvement, as it corresponds to the most prominent expression of the AQP4 antigen (Dutra et al., 2018; Wingerchuk et al., 2015). Following

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contrast administration, patchy or lens-shaped enhancement of the aforementioned lesions in sagittal view can be distinctive for NMO (see Fig. 40.115, C). Although the LETM pattern is characteristic of NMOSD, 7%–14% of myelitis attacks in AQP4-IgG-seropositive patients do not meet the LETM definition. Therefore, NMOSD must also be considered in the differential diagnosis in patients presenting with short myelitis lesions (Wingerchuk et al., 2015). In the chronic phase, sharply demarcated extensive atrophy with or without T2 signal changes are visible. Acute disseminated encephalomyelitis. The widespread demyelinating lesions in this condition commonly involve the spinal cord as well. Diffuse or multifocal T2 hyperintense signal changes with variable degrees of cord swelling may be seen (Fig. 40.116). There is a variable amount of enhancement after gadolinium administration. Transverse myelitis. Transverse myelitis is an inflammatory disorder of the spinal cord that involves the gray as well as the white matter. The inflammation involves one or more (typically 3–4) cord segments and usually more than two-thirds of the cross-sectional area of the cord (Fig. 40.117). Transverse myelitis etiologies include viral infection, postviral or post-vaccine autoimmune reactions, vasculitis, mycoplasma infection, syphilis, antiparasitic and antifungal drugs, and even intravenous heroin use (Sahni et al., 2008). Brain MRI abnormalities suggestive of MS and a history of clinically apparent optic neuritis exclude the diagnosis of idiopathic transverse myelitis. The imaging modality of choice is MRI. Acutely, there is T2 hyperintense signal change and cord swelling. In more severe cases, hemorrhage and necrosis may also occur. Following gadolinium administration, diffuse or multifocal patchy enhancement is seen. In the subacute and chronic stages, the swelling and enhancement subside, and the T2 hyperintense signal decreases in extent. In the chronic stage, there may be a variable amount of faint residual T2 hyperintensity. In more severe cases, focal cord atrophy or myelomalacia may be seen.

Spinal sarcoidosis and vacuolar myelopathy are described online at http://www.expertconsult.com.

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Sarcoidosis. Spinal cord sarcoid lesions occur in less than 1% of patients with sarcoidosis (Maroun et al., 2001). The cervical and upper thoracic regions are preferentially affected. The disease involves the leptomeninges as well as the spinal cord parenchyma. The cord lesions are multiple, with a tendency to be located at the periphery, reaching the cord surface with a broad base. In active disease the cord may be enlarged, while it may become atrophic in the chronic stage. Following gadolinium administration, leptomeningeal enhancement may be seen together with a variable number of enhancing parenchymal lesions. Sarcoidosis can simultaneously involve the peripheral nervous system as well, and, in these cases, enhancement and sometimes nodular thickening of the nerve roots may be present.

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Vacuolar myelopathy. Vacuolar myelopathy is a late complication of HIV infection. It causes vacuolar changes in the myelin sheath of the dorsal and lateral column pathways. HIV-induced metabolic abnormalities or neurotoxic cytokines may be causative factors. MRI may be normal or reveal longitudinal T2 hyperintense signal change, usually confined to the dorsal and lateral columns of the cord. On follow-up studies, cord atrophy may be seen. The MRI appearance has some resemblance to vitamin B12 deficiency–associated subacute combined degeneration, which preferentially affects the dorsal and lateral columns. The differential diagnosis also includes hypocupremia and tropical spastic paraparesis (HTLV1-associated myelopathy).

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Fig. 40.113 Diskitis, Osteomyelitis, and Epidural Abscess. A, Sagittal fat-suppressed image reveals hyperintense signal in the involved disk and hyperintense edema in the vertebral body marrow. Note associated hyperintense epidural collection that displaces the spinal cord. B, Sagittal T2-weighted image reveals the diskitis and involvement of the inferior endplate of the vertebral body above. The epidural abscess is hyperintense, and the hypointense contour of the dura is well seen (arrowheads). C, Sagittal T1-weighted postcontrast image demonstrates intense enhancement of the abscess.

Trauma Traumatic lesions to the spine are discussed online, available at http://www.expertconsult.com. Metabolic and Hereditary Myelopathies Here we group metabolic disorders that potentially cause myelopathy, as well as hereditary and degenerative diseases that result in myelopathy by progressive loss of spinal neurons and/or degeneration of spinal cord pathways. Some of the pathologies result in characteristic signal alterations of the spinal cord, such as that seen in subacute combined degeneration due to vitamin B12 deficiency. Others (most degenerative diseases) do not alter the signal characteristics but cause cord atrophy, with or without atrophy of other CNS structures.

The most common entities belonging to this group of myelopathies (subacute combined degeneration, adrenomyeloneuropathy, SCA, Friedreich ataxia, amyotrophic lateral sclerosis, and hereditary spastic paraplegia) are discussed online at http://www.expertconsult.com. Degenerative Spine Disease Degenerative changes are very commonly seen on neuroimaging studies of the spine. These changes may involve the intervertebral disks, the vertebral bodies, and the posterior elements (facet joints, ligamentum flavum) in various combinations. Degenerative disk disease. In young people, the intervertebral disks have a fluid-rich center (nucleus pulposus) that appears hyperintense on T2-weighted images (Fig. 40.127). With aging, the nucleus pulposus loses water, becoming progressively more hypointense, and the disk flattens. This phenomenon is no longer considered to be abnormal but an age-related involutional change.

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However, the often concurrent weakening of the annulus fibrosus raises the chance of annular tear and resultant disk abnormalities. The nomenclature of disk abnormalities (Fardon and Milette, 2001) is complex (Fig. 40.128). A disk bulge is symmetrical presence of disk tissue “circumferentially” (50%–100%) beyond the edges of the ring apophyses. On sagittal views, disk bulges have a “flat-tire” appearance. Disk bulges are not categorized as herniations and in the majority of cases do not have any clinical significance. The term disk protrusion refers to extension of a disk past the borders of the vertebral body. A disk protrusion (1) is not classifiable as a bulge, and (2) any one distance between the edges of the disk material beyond the disk space is less than the distance between the edges of the base when measured in the same plane. We distinguish between focal and broad-based disk protrusions depending on whether the base of protrusion is less or more than 25% of the entire disk circumference. Disk protrusions may or may not be clinically significant. Whether they affect the neural structures depends on multiple factors. In a congenitally narrow spinal canal, even a small disk protrusion may result in spinal cord or cauda equina compression. In a normal spinal canal, a central disk protrusion may not do anything other than indent the thecal sac. A protrusion of the same size, however, may cause nerve root compression when situated in the lateral recess (Fig. 40.129) or neural foramen (paracentral or lateral disk protrusion). Disk extrusion refers to a herniation in which any one distance between the edges of the disk material beyond the disk space is greater than the distance between the edges of the base measured in the same plane. It occurs when the inner content of the disk, the nucleus pulposus, herniates through a tear of the outer annulus fibrosus. If the extruded disk material loses its continuity with the disk of origin, it is referred to as a sequestrated or free fragment.

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eFig. 40.119 Burst Fracture. Sagittal computed tomography scan of the spine demonstrates significantly decreased height of the involved vertebra (asterisk). Note extrusion of the bone fragment into the epidural space (arrows).

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eFig. 40.118 Odontoid Fracture. A, Sagittal computed tomography (CT) scan of the cervical spine reveals a type 2 odontoid fracture that involves the base of the odontoid (arrowheads). B, Sagittal CT scan of the cervical spine, with type 3 odontoid fracture extending into the vertebral body (arrowheads).

Structural neuroimaging has an essential role in the emergency evaluation and surgical planning of injured patients. Bone window CT images are an excellent tool for evaluating vertebral column trauma, whereas MRI is more useful in displaying disk trauma, injury involving the spinal cord parenchyma and/or nerve roots, and for the assessment of hemorrhage and soft-tissue damage. Some mechanisms of injury have a predilection for certain spine segments, such as burst fractures due to axial force in the lower thoracic and lumbar spine or axial flexion/extension and resultant distraction injuries at the junctions of mobile and rigid segments of the spine (cervicothoracic and thoracolumbar junctions). Traumatic injuries are typically not isolated but occur in various combinations; for instance, facet joint subluxation may be combined with spondylolisthesis, disk rupture, and spinal cord contusion. Hangman fracture. Hangman’s fracture involves one or both of the pars interarticularis of the C2 vertebra (axis), resulting in separation of the vertebral body from the arch. The vertebral body is usually anteriorly displaced. Fracture of anterior or posterior arch of C1 (atlas) is often seen as well. The underlying mechanism is hyperextension of the neck, and the name hangman fracture comes from its historically frequent occurrence during hanging when the rope suddenly pulls the chin up and the weight of the body forces the neck into hyperextension, resulting in this type of fracture. Odontoid fracture. Fracture of the odontoid process of the axis (dens) is another potential result of trauma. It may be caused by hyperflexion or hyperextension injuries. In hyperflexion, the dens is displaced anteriorly together with the C1 vertebra if the transverse ligament that connects them is intact. In hyperextension injury, the dens and C1 vertebra move posteriorly. CT scan with bone windows effectively demonstrates this fracture and displacement. The fracture may involve the tip or the base of the odontoid or may extend into the C2 body as well. Accordingly, types 1, 2, and 3 odontoid fractures are distinguished (eFig. 40.118).

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eFig. 40.120 Jefferson Fracture. Axial computed tomography scan reveals multiple fractures involving the anterior and posterior arches of the atlas (arrows).

Burst fracture. Burst fracture involves the vertebral body, usually extending through both the superior and inferior endplates. It is usually due to an axial traumatic force and most commonly involves the lower thoracic and lumbar vertebral bodies. The involved vertebral body is decreased in height, and there is retropulsion of bone or its fragments into the vertebral canal (eFig. 40.119). Frequently there is a coexistent arch fracture or disk disruption. Disk herniation may also occur through the endplate into the vertebral body. Spinal cord contusion or spinal cord/cauda equina compression by the displaced bony fragments may be noted as well. Jefferson fracture. A Jefferson fracture is a burst fracture that involves the atlas and results in unilateral or bilateral, single or multiple fractures of its anterior and posterior arches (eFig. 40.120). The cause of this type of fracture is an axial compressive force transmitted by the occipital condyles on the erect spine. Thin-cut CT bone window images are the study of choice. Facet joint disruption, traumatic spondylolisthesis. Disruption of the facet joints occurs when the superior and inferior articular processes of the joint are displaced relative to each other due to ligamentous injury. Facet joint disruption can be unilateral or bilateral.

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B eFig. 40.121 Traumatic Spondylolisthesis. A, Sagittal computed tomography (CT) scan reveals a grade 1 anterolisthesis (arrows). B, Sagittal CT scan in the same patient shows disruption of the facet joint, with one articular process “riding” on top of the other, also referred to as a perched facet (arrow).

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eFig. 40.122 Traumatic Rotatory Subluxation. Computed tomography scan from a 35-year-old patient with painful, fixed torticollis. Note leftward-rotated position of the anterior arch of the atlas (arrow) relative to the odontoid process (asterisk).

The direction of the traumatic force can be rotational, in hyperflexion, or hyperextension. This injury type tends to occur at the junction of rigid and mobile parts of the spine such as the thoracolumbar junction. A typical example is the “seatbelt injury,” which occurs when the lap belt holds the lower part of the spine immobile while the upper segment is hyperflexed and moves anteriorly, resulting in facet joint disruption. The facet joint is formed by the inferior articular process of the superior vertebra and the superior articular process of the inferior vertebra. In the normal anatomical situation, the inferior articular process of the superior vertebra is posterior to the superior articular process of the inferior vertebra. When the joint is disrupted, the normally posteriorly located inferior articular process moves anteriorly. When this anterior movement is to the point that the inferior articular process is riding on the top of the superior articular process, the term

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perched facet is used. If the force is more violent, the inferior articular process moves more anteriorly and becomes wedged in place anterior to the superior articular process. This phenomenon is referred to as locked facet. The traumatic force that causes such change often damages the vertebral body as well, resulting in an anterior wedge-shaped fracture. The disruption of the facet joint may cause forward shift, injury of the posterior longitudinal ligament, and traumatic spondylolisthesis of the vertebral body. These changes in alignment lead to narrowing of the spinal canal, with variable degrees of spinal cord or cauda equina injury and severe neurological impairment. These disruptive changes to the spinal column architecture are well seen on CT (eFigs. 40.121 and 40.122) as well as on MR images. For visualization of trauma to the spinal cord or cauda equina, MRI is the imaging modality of choice. Trauma to the spinal column is often accompanied by soft-tissue injury, including traumatic changes of the paraspinal musculature. The traumatic strain and stretch results in edema of the muscles, which is well demonstrated as hyperintense signal change on STIR images. Spinal epidural hematoma. Epidural hematoma appears as an extradural, usually spindle-shaped collection of blood. It may occur at any segment of the spinal column. Varying degrees of spinal cord or cauda equina compression may be present. In the acute stage, the hematoma is hyperdense on CT. On MRI, the acute hematoma is usually isointense to the cord on T1 and appears hypointense on T2-weighted images. The signal characteristics change as the hematoma undergoes degradation. In subacute and chronic cases, the signal becomes hyperintense (eFig. 40.123). Similar to spinal subdural hematomas, epidural hematomas enhance after gadolinium administration along their periphery; this is due to dural hyperemia. Occasionally, contrast material may also leak into the hematoma. Spinal subdural hematoma. Hemorrhage into the spinal subdural space may occur after trauma or as an iatrogenic phenomenon after LP in patients with coagulopathy. With structural neuroimaging, an intradural collection is seen that exerts a variable degree of mass effect on the spinal cord or cauda equina. The collection is hyperdense on CT and exhibits variable signal intensity on MRI, depending on the stage of the hematoma. A large intradural hypointensity on T2 or gradient echo pulse sequences is a common finding in the acute stage, with hyperintense epidural fat along its periphery. The lower thoracic or lumbar spine is affected most frequently. In posttraumatic cases, the imager should look for other stigmata of trauma such as spinal cord

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contusion/hematoma, vertebral fracture, disk rupture, or changes in vertebral alignment. Spinal subarachnoid hemorrhage. Traumatic subarachnoid hemorrhage in the spinal canal may be seen in primary spinal trauma or after an LP but also as a secondary phenomenon in cases of intracranial subarachnoid hemorrhage when the blood reaches the

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eFig. 40.123 Spinal Epidural Hematoma. A, Sagittal T2-weighted image demonstrates a prominent mixed but mostly hyperintense epidural collection (arrowheads) that displaces the spinal cord. Note the hyperintense signal change in the compressed cord parenchyma (arrow). B, Sagittal fat-suppressed image shows the epidural hematoma (arrowheads) and demonstrates the cord signal change even more conspicuously (arrow).

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spinal compartment via CSF circulation. In the acute phase, CT scan is a sensitive imaging modality to detect hyperdense subarachnoid blood (eFig. 40.124). Spinal cord trauma. While CT bone window images are best for evaluating traumatic changes of the vertebral column, the imaging modality of choice for spinal cord trauma is MRI. Spinal cord trauma may cause early and delayed changes. Early changes include cord contusion, compression, or varying degrees of transsection due to the traumatic displacement of an intervertebral disk or bony elements. On MRI, they are expressed as variable degrees of cord swelling, with T2 hyperintensity due to edema and complex signal changes due to hemorrhage (see the hemorrhage section for a review). In this early phase, gradient echo images are useful for assessment of cord hemorrhage, which appears as hypointense signal change within the parenchyma. A milder form of early traumatic change is in spinal cord concussion, where imaging may reveal some transient swelling and faint T2 hyperintense signal change only. The spinal cord may be damaged without bony compression; in cases of hyperextension, axonal shear injury and cord hemorrhage may develop, typically causing a central cord syndrome. Chronically, after severe spinal cord trauma, myelomalacia tends to develop, with microcystic changes and reactive gliosis in the damaged parenchyma, which is hyperintense on T2-weighted images; the involved cord segment is normal in size or atrophic. Besides early traumatic changes, delayed progressive forms of posttraumatic myelopathy may occur. They include spinal cord cysts with CSF signal characteristics (eFig. 40.125). These cysts may enlarge and show CSF pulsation. Cyst shunting may relieve the pressure on the remaining functional cord tissue. Another chronic phenomenon, fibrotic changes in the spinal canal, may result in progressive tethering of the spinal cord to the dura, which can be toward the anterior, lateral, or posterior border of the spinal canal. In addition to deforming the cord and causing neurological symptoms, tethering may also contribute to delayed spinal cord cyst formation. For a clinical review of spinal cord trauma, see also Chapter 63. Spinal cord injury without radiological abnormality. Spinal cord injury without radiological abnormality (SCIWORA) was

B eFig. 40.124 Spinal Subarachnoid Hemorrhage. Sagittal (A) and axial (B) computed tomography images reveal hyperdense blood throughout the spinal and visible intracranial subarachnoid space (arrows).

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PART II Neurological Investigations and Interventions described in the early 1980s (Pang and Wilberger, 1982) and has been predominantly seen in the pediatric population, where the flexibility of the spinal canal enables severe spinal cord injury without obvious traumatic changes to the bony elements. It is to be noted that this term was created when spine trauma imaging was largely limited to x-ray, CT, and myelography. Various injury types that may be associated with SCIWORA, including injury to spinal ligaments or axonal shearing injury of the spinal cord due to hyperextension, are not visualized well with these techniques. With the advent of the higher-resolution imaging capabilities of MRI, cases that earlier would have belonged to this group have been shown to exhibit visible spinal cord parenchymal signal abnormalities, such as due to small hemorrhages or mild edema (Pang, 2004). However, this trauma category is still not extinct: MRI-negative cases are known. With continued improvement in imaging techniques and use of higher magnetic field strengths, it is likely the number of such cases will decline even further.

eFig. 40.125 Posttraumatic Syrinx. Sagittal T2-weighted image shows a chronic vertebral body compression fracture (white arrow). The formerly traumatized spinal cord reveals a hyperintense posttraumatic syrinx (arrowheads). The surrounding hyperintense signal in the cord parenchyma is reactive gliosis (black arrow).

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Subacute combined degeneration. A consequence of severe vitamin B12 deficiency, subacute combined degeneration represents the most common form of metabolic myelopathy. In this disease, vitamin B12 deficiency results in demyelination and eventually degeneration of the lateral and dorsal columns of the spinal cord. The imaging modality of choice is MRI. T1-weighted images may reveal hypointensity in the dorsal columns, sometimes with mild enlargement of the cord. On T2-weighted images, hyperintense signal change is seen, typically involving the dorsal columns, sometimes also the lateral columns (eFig. 40.126). There is no enhancement after gadolinium administration. Adrenomyeloneuropathy. In adrenomyeloneuropathy, there is impaired oxidation of very long chain fatty acids in the peroxisomes. This condition results in a metabolic myelopathy. Conventional MRI may not reveal signal abnormalities, but with magnetization transfer imaging, hyperintense lateral and dorsal column lesions may be seen (Fatemi et al., 2005).

Spinocerebellar ataxias. In these genetically heterogeneous disorders, variable degrees of cerebellar, brainstem, and spinal cord atrophy are seen. Friedreich ataxia. Although cerebellar and brainstem atrophy also occur in Friedreich ataxia, the characteristic finding is striking atrophy of the spinal cord. This is best appreciated on sagittal T1-weighted images. Amyotrophic lateral sclerosis, hereditary spastic paraplegia.

In amyotrophic lateral sclerosis, there is variable atrophy of the spinal cord, which is due to degeneration of spinal motor neurons as well as degeneration of the corticospinal tracts. In addition to cord atrophy, T2-weighted images may reveal hyperintense signal change along the trajectory of the corticospinal tracts. In hereditary spastic paraplegia, degeneration of the lateral and dorsal columns results in atrophy of these regions of the cord.

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eFig. 40.126 Two Cases of Subacute Combined Degeneration Due to Vitamin B12 Deficiency. A, B, Sagittal T2-weighted images demonstrate longitudinal hyperintense signal change, predominantly within the posterior columns of the spinal cord (arrowheads). C, D, On axial T2-weighted images, the hyperintense lesions are well seen in both the posterior and lateral columns (small arrows). F ECF

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E Fig. 40.114 Multiple Sclerosis. A, Sagittal fat-suppressed image reveals multiple hyperintense demyelinating lesions in the spinal cord parenchyma (arrowheads), including at the cervicomedullary junction (arrow). On axial T2-weighted images, hyperintense demyelinating lesions are seen in the (B) anterior, (C) lateral, and (D) posterior columns of the cord (arrows). E, Sagittal T1-weighted postcontrast image reveals an enhancing lesion in the cord parenchyma (arrow).

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Fig.40.115 Neuromyelitis Optica. In sagittal T2 (A) and STIR sequence (B), longitudinally extensive transverse myelitis (LETM) is present, extending from C2 to T5 (arrows). Following contrast administration (C), lens-shaped enhancement (arrowheads) is noted, extending from C6 to T2.

Fig. 40.116 Acute Disseminated Encephalomyelitis (ADEM). Sagittal T2-weighted image shows a diffuse hyperintense lesion spanning the length of the cervical cord (arrows). Note the enlarged caliber of the cord, which is due to swelling.

Sometimes it is difficult to determine whether continuity exists or not. The term migration is used when there is displacement of disk material away from the site of extrusion, regardless of whether it is sequestrated or not, so it may be applied to displaced disk material irrespective of its continuity with the disk of origin (Fig. 40.130). On T2-weighted images, an annular tear may be appreciated as

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a dotlike or linear hyperintensity against the hypointense background of the annulus fibrosus. This is sometimes also referred to as a high intensity zone (HIZ). Disk herniation frequently reaches considerable size and clinical significance owing to compression of the exiting/descending nerve roots of the spinal cord (Fig. 40.131). Disk protrusions and extrusions/ herniations may compromise the spaces to various degrees. As a general guide, spinal canal or neural foraminal stenosis of less than onethird of their original diameter is mild, between one- and two-thirds is moderate, and stenosis involving more than two-thirds of the original caliber is considered severe. Disk abnormalities are most common in the lumbar spine, particularly at the L4/5 and L5/S1 levels, and second most common at the cervical levels C5/6 and C6/7. These regions represent the more mobile parts of the spinal column. Degenerative changes of the vertebral bodies. The bone marrow of the vertebral bodies undergoes characteristic changes with age that are well demonstrated by MRI. In younger people, it is largely red marrow composed of hemopoietic tissue. In this age group, the only area of fatty conversion, appearing as a linear T1 hyperintensity, is at the center of the vertebral body around the basivertebral vein. In people older than 40 years, additional foci of fatty marrow changes appear T1 hyperintense in other regions of the vertebral body. The size and extent of these fatty deposits increases with advancing age. In degenerative disk disease, characteristic degenerative changes often occur in the adjacent vertebral body endplates as well, seen as linear areas of signal change in these regions (Fig. 40.132). The process of degenerative endplate changes has been thought to occur in stages which have their characteristic MRI signal change patterns. These patterns were traditionally referred to as Modic type 1, 2, and 3 endplate changes (for review, see Rahme and Moussa, 2008). This nomenclature has been largely abandoned. The most common change, formerly Modic type 2, is a linear hyperintensity in the endplate region of variable width on T1- as well as T2-weighted images, with corresponding hypointense signal loss on STIR sequences.

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B

Fig. 40.117 Transverse Myelitis. A, Sagittal T2-weighted image demonstrates a longitudinal hyperintense spinal cord lesion spanning three vertebral segments (arrows). B, On an axial T2-weighted image, the lesion involves more than two-thirds of the cord’s cross-sectional area (arrow). C, Sagittal T1-weighted postcontrast image shows an enhancing area within the lesion (arrow).

*

Fig. 40.127 Normal Intervertebral Disks. Sagittal T2-weighted image demonstrates normal disk height. Note the T2 hyperintense nucleus pulposus (asterisk) and the hypointense annulus fibrosus (arrowheads). The disk does not extend beyond the borders of the vertebral body (arrow).

These changes have been attributed to degenerative fat deposition in these regions. Besides signal changes, vertebral bodies may also undergo morphological changes. In cases of disk protrusion or extrusion, the bone of the vertebral body may grow along the disk and form osteophytes or spurs. These may contribute to the narrowing of spaces and compromise of the neural elements. Large osteophytes may fuse across vertebral bodies, forming spondylotic bars. Degenerative changes of the posterior elements. Facet joint arthropathy and ligamentum flavum hypertrophy are common findings in degenerative disease of the spine. In facet arthropathy, the synovial surface of the joint becomes poorly defined, and hyperintense synovial fluid may accumulate. The joint becomes hypertrophied. Sometimes the synovial fluid accumulation results in outpouching of

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Fig. 40.128 Disk Bulge, Protrusion, and Herniation. T2-weighted image demonstrates examples for all stages pathology. Going from rostral to caudal, a disk bulge (arrow), and more prominent protrusion (arrowheads), and a herniation arrowhead) are seen.

Sagittal of disk a small (double

the synovium, which emerges from the joint, forming a synovial cyst. When prominent enough, this cyst may compromise the diameter of the spinal canal and (rarely) compress the neural elements (Fig. 40.133). Hypertrophy of the T2 hypointense ligamentum flavum is also frequent and may contribute to compromise of the spaces and neural elements. Spondylolysis, spondylolisthesis. Spondylolysis and spondylolisthesis are pathological changes that often occur together and are most common in the lumbar spine. Spondylolysis refers to a defect in the pars interarticularis of the vertebral arch, resulting in separation of the articular processes from the vertebral body. A

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traumatic etiology is common, but it may happen in the setting of advanced degenerative disease as well. A common cause is stress microfractures resulting from episodes of axial loading force on the erect spine, such as when landing after a jump, diving, weightlifting, or due to rotational forces. This abnormality can be visualized with CT or MRI. On sagittal views, the pars defect is well seen; on axial images, the spinal canal may appear slightly elongated at the level of the spondylolysis. Spondylolisthesis is shifting of one vertebral body relative to its neighbor, either anteriorly (anterolisthesis) or posteriorly (retrolisthesis). It is often associated with spondylolysis (Fig. 40.134). Four grades of spondylolisthesis are distinguished, depending on the degree of shifting. Grade I spondylolisthesis refers to shifting over less than one-fourth of a vertebral body’s anteroposterior diameter; grade II is

shifting over one-fourth to one-half the diameter; grade III is up to three-fourths; and the most severe, grade IV, is shifting over the full vertebral body diameter. Isolated spondylolysis results in elongation of the spinal canal, whereas spondylolisthesis causes segmental spinal canal narrowing, the extent of which depends on the degree of listhesis. In severe cases, there is compression of the spinal cord or cauda equina, and the changes also frequently cause narrowing of the neural foramina and compromise of the exiting nerve roots at the involved level.

INDICATIONS FOR COMPUTED TOMOGRAPHY OR MAGNETIC RESONANCE IMAGING Structural neuroimaging studies are probably the most commonly ordered diagnostic tests in both inpatient and outpatient neurological practice. Imaging greatly helps with the diagnosis of various neurological diseases and does so in a relatively quick and noninvasive way. This section (available online at http:// www.expertconsult.com) summarizes the most common indications for obtaining a neuroimaging study in clinical neurological practice. Selection of the imaging study should be guided by the patient’s history and objective findings on neurological examination, as opposed to shooting in the dark and obtaining “all-inclusive” imaging studies of the entire neuraxis. The availability and cost of the various techniques should also be factored into the decision of what tests to obtain in a given clinical situation.

Neuroimaging in Various Clinical Situations

Fig. 40.129 Disk Protrusion. Axial T2-weighted image shows a left paracentral disk protrusion (arrow) that indents the thecal sac and narrows the left lateral recess.

A

This section, including a summary (eTable 40.3) on selection of imaging modalities in various clinical situations, based on the current American College of Radiology (ACR) Appropriateness Criteria, is available online at http://www.expertconsult.com. The complete reference list is available online at https://expertconsult. inkling.com/.

B Fig. 40.130 Disk Migration. A, Sagittal T2-weighted image shows disk material that did not stay at the level of the disk of origin but migrated cranially (arrow). B, Axial T2-weighted image demonstrates the migrated disk material (arrow) and the compressed thecal sac (arrowheads).

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Selecting Computed Tomography Versus Magnetic Resonance Imaging for Neuroimaging in Practice The decision whether to obtain a CT scan or an MRI is guided by practical factors and the nature of the disorder to be studied. Although MRI often allows for better visualization of anatomy and pathology, availability may limit its more widespread usage. Smaller practices and smaller local or rural hospitals often do not have MRI on site, and the delay in transportation to an MR imaging facility may be a concern. Even larger tertiary-care centers may not have overnight or weekend MRI coverage. In these situations, regardless of the suspected pathology, CT scanning is the first step in the imaging diagnostic process, especially if the patient’s condition is urgent. CT scanning has the additional advantage of being less expensive and faster to obtain, minimizing the need for patient cooperation. Patients with pacemakers and other implanted devices cannot have MRI, nor can those with claustrophobia, unless the study is performed in an open unit. Besides these practical issues, CT renders better images of bony structures

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and calcification. Subarachnoid hemorrhage is better visualized on CT than on MRI, although FLAIR sequences are being found to be of comparable efficacy. CT angiogram, especially when color-coded 3D reconstruction is used, is superior to conventional MR angiogram in evaluating aneurysms. On the other hand, when neural parenchymal lesions are being investigated, the better resolution of MRI makes it the ideal study. MRI is especially useful in the evaluation of posterior fossa lesions, where CT images are often compromised by artifact. Imaging of acute stroke, staging of hemorrhage, detection of microbleeds, evaluation of brain tumors, or detection of subtle structural or congenital lesions, such as in a seizure patient, are some of the instances when MRI should be used if possible. MRI has the additional advantage of not exposing the patient to harmful irradiation. MRI has no known harmful effects on humans. MRI—without gadolinium administration—is also considered safe in the second and third trimesters of pregnancy and is in fact suitable for examination of the fetus as well.

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ETABLE 40.3

Guide for Selection of Imaging Modalities in Various Clinical Situations

Clinical Situation

Imaging Modality

Rating

Comments

Acute focal neurological deficit, progressive

MRI with and without contrast MRI without contrast CT without contrast CT with and without contrast CT with contrast MRI with and without contrast MRI without contrast CT without contrast CT with and without contrast CT with contrast MRI with and without contrast MRI without contrast CT without contrast CT with and without contrast CT with contrast MRI with and without contrast MRI without contrast CT without contrast CT with and without contrast CT with contrast MRI with and without contrast MRI without contrast CT without contrast CT with and without contrast CT with contrast MRI head and orbits with and without contrast

8 8 8 6 4 8 7 8 5 4 8 7 8 6 4 8 8 7 6 4 8 8 8 5 4 8

Both CT and MRI may be necessary. CT without contrast screens for acute hemorrhage, MRI screens for infarction and masses. CT with and without contrast if MRI is unavailable or contraindicated Both CT and MRI may be necessary. CT without contrast screens for acute hemorrhage, MRI screens for infarction and masses. CT with and without contrast if MRI is unavailable or contraindicated Both CT and MRI may be necessary. CT without contrast screens for acute hemorrhage, MRI screens for infarction and masses. CT with and without contrast if MRI is unavailable or contraindicated MRI preferred. CT without contrast for acute screening. CT with and without contrast if MRI is unavailable or contraindicated

MRI head and orbits without contrast

7

CT without contrast

5

CT with and without contrast

5

CT with contrast

6

MRI head and orbits with and without contrast

8

MRI head and orbits without contrast

7

CT with contrast

6

CT with and without contrast

6

CT without contrast

5

Acute focal neurological deficit, stable or incompletely resolving

Acute focal neurological deficit, completely resolving

Focal neurological deficits, subacute onset, progressive or fluctuating Acute confusion or altered level of consciousness

Sudden onset painless or painful visual loss

Proptosis and/or painful visual loss

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Both CT and MRI may be necessary. CT without contrast screens for acute hemorrhage, MRI screens for infarction and masses. CT with and without contrast if MRI is unavailable or contraindicated CT may be considered the preferred imaging modality when rhinological or paranasal sinus disease is the suspected etiology for the signs and symptoms CT may be considered the preferred imaging modality when rhinological or paranasal sinus disease is the suspected etiology for the signs and symptoms Thin slices dedicated to the orbits are useful for orbit disease and may be substituted for the complete head examination in selected patients Thin slices dedicated to the orbits are useful for orbit disease and may be substituted for the complete head examination in selected patients Thin slices dedicated to the orbits are useful for orbit disease and may be substituted for the complete head examination in selected patients CT may be considered the preferred imaging modality when rhinological or paranasal sinus disease is the suspected etiology for the signs and symptoms CT may be considered the preferred imaging modality when rhinological or paranasal sinus disease is the suspected etiology for the signs and symptoms CT may be considered the preferred imaging modality when rhinological or paranasal sinus disease is the suspected etiology for the signs and symptoms Thin slices dedicated to the orbits are useful for orbit disease and may be substituted for the complete head examination in selected patients Thin slices dedicated to the orbits are useful for orbit disease and may be substituted for the complete head examination in selected patients 1.

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Guide for Selection of Imaging Modalities in Various Clinical Situations—cont’d

ETABLE 40.3 Clinical Situation

Imaging Modality

Rating

Ophthalmoplegia

MRI head and orbits with and without contrast MRI head and orbits without contrast MRA head and neck without contrast MRA head and neck with and without contrast CT with contrast

9 6 6 6

CT with and without contrast

6

CT without contrast

5

MRI head without contrast MRI head with and without contrast CT head with contrast CT head without contrast MRI head with and without contrast MRI head without contrast CT head with contrast CT head without contrast MRI head with and without contrast MRI head without contrast CT head with contrast CT head without contrast CT head without contrast MRI head with and without contrast MRI head without contrast CT head with contrast MRI head with and without contrast MRI head without contrast CT head without contrast CT head with contrast MRI head with and without contrast MRI head without contrast CT head with contrast CT head without contrast MRI head with and without contrast MRI head without contrast CT head with contrast CT head without contrast CT head with and without contrast CT head without contrast MRI head without contrast CT head with and without contrast MRI head with and without contrast CT head with contrast CT head without contrast MRI head without contrast MRI head with and without contrast CT head with and without contrast CT head with contrast CT head without contrast MRI head without contrast CT head with and without contrast MRI head with and without contrast CT head with contrast

8 7 6 5 8 7 6 5 8 8 7 6 9 8 7 5 8 8 7 6 8 7 6 5 8 8 6 5 4 7 4 3 2 1 9 6 3 2 1 9 6 2 2 1

New-onset seizure, unrelated to trauma, age 18–40 New-onset seizure, unrelated to trauma, age >40 New-onset seizure, unrelated to trauma, focal neurological deficit New-onset seizure, posttraumatic, acute

New-onset seizure, posttraumatic, subacute or chronic New-onset seizure, unrelated to trauma, alcohol or drug-related Medically refractory epilepsy; surgical candidate/planning

Head trauma, acute. Minor, mild closed head injury, without risk factors and neurological deficits Head trauma, acute. Minor or mild, with focal neurological deficits, and/or risk factors Head trauma, acute. Moderate or severe closed head injury

6

Comments

Thin slices dedicated to the orbits are useful for orbit disease and may be substituted for the complete head examination in selected patients Thin slices dedicated to the orbits are useful for orbit disease and may be substituted for the complete head examination in selected patients Thin slices dedicated to the orbits are useful for orbit disease and may be substituted for the complete head examination in selected patients In the acute or emergency setting, CT may be the imaging study of choice

In the acute or emergency setting, CT may be the imaging study of choice

In the acute or emergency setting, CT may be the imaging study of choice

If intravenous contrast is contraindicated

If intravenous contrast is contraindicated

In the acute or emergency setting, CT may be the imaging study of choice

FDG-PET/CT head, functional MRI (fMRI) may be helpful in surgical planning

Known to have low yield

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ETABLE 40.3

Guide for Selection of Imaging Modalities in Various Clinical Situations—cont’d

Clinical Situation

Imaging Modality

Rating

Head trauma, subacute or chronic closed head injury, with cognitive and/or neurological deficits Skull fracture

MRI head without contrast CT head without contrast MRI head with and without contrast CT head with and without contrast CT head with contrast CT head without contrast MRI head without contrast MRI head with and without contrast CT head with and without contrast CT head with contrast CT spine without contrast MRI spine without contrast MRI spine with and without contrast

8 6 3 2 2 9 6 4 4 2 9 8 2

CT spine with contrast CT spine with and without contrast MRI spine without contrast MRI spine with and without contrast CT spine without contrast CT spine with contrast CT spine with and without contrast MRI spine without contrast MRI spine with and without contrast CT spine without contrast CT spine with contrast CT spine with and without contrast MRI spine with and without contrast MRI spine without contrast CT spine without contrast CT spine with contrast CT spine with and without contrast MRI spine without contrast MRI spine with and without contrast CT spine without contrast CT spine with contrast CT spine with and without contrast MRI lumbar spine without contrast CT lumbar spine without contrast CT lumbar spine with contrast MRI lumbar spine with and without contrast CT lumbar spine with and without contrast MRI lumbar spine without contrast CT lumbar spine without contrast MRI lumbar spine with and without contrast CT lumbar spine with contrast CT lumbar spine with and without contrast MRI lumbar spine with and without contrast MRI lumbar spine without contrast

2 1 9 8 5 3 1 9 9 5 4 2 9 8 6 5 2 9 8 6 4 2 2 2 2 2

CT lumbar spine with contrast

6

CT lumbar spine without contrast

6

CT lumbar spine with and without contrast

3

Myelopathy, traumatic

Myelopathy, sudden onset, nontraumatic

Myelopathy, slowly progressive

Myelopathy in infectious disease patient

Myelopathy in oncology patient

Low back pain. Acute, uncomplicated, no deficits

Low back pain. Trauma, osteoporosis, focal or progressive deficit, prolonged duration, older >70

Low back pain. Suspicion for cancer, infection or immunosuppression

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Comments

First test for acute management For problem solving/operative planning. Most useful when injury is not explained by bony fracture

If MRI is unavailable or contraindicated

If MRI is unavailable or contraindicated

1 8 6 3

MRI is preferred. Use CT if MRI is contraindicated or unavailable or for problem solving

3 1 8 7

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Contrast useful for neoplasia subjects suspected of epidural or intraspinal disease Noncontrast MRI may be sufficient if there is low suspicion for epidural and/or intraspinal disease MRI is preferred. Use CT if MRI is contraindicated or unavailable or for problem solving MRI is preferred. Use CT if MRI is contraindicated or unavailable or for problem solving

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Guide for Selection of Imaging Modalities in Various Clinical Situations—cont’d

Clinical Situation

Imaging Modality

Rating

Low back pain/radiculopathy. Surgical candidate

MRI lumbar spine without contrast CT lumbar spine with contrast

8 5

CT lumbar spine without contrast

5

MRI lumbar spine with and without contrast CT lumbar spine with and without contrast MRI lumbar spine with and without contrast CT lumbar spine with contrast

5

CT lumbar spine without contrast

6

MRI lumbar spine without contrast CT lumbar spine with and without contrast MRI lumbar spine without contrast MRI lumbar spine with and without contrast CT lumbar spine with contrast CT lumbar spine without contrast CT lumbar spine with and without contrast

6 3

Low back pain. Prior lumbar surgery

Low back pain. Cauda equina syndrome, multifocal deficits, progressive deficits

Comments MRI is preferred. Use CT if MRI is contraindicated or unavailable or for problem solving MRI is preferred. Use CT if MRI is contraindicated or unavailable or for problem solving Indicated if noncontrast MRI is nondiagnostic or indeterminate

3 8

Can differentiate disk from scar

6

Most useful in postfusion patients or if MRI contraindicated or indeterminate Most useful in postfusion patients or if MRI contraindicated or indeterminate Contrast often necessary

9 8

Use of contrast depends on clinical circumstances Use of contrast depends on clinical circumstances

5 5 3

If MRI is nondiagnostic or contraindicated If MRI is nondiagnostic or contraindicated

Adapted from the American College of Radiology (ACR) Appropriateness Criteria (expert panel consensus, based on current literature review). Rating scale: 1, 2, 3 Usually not appropriate; 4, 5, 6 May be appropriate; 7, 8, 9 Usually appropriate. CT, Computed tomography; FDG, fluorodeoxyglucose; MRI, magnetic resonance imaging; PET, positron emission tomography.

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Sudden Neurological Deficit Sudden onset and/or rapid evolution of neurological deficits, especially when focal and localized to the CNS, represent an obvious indication for imaging. Ischemic or hemorrhagic strokes, space-occupying lesions in the intracranial or intraspinal region, and lesions due to trauma have to be evaluated on an emergent basis. Unless a subarachnoid hemorrhage is strongly suspected, MRI is the technique of choice; it provides better visualization not only of the compromised tissue but also of the vessels, thus facilitating an etiological diagnosis. Diffusion- and perfusion-weighted images should be performed in suspected ischemia. If a 64 CT is available, a comparable study may be obtained, although using radiation and contrast is not necessarily innocuous in an acute stroke patient.

Headache There are several potential features in the presentation of a headache patient which, if present, raise a red flag and require an imaging study. These include new-onset severe headaches in a patient with no significant headache history (such as thunderclap headaches, often associated with aneurysm rupture), progression of the headaches including increasing frequency or severity, the worst headache ever experienced, headaches that are always localized to one area, headaches that do not respond to treatment, headaches in a cancer patient (always with contrast administration), and headaches associated with fever, altered mental status, or a focal neurological deficit. MRI, often followed by gadolinium administration if the nonenhanced study is negative, is the technique of choice.

Visual Impairment The most common imaging indications that belong to this group include sudden unilateral visual loss, amaurosis fugax that is potentially due to embolism from an ipsilateral carotid stenosis, visual field deficits, such as hemianopia due to temporo-occipital lesions, bitemporal hemianopia due to compression of the optic chiasm, bilateral visual loss/cortical blindness, and double vision that raises the suspicion of pathology in the brainstem or base of the brain. MRI, often followed by gadolinium administration depending on the findings on the nonenhanced study, is the technique of choice.

Vertigo and Hearing Loss Although there are several neurological signs that help to distinguish between vertigo of central and peripheral origin, new-onset vertigo— especially when associated with headache, impairment of consciousness, or ataxia—or vertigo that does not respond to therapy requires imaging to look for posterior fossa lesions, including cerebellopontine angle pathology. Although vertigo with prominent autonomic symptoms usually signals a peripheral etiology, a cerebellar hematoma or an expanding tumor may present with an identical clinical appearance. Sudden or progressive hearing loss also necessitates evaluation of the cerebellopontine angle, internal acoustic canal, and visible structures of the inner ear. MRI, often followed by gadolinium administration, is the technique of choice.

requires imaging of the thoracic and lumbar spine, respectively. Coexisting progressive upper and lower motor neuron signs and weakness in all four extremities, although typical for ALS, requires MRI imaging of the cervical spine, because pathologies there may cause an identical clinical presentation.

Progressive Ataxia, Gait Disorder A neurological examination is essential to localize the level of dysfunction, and the history will provide the most likely etiology. Cerebellar ataxia warrants MRI imaging to look for cerebellar or spinocerebellar atrophy or an expanding tumor. Unsteadiness may have multiple other intracranial causes as well, including subdural hematomas, hydrocephalus, microvascular disease of the brain, or cerebellar/brainstem demyelinating lesions. Ataxia due to impaired dorsal column sensory modalities requires MRI imaging of the spinal cord.

Movement Disorders Diagnosis of the majority of movement disorders remains firmly based on history and neurological examination. Nevertheless, in certain circumstances, structural imaging is also helpful. Examples include Huntington disease, with its typical finding of bilateral caudate atrophy, and cervical dystonia in children, which may result from a posterior fossa tumor. Visualization of the posterior fossa requires MRI.

Cognitive or Behavioral Impairment Imaging is justified in both slowly and rapidly evolving cognitive deficits. Rapidly evolving cognitive and behavioral impairment requires urgent imaging of the brain to look for acute pathology such as stroke, trauma, or an expanding mass lesion. Structural neuroimaging has a role in evaluation of the slowly progressive cognitive disorders (e.g., degenerative dementias) as well. The purpose of imaging in these cases is to look for changes that are compatible with the disease (e.g., atrophy of the frontal and temporal lobes in FTLD) and also to look for other possible pathologies that may have similar presentations, such as multiple strokes, extensive microvascular changes, or a slowly expanding space-occupying lesion (e.g., olfactory groove meningioma). Structural imaging with CT or MRI is sufficient to rule out nondegenerative dementias and provides some useful data for the diagnosis of degenerative dementia. For instance, predominant medial temporal atrophy is characteristic of AD. However, characteristic changes appear earlier on functional imaging with PET, which can also be used to visualize amyloid deposition in the brain.

Epilepsy Imaging is essential for the evaluation of patients with seizures. Besides showing pathology that may require immediate attention (trauma, stroke, expanding tumor), MRI is useful for more subtle underlying pathologies including developmental abnormalities (cortical dysplasia, heterotopia, polymicrogyria, etc.) and mesial temporal sclerosis. When epilepsy surgery is planned, MRI is indispensable to delineate the seizure focus in conjunction with electroencephalography (EEG) and functional imaging studies.

Progressive Weakness or Numbness of Central or Peripheral Origin

Trauma

A careful neurological examination is needed to determine whether progressive weakness is of central or peripheral origin and, if central, what level of the neuraxis is involved. Hemiparesis that includes the face implies intracranial pathology. Hemiparesis without facial involvement or quadriparesis calls for imaging of the cervical spine. Paraparesis, central or peripheral-type with sphincter abnormalities,

Serious head or spine trauma may require imaging even in the absence of a neurological deficit. An unstable fracture or an expanding epidural hematoma should be detected before neural tissue is compressed and a deficit ensues. A fracture can sometimes be detected on plain x-ray films, but CT scanning is more sensitive and allows visualization of intracranial or paraspinal tissues. It is also superior to MRI for imaging

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the bony skull and spine. Bone window images should be performed in cranial or spinal trauma, especially when a fracture is suspected. MRI is better than CT for depicting small areas of contusion and white matter injury with edema and microhemorrhages.

Myelopathy Signs and symptoms of myelopathy on neurological evaluation necessitate imaging, which may be required urgently depending on the nature of the suspected myelopathy. If there is no contraindication (such as a pacemaker), MRI is the study of choice. The neurological examination should guide which level of the neuraxis is imaged. However, in certain cases, for instance in a cancer patient who presents with myelopathy and may have widespread disease, the entire spine has to be evaluated.

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Low Back Pain Besides headaches, low back pain is one of the most common reasons for neurological consultation. While the majority of cases (especially chronic back pain) are due to musculoskeletal causes, and on examination there is no evidence of involvement of the neural elements, there are potential signs and symptoms in a back pain patient that necessitate obtaining an imaging study. These include low back pain patients with objective signs of radiculopathy or a conus lesion (weakness, sensory loss, reflex loss in a radicular distribution, sphincter abnormalities). Other presentations necessitating an imaging study include patients with progressively worsening pain, pain aggravated by Valsalva maneuver, worsening of pain in the recumbent position, low back pain after trauma, pain with fever and/or palpation tenderness, and back pain in a patient with cancer. In these cases, the ideal imaging modality is MRI.

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A

B Fig. 40.131 Disk Herniation, Spinal Cord Compression. A, Sagittal T2-weighted image demonstrates a disk herniation at the C3–C4 level that compresses the cervical spinal cord (arrow). Note the hyperintense signal abnormality in the compressed cord parenchyma (arrowheads). B, Axial T2-weighted image shows the herniation, which has a central component (arrow). The hyperintense signal change in the cord is also well seen (arrowheads).

Fig. 40.132 Degenerative Endplate Change. Sagittal T2-weighted image reveals hyperintense bands of signal change parallel with the disk space in the endplate region of the adjacent vertebral bodies (arrows).

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B Fig. 40.133 Synovial Cyst. A, Sagittal T2-weighted image demonstrates a hyperintense cyst with hypointense rim in the spinal canal (arrow). B, Axial T2-weighted image reveals that this cyst (arrow) arises from the left facet joint (arrowhead), consistent with a synovial cyst. It narrows the left lateral recess and neural foramen.

A

C

B

Fig. 40.134 Spondylolysis, Grade 2 Anterolisthesis. A, Sagittal T2-weighted image demonstrates grade 2 anterolisthesis of the L5 vertebral body on S1. B, Sagittal T2-weighted image reveals separation of the L4/ L5 facet joint (arrowhead) and forward displacement of the L5 articular process (arrow). C, Axial T2-weighted image also reveals the spondylolysis (arrows).

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41 Vascular Imaging: Computed Tomographic Angiography, Magnetic Resonance Angiography, and Ultrasound Peter Adamczyk, David S. Liebeskind

OUTLINE Computed Tomographic Angiography, 547 Methods, 547 Limitations, 547 Applications, 548 Magnetic Resonance Angiography, 555 Methods, 555

Limitations, 556 Applications, 556 Ultrasound, 567 Methods, 567 Techniques, 568 Applications, 570

COMPUTED TOMOGRAPHIC ANGIOGRAPHY

including multiplanar reformatting, thin-slab maximum-intensity projection (MIP), and 3D volume rendering. More recent CT with 320 detector rows enables dynamic scanning, providing both high spatial and temporal resolution of the entire cerebrovasculature (fourdimensional [4D] CTA). The cervical vessels are imaged by acquisition of an additional helical CT scan analogous to 64-detector row CT. An increasing spectrum of clinical applications utilizing this advanced technique remains under investigation (Diekmann et al., 2010).

Computed tomographic angiography (CTA) is a relatively rapid, thin-section, volumetric, helical CT technique performed with a time-optimized bolus of contrast medium to enhance visualization of the cerebral circulation. This approach may be tailored to illustrate various segments of the circulation, from arterial segments to the venous system. The ongoing development of multidetector CT scanners has advanced CTA, with increasing numbers of detectors used to further improve image acquisition and visualization.

Methods Helical CT scanner technology, providing uninterrupted volume data acquisition, can rapidly image the entire cerebral circulation from the neck to the vertex of the head within minutes. Typical CT parameters use a slice (collimated) thickness of 1–3 mm with a pitch of 1–2, which represents the ratio of the table speed per rotation and the total collimation. Data are acquired as a bolus of iodinated contrast medium traverses the vessels of interest. For CTA of the carotid and vertebral arteries in the neck, the helical volume extends from the aortic arch to the skull base. Typical acquisition parameters are 7.5 images per rotation of the x-ray tube, 2.5-mm slice thickness, and a reconstruction interval (distance between the centers of two consecutively reconstructed images) of 1.25 mm. For CTA of the circle of Willis and proximal cerebral arteries, the data acquisition extends from the skull base to the vertex of the head. Typical acquisition parameters for this higher spatial resolution scan are 3.75 images per rotation, 1.25-mm slice thickness, and an interval of 0.5 mm. A volume of contrast ranging from 100 to 150 mL is injected into a peripheral vein at a rate of 2–3 mL/sec and followed by a saline flush of 20–50 mL. Adequate enhancement of the arteries in the neck or head is obtained approximately 15–20 seconds after injection of the contrast, although this may vary somewhat in each case. Image acquisition uses automated detection of bolus arrival and subsequent triggering of data acquisition. The resulting axial source images are typically postprocessed for two-dimensional (2D) and three-dimensional (3D) visualization using one or more of several available techniques,

Limitations

Contrast-Induced Nephropathy Careful consideration must be made for performing contrast-enhanced CT studies in patients with renal impairment. Exposure to all contrast agents may result in acute renal failure, called contrast-induced nephropathy (CIN), which is typically reversible but may potentially result in adverse outcomes. The incidence of renal injury appears to be associated with increased osmolality of contrast agents, which have been steadily declining with the newer generations of nonionic agents. Due to the perceived risk of CIN, many centers require that pre-imaging serum creatinine levels be taken and extra caution used with patients who have a creatinine level above 1.5 gm/dL or an estimated glomerular filtration rate below 60 mL/min/1.73 m2. Treatment for this condition relies on prevention of this disorder, and agents such as N-acetylcysteine and intravenous (IV) saline and/or sodium bicarbonate may reduce the incidence of CIN. Avoidance of volume depletion and discontinuation of potential nephrotoxic agents, such as nonsteroidal anti-inflammatory drugs or metformin, is often recommended for patients prior to the procedure. Patients who are on hemodialysis should undergo dialysis as soon as possible afterwards to reduce contrast exposure (Kim et al., 2010). For patients who undergo CTA on an emergent basis and cannot take these precautionary steps, there is emerging evidence that the risk of CIN remains low. A 2017 systematic review evaluating ischemic stroke patients undergoing both CTA with CT perfusion (CTP) studies found that the overall rate of acute kidney injury (AKI) was 3% and the overall rate of hemodialysis was 0.07%. There was no difference in AKI among these patients with and without chronic kidney disease

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Neurological Investigations and Interventions between 3D CTA and DSA was 95%. In addition, CTA was significantly correlated with DSA in depicting the length of the stenotic segment. In reference to DSA, multiple studies have demonstrated a sensitivity of 77%–100% and a specificity of 95%–100% for CTA in detecting severe (70%–99%) stenosis (Binaghi et al., 2001). Data for moderate (50%– 69%) stenoses remain less reliable (Wardlaw et al., 2006). For detection of a complete occlusion, the sensitivity and specificity have been found to be 97% and 99%, respectively (Koelemay et al., 2004). Saba et al. (2007) evaluated the use of multidetector CTA and carotid ultrasound in comparison to surgical observation for evaluating ulceration, which is a severe complication of carotid plaques. CTA was found to be superior, with 93.75% sensitivity and 98.59% specificity compared with carotid ultrasound, which demonstrated 37.5% sensitivity and 91.5% specificity. Furthermore, another study found that plaque ulceration on CTA had a high sensitivity (80.0%–91.4%) and specificity (92.3%–93.0%) for the prediction of intraplaque hemorrhage, an important marker of atherosclerotic disease progression, as defined on magnetic resonance imaging (MRI; U-King-Im et al., 2010). Fibromuscular dysplasia (FMD), which often involves a unique pattern of stenoses in the cervical vessels, may be detected by CTA, although no large studies have evaluated the sensitivity and specificity for detection. This disorder, which characteristically demonstrates a string-ofbeads pattern of vascular irregularity on angiography, has been reliably demonstrated on carotid artery evaluations from case reports. This may potentially reduce the need for more invasive angiographic imaging in the future, although further studies in this area are required (de Monye et al., 2007). Currently, either CTA or MRA is used to evaluate suspected carotid occlusive disease, with the choice of method determined by clinical conditions (e.g., pacemaker), accessibility of CT and MR scanners, and additional imaging capabilities (CT or MR perfusion brain imaging). In contrast to occlusions due to atherosclerosis or dissection, the absence of opacification on CTA may be seen during pseudo-occlusion. This phenomenon may occur due to sluggish or stagnant flow in the patent artery produced by a distal intracranial occlusion. Retrospective studies on patients who underwent mechanical thrombectomy have demonstrated a sensitivity ranging from 82% to 96% and a specificity ranging from 70% to 86% for the detection of pseudo-occlusions on CTA compared with DSA. The presence of an intracranial internal carotid artery (ICA) bifurcation (carotid-T) occlusion was more frequently associated with

(odds ratio [OR] = 0.63; 95% confidence interval [CI] = 0.34–1.12). When adjusting for baseline creatinine, there was no difference in AKI between patients undergoing CTA/CTP and those who underwent noncontrast scans (OR = 0.34; 95% CI = 0.10–1.21). These findings suggest that the current contrast exposure involved with CTA may not be associated with a statistically significant increase in the risk of AKI in stroke patients, including those with known chronic renal impairment (Brinjikji et al., 2017).

Metal Artifacts Metallic implants, such as clips, coils, and stents, are generally safe for CT imaging, but it should be noted that they may lead to severe streaking artifacts, limiting image evaluation. These artifacts occur because the density of the metal is beyond the normal range of the processing software, resulting in incomplete attenuation profiles. Several processing methods for reducing the artifact signal are available, and operator-dependent techniques such as gantry angulation adjustments and use of thin sections to reduce partial volume artifacts may help decrease this signal distortion. Generally, knowledge of the composition of metallic implants may help in determining the potential severity of artifacts on CT. Cobalt aneurysm clips produce a lot more artifacts than titanium clips. For patients with stents, careful consideration must be made in evaluating stenosis, as these implants may lead to artificial lumen narrowing on CTA. The degree of artificial lumen narrowing decreases with increasing stent diameter. Lettau et al. evaluated patients with various types of stents and found that CTA may be superior to magnetic resonance angiography (MRA) at 1.5 tesla (1.5 T) for stainless steel and cobalt alloy carotid stents, whereas MRA at 3 T may be superior for nitinol carotid stents (Lettau et al., 2009). Data remain limited for patients undergoing intracranial stent placement, but, compared with digital subtraction angiography (DSA), inter-reader agreement for the presence of in-stent stenosis is noted to be inferior.

Applications

Extracranial Circulation

Carotid artery stenosis. In evaluating occlusive disease of the extracranial carotid artery, CTA complements DSA and serves as an alternative to MRA (Fig. 41.1). In the grading of carotid stenosis using the North American Symptomatic Carotid Endarterectomy Trial (NASCET) criteria, Randoux and colleagues (2001) found that the rate of agreement

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Fig. 41.1 Computed Tomographic Angiography (CTA) Compared With Digital Subtraction Angiography (DSA) in a Patient With Proximal Internal Carotid Artery (ICA) Stenosis. A, Three-dimensional reconstructed CTA image of left ICA reveals severe stenosis distal to the ICA bifurcation. B, DSA confirms severe stenosis seen on CTA due to an atherosclerotic plaque.

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pseudo-occlusions rather than true occlusions. (Kappelhoff et al., 2018; Rocha et al., 2018) Clinicians should be acquainted with this potential finding as it may impact planning for acute endovascular stroke therapy. Carotid and vertebral dissection. Dissections of the cervicocephalic arteries, including the carotid and vertebral arteries, remain an important cause of ischemic strokes in young adults. CTA findings include demonstration of a narrowed eccentric arterial lumen in the presence of a thickened vessel wall, with occasional detection of a dissecting aneurysm. In subacute and chronic dissection, CTA has been shown to detect a reduction in the thickness of the arterial wall, recanalization of the arterial lumen, and reduction in the size or resolution of the dissecting aneurysm. Compared with DSA, CTA of the anterior and posterior circulations (pc) has been found to have a sensitivity of 51%– 100% and a specificity of 67%–100% (Provenzale et al., 2009; Pugliese et al., 2007). CTA is likely superior to MRI in evaluating aneurysms of the distal cervical ICA, a common site of dissection, because MRI findings are often complicated by the presence of flow-related artifacts. CTA depiction of dissections at the level of the skull base may be complicated in some cases because of beam hardening and other artifacts that obscure dissection findings, including similarities in the densities of the temporal and sphenoid bones with the dissected vessel.

Intracranial Circulation Acute ischemic stroke. CTA is a reliable alternative to MRA for evaluating arterial occlusive disease near the circle of Willis in patients with symptoms of acute stroke (Fig. 41.2). The rapid imaging time has resulted in a significant escalation in the use of this modality during acute strokes (Vagal et al., 2014). A large database of acute stroke patients across multiple community and academic hospitals in Los Angeles and Orange counties found that the proportion of ischemic stroke patients undergoing CTA steadily increased from 4% in 2005 to 26% in 2012 (Powers et al., 2018; Sanossian et al., 2017). CTA shows clinically relevant occlusions of major cerebral arteries and enhancement caused by collateral flow distal to the site of occlusion. Several published studies have noted sensitivities ranging from 92% to 100% and specificities of 82%–100% for the detection of intracranial vessel occlusion. (Latchaw et al., 2009; Nguyen-Huynh et al., 2008). Bash et al. (2005) have suggested that CTA has a higher sensitivity when directly compared with 3D time-of-flight MRA (TOF-MRA), with sensitivities of 100% and 87%, respectively. CTA source images (CTA-SI) may be used to provide an estimate of perfusion by taking advantage of the contrast enhancement in the brain vasculature that occurs during a CTA, possibly making it unnecessary to perform a separate CTP study with a second contrast bolus. In normal perfused tissue, contrast dye fills the brain microvasculature and

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appears as increased signal intensity on the CTA-SI. In ischemic brain regions with poor collateral flow, contrast does not readily fill the brain microvasculature. Thus, these regions demonstrate low attenuation. The hypoattenuation seen on CTA-SI correlates with abnormality on diffusion-weighted MRI (DWI), and they have been found to be more sensitive than noncontrast CT scans in the detection of early brain infarction (Camargo et al., 2007). The sensitivity of CTA-SI and DWI when directly compared has been found to be similar in detecting ischemic regions, but DWI is better at demonstrating smaller infarcts and those in the brainstem and posterior fossa. Such findings may be useful for patients with symptoms of acute infarction who cannot undergo MRI (Latchaw et al., 2009). In addition to anatomical pathology and perfusion status, CTA imaging may potentially be used for prognostication in patients undergoing acute stroke intervention. The 10-point Clot Burden Score (CBS) was devised as a semiquantitative analysis of CTA to help determine prognosis in acute stroke (Fig. 41.3). The CBS subtracts 1 or 2 points each for absent contrast opacification on CTA in the infraclinoid ICA (1), supraclinoid ICA (2), proximal M1 segment (2), distal M1 segment (2), M2 branches (1 each), and A1 segment (1). The CBS applies only to the symptomatic hemisphere. A CBS below 10 was associated with reduced odds of independent functional outcome (OR 0.09 for a CBS of 5 or less; OR 0.22 for CBS 6–7; OR 0.48 for CBS 8–9; all vs. CBS 10). The quantification of intracranial thrombus extent with the CBS predicts functional outcome, final infarct size, and parenchymal hematoma risk acutely (Puetz et al., 2008). An increased CBS is correlated with good clinical outcomes with a sensitivity of 58% and a specificity of 77% (Dehkharghani et al., 2015). This scoring system requires external validation and may be useful for patient stratification in future stroke trials. The Alberta Stroke Program Early CT Score (ASPECTS) is a 10-point analysis of the topographic CT scan score used in patients with middle cerebral artery (MCA) stroke (Fig. 41.4 and Box 41.1). Segmental assessment of MCA territory is made, and 1 point is removed from the initial score of 10 if there is evidence of infarction in the following regions: putamen, internal capsule, insular cortex, anterior MCA cortex, MCA cortex lateral to insular ribbon, posterior MCA cortex, anterior MCA territory immediately superior to M1, lateral MCA territory immediately superior to M2, and posterior MCA territory immediately superior to M3. An ASPECTS score of 7 or less predicts a worse functional outcome at 3 months and symptomatic hemorrhage. The ASPECTS scoring system can be similarly applied to CTA-SI and, compared with noncontrast CT, has been found to be more reliable in predicting the final infarct size, particularly in early time windows (Bal

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Fig. 41.2 Right Middle Cerebral Artery (MCA) Stenosis in a Patient Who Subsequently Received Intracranial Stent Placement. A, Coronal image from computed tomographic angiography (CTA) shows focal distal M1 segment stenosis prior to stenting. B, 1.5 T 3D time-of-flight magnetic resonance angiography (MRA) demonstrates a focal flow gap of the right M1. MRA overestimates degree of stenosis when compared with CTA. C, Digital subtraction angiography image after stent placement reveals right MCA restenosis.

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Alberta Stroke Program Early Computed Tomography Score (ASPECTS)*

BOX 41.1

ASPECTS Territories Caudate Putamen Internal capsule Insular cortex M1—Anterior MCA cortex M2—MCA cortex lateral to insular ribbon M3—Posterior MCA cortex M4—Anterior MCA territory immediately superior to M1 M5—Lateral MCA territory immediately superior to M2 M6—Posterior MCA territory immediately superior to M3 *This

is a 10-point quantitative scoring system for patients with acute MCA-territory strokes. Segmental assessment of MCA territory is made, and 1 point is removed from the initial score of 10 if there is evidence of infarction in that region. MCA, Middle cerebral artery.

Fig. 41.3 The Clot Burden Score (CBS) on Computed Tomographic Angiography (CTA). This is a 10-point imaging-based score where two points are subtracted for thrombus found on CTA in the supraclinoid internal carotid artery (ICA) and each of the proximal and distal segments of the middle cerebral artery trunk. One point is subtracted for thrombus in the infraclinoid ICA and A1 segment and for each M2 branch. ACA, Anterior Cerebral Artery.

Fig. 41.5 Cerebral map defining the posterior circulation Acute Stroke Prognosis Early Computed Tomography Score (pc-ASPECTS) territories. From 10 points, 1 or 2 points each (as indicated) are subtracted for early ischemic changes or hypoattenuation on computed tomographic angiography source images in left or right thalamus, cerebellum, or posterior cerebral artery territory, respectively (1 point); and any part of midbrain or pons (2 points).

Fig. 41.4 Axial noncontrast head computed tomography (CT) demonstrating middle cerebral artery territory regions defined by the Alberta Stroke Program Early CT Score (ASPECTS). C, Caudate, I, insular ribbon, IC, internal capsule, L, lentiform nucleus.

et al., 2012). Kawiorski et al. (2016) evaluated acute stroke patients receiving IV thrombolysis and/or thrombectomy and found that CTASI-ASPECTS was a reliable predictor of a poor clinical outcome despite successful revascularization with a sensitivity of 35% and a specificity 97% (positive predictive value [PPV] 86%; negative predictive value [NPV] 7%). Subsequent studies on patients undergoing endovascular

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treatment have demonstrated that CTA SI-ASPECTS correlates with follow-up MR DWI better than noncontrast CT ASPECTS and was better able to predict favorable functional outcomes (Park et al., 2018; Sallustio et al., 2017). This scoring method may serve to reliably predict futile recanalization and remains a valuable tool for treatment decisions regarding the indication of revascularization therapies. Puetz et al. (2010) sought to determine whether CTA-SI ASPECTS could be combined with the CBS system for improved prognostication. A 10-point ASPECTS score based on CTA-SI and the 10-point CBS were combined to form a 20-point score for patients presenting acutely with stroke who received thrombolysis treatment. For patients with a combined score of 10 or less, only 4% were functionally independent, and mortality was 50%. In contrast, 57% of patients with scores of 10 or greater were functionally independent, and mortality was 10%. Additionally, parenchymal hematoma rates were 30% versus 8%, respectively. A similar semiquantitative scoring system for CTA-SI was devised for patients presenting with acute basilar artery occlusion and termed the pc-ASPECTS (Fig. 41.5). This 10-point scoring system subtracts 1 or 2 points each for areas of hypoattenuation in the left or right thalamus, cerebellum, or posterior cerebral artery (PCA) territory, respectively (1 point), or any part of the midbrain or pons (2 points). Median follow-up pc-ASPECTS was lower in patients with a CTA-SI pc-ASPECTS less than 8 than in patients with a CTA-SI

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pc-ASPECTS of 8 or higher, respectively. Hemorrhagic transformation rates were 27.3% versus 9.5%, respectively, for patients who received thrombolysis. The results indicate that such analysis can predict a larger final infarct extent in patients with basilar artery occlusion. Larger prospective trials are required for validation, but the systematic acute evaluation of CTA along with CTA-SI may potentially be used to help guide future stroke treatments (Puetz et al., 2009). Whole-brain dynamic time-resolved CTA or 4D CTA is a novel technique capable of generating time-resolved cerebral angiograms from skull base to vertex. This modality offers additional hemodynamic information on leptomeningeal collateral status as well as the extent of any retrograde flow. Unlike a conventional cerebral angiogram, this technique also visualizes simultaneous pial arterial filling in all vascular territories (Menon et al., 2012). Due to the increased sensitivity for collateral flow, 4D CTA has been shown to more closely outline intracranial thrombi than conventional single-phase CTA, which may potentially assist neurointerventional treatment planning, and prognostication (Frölich et al., 2013). Significant advancements have recently been made in the treatment of acute ischemic stroke. An increasing proportion of acutely presenting stroke patients are receiving successful recanalization with mechanical thrombectomy devices. However, treatment is often time dependent, requiring an ideal imaging selection tool that is able to accurately detect salvageable brain rapidly with widespread availability. Cerebrovascular collateral status at baseline has been found to be an important determinant of future clinical outcomes among patients with acute ischemic stroke undergoing mechanical thrombectomy. CTA is increasingly recognized as a valid tool for assessing collateral flow and predicting clinical outcomes in these patients. A higher rate of patients with good collaterals on CTA have improved functional outcomes compared with those with poor collaterals (Sallustio et al., 2017). One study found that the evaluation of collateral flow was noted to be consistent by both CTA and conventional angiography and remains the strongest predictor of clinical outcome (Nambiar et al., 2014). Multiple methods have been ascribed for the assessment of collateralization on CTA in acute ischemic stroke patients, but there is no clear consensus yet on the optimal scoring system. The most common methods utilize the presence and extent of leptomeningeal vascular enhancement in the symptomatic hemisphere relative to the asymptomatic side. One such scoring system adapted from conventional angiography is the modified American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR) system that assigns a score of 0 for nonexistent or barely visible pial collaterals on the ischemic site during any point in time, 1 for partial collateralization of the ischemic site until the late venous phase, 2 for partial collateralization of the ischemic site before the venous phase, 3 for complete collateralization of the ischemic site by the late venous phase, and 4 for complete collateralization of the ischemic site before the venous phase. A higher modified ASITN/SIR score is associated with better collateral flow on the symptomatic side. In comparing multiple CTA-based collateral scores with CTP scans among patients with emergent large vessel occlusions, one study found that modified ASITN/SIR collateral scores demonstrated good correlation with early infarct core (rho = −0.696, P < .001) and mismatch ratio (rho = 0.609, P < .001; Seker 2016). Multiphase CT angiography (mCTA) is an imaging technique that can be helpful in identifying patients that will benefit from mechanical thrombectomy by quickly evaluating the degree and extent of pial arterial filling in the whole brain in a time-resolved manner. Imaging of the brain vasculature from the skull base to the vertex is attained in three phases after contrast material injection. The first phase is composed of angiography from the aortic arch to the vertex on a multidetector CT scanner. Imaging acquisition during this phase is timed to occur during the peak arterial phase in the healthy brain tissue and is triggered by bolus monitoring.

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Imaging acquisition during the second and third phases occurs from the skull base to the vertex in the equilibrium/peak venous and late venous phases in the healthy brain. The two additional phases of mCTA use no additional contrast material. One collateral scoring system adapted for mCTA is the ASPECTS on collaterals system, which includes a six-point scale that also assigns a higher value for better collateral flow in the ischemic region. A score of 0 is assigned if no vessels are visible in any phase. A score of 1 indicates that only a few vessels are visible in the ischemic territory on any phase. A score of 2 is given if there is a two-phase delay associated with reduced prominence and extent of peripheral vascular filling or if there is a single-phase delay associated with ischemic regions with no vascular enhancement. A score of 3 is assigned for a delay on two phases or a single-phase delay associated with significantly reduced number of vessels in the ischemic territory. A score of 4 indicates that contrast delay is present on one phase, but the prominence and extent of peripheral vascular enhancement remains unchanged. A score of 5 is given if there is no delay in enhancement of pial vessels on all phases. The six-point scale can be further trichotomized into a descriptive categorization of collaterals as being poor (0–1), intermediate (2–3) or good (4–5). Interrater reliability using this technique has been noted to be excellent among readers (Menon et al., 2015). Furthermore, the interpretation of mCTA can easily be adopted as one study demonstrated a high interrater agreement between stroke neurology trainees and an experienced neuroradiologist (Yu et al., 2016). When compared with single-phase CTA, mCTA has been shown to be superior in both interrater reliability as well as the ability to predict clinical outcomes in patients undergoing acute reperfusion therapy. Poor collaterals noted on mCTA have been shown to be an independent predictor of development of malignant MCA infarction (Flores et al., 2015). The interpretation of collaterals on mCTA has been compared with standard CTP imaging, as described elsewhere. Investigators have demonstrated that mean Tmax, cerebral blood flow, and cerebral blood volume values on CTP correspond with different score categories on mCTA (D’Esterre et al., 2017). The use of mCTA may provide a viable alternative for CTP in the evaluation of acute ischemic stroke patients in centers where such modality is not available or where time constraints may deter performing additional imaging. In addition to collateral assessment, mCTA has also been found to be useful in better identifying distal vessel occlusions due to delayed distal opacification, termed the “delayed vessel sign.” When compared with single-phase CTA, the use of later phases may significantly improve the sensitivity and time to interpretation in identifying such occlusions (Byrme et al., 2017). Intracranial stenosis. CTA offers a more readily available and less costly alternative to DSA in the evaluation of intracranial atherosclerotic disease (ICAD). The sensitivities for detection of intracranial stenoses range from 78% to 100%, with specificities of 82%–100% (Latchaw et al., 2009). The Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis (SONIA) study more recently evaluated CTA findings of intracranial atherosclerosis against DSA in a prospective blinded multicenter setting. Based on DSA stenosis defined as 50%–99%, the PPV of CTA was only 46.7% and the NPV was 73.0%. For DSA stenosis defined as 70%–99%, the PPV of CTA was 13.3% and the NPV was 83.8% (Liebeskind et al., 2014). CTA is considered to be superior to transcranial Doppler (TCD) ultrasound in detecting intracranial stenoses with a high false-negative rate noted for Doppler ultrasound (Suwanwela et al., 2002). Studies also suggest that CTA has a higher sensitivity when directly compared with 3D TOF-MRA. Bash et al. (2005) found that CTA had a sensitivity of 98%, while MRA had a sensitivity of 70% for detection of intracranial stenosis. Additionally, CTA may be superior to both MRA and DSA in detecting pc stenoses when slow or balanced flow states were present, possibly owing to a longer scan time, which allows for more contrast to pass through a critical stenosis. Although previous studies noted decreased accuracy with

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the presence of atheromatous calcifications, the sensitivity and specificity of CTA for stenosis quantification remains consistent when appropriate window and level adjustments are made to account for frequently associated blooming artifacts. Cerebral venous thrombosis. The diagnosis of cerebral venous thrombosis (CVT) was previously often made with conventional angiography and more recently by MRI techniques. Magnetic resonance venography (MRV) is commonly considered the most sensitive noninvasive test in diagnosing CVT. However, given the prolonged imaging time and often limited availability, CTA has been studied as a potential alternate means of detecting CVT. Spiral CT with acquisition during peak venous enhancement has been implemented with single-section systems but remains limited in spatial and temporal resolution. One study directly comparing CTV with MRV demonstrated a sensitivity and a specificity of 75%–100%, depending on the sinus or venous structure involved (Khandelwal et al., 2006). Multidetector-row CTA (MDCTA) offers higher spatial and temporal resolution, which allows for high-quality multiplanar and 3D reformatting. Two small studies found 100% specificity and sensitivity with MDCTA when compared with MRV. The venous sinuses could be identified in 99.2% and the cerebral veins in 87.6% of cases. MDCTA may be equivalent to MRV in visualizing cerebral sinuses, but further studies are needed to evaluate the diagnostic potential of MDCTA in specific types of CVT, such as cortical venous thrombosis, thrombosis of the cavernous sinus, and thrombosis of the deep cerebral veins. The advantages of MDCTA include the short examination duration and the possible simultaneous visualization of the cerebral arterial and venous systems with a single bolus of contrast. MDCTA visualizes thrombus via contrast-filling defects and remains less prone to flow artifacts. A potential problem with this technique lies in the fact that in the chronic state of a CVT, older organized thrombus may show enhancement after contrast administration and may not produce a filling defect, leading to a false-negative result. The addition of a noncontrast CT with the MDCTA is sometimes used to remove another potential to obtain falsenegative results from the presence of a spontaneously hyperattenuated clot that could be mistaken for an enhanced sinus. This phenomenon is known as the cord sign and may be seen in 25%–56% of acute CVT cases (Gaikwad et al., 2008; Linn et al., 2007). Intracerebral hemorrhage. Patients presenting acutely with intracerebral hemorrhage (ICH) within the first few hours of symptom onset are known to be at increased risk for hematoma expansion. However, only a fraction of such patients arrive at a hospital within this time frame, so alternative means of identifying potential hemorrhage expansion have been sought because it is an important predictor of 30-day mortality. One such prognostic marker has been identified on CTA: the spot sign, defined as tiny, enhancing foci seen within hematomas, with or without clear contrast extravasation. The predicting hematoma growth and outcome in ICH using contrast bolus CT (PREDICT) investigation was a multicenter prospective study that validated the CTA spot sign as an independent predictor of hematoma expansion. The CTA spot sign demonstrated an excellent interrater agreement with a sensitivity of 51% and specificity of 85%, with a PPV of 61% and a NPV of 78% (Demchuk et al., 2012; Huynh et al., 2013). A more recent meta-analysis of 29 studies observed similar findings with a pooled sensitivity of 62% and a specificity of 88%. The spot sign was significantly associated with increased risk of hematoma expansion, a higher risk of in-hospital death, poor discharge outcomes, and increased 3-month mortality (Xu, 2018). Later image acquisition may improve detection for the spot sign, and this marker is seen more frequently in the venous phase compared with the arterial phase of CTA evaluation. Ciura et al. (2014) noted that when a 90-second delayed CTA acquisition was added, the

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sensitivity increased from 55% to 64%. However, the presence of significant hematoma expansion and higher total hematoma enlargement were observed more frequently among spot sign–positive patients with earlier phases of image acquisition (Rodriguez, 2014). The timing of CTA evaluation relative to the onset of the patient’s symptoms also has a significant impact in the detection of this radiographic marker. One systematic review demonstrated that the frequency of the spot sign significantly decreased from 39% within 2 hours of onset to 13% beyond 8 hours. Additionally, there was a significant decrease in hematoma expansion in spot-positive patients as onset-to-CTA time increased with PPVs decreasing from 53% to 33% (Dowlashahi et al., 2016). Cerebral aneurysms. DSA has been the standard imaging method for diagnosis and preoperative evaluation for patients with ruptured and unruptured cerebral aneurysms. However, DSA is invasive and subject to complications resulting from catheter manipulation. Thus, in patients at greater risk for cerebral aneurysms, the use of noninvasive techniques such as CTA to screen for aneurysms is particularly attractive. The main disadvantages of CTA are radiation exposure, the use of iodinated contrast material, difficulty in detecting very small aneurysms, and imaging artifacts from endovascular coils in treated aneurysms. CTA has diagnostic limitations for determining the presence of a residual lumen and the size/location of the remnant neck of a treated aneurysm because of the streak artifacts caused by clips, coils, flow diverters, and other embolization-related devices. In general, the accuracy of CTA is felt to be at least equal if not superior to that of MRA (Figs. 41.6 and 41.7) in most circumstances, and in some cases, its overall accuracy approaches that of DSA (Latchaw et al., 2009). CTA can provide quantitative information, such as dometo-neck ratios and aneurysm characterization, such as the presence of mural thrombi or calcium, branching pattern at the neck, and the incorporation of arterial segments in the aneurysm. The incorporation of 3D volume-rendered images in particular provided a surgically useful display of the aneurysm sac in relation to skull base structures (see Fig. 41.7). Additionally, 3D CTA may help identify cerebral veins, which generally display more anatomical variation than arteries. The presence of an unexpected vein or the lack of collateral drainage from a region drained by a vein that may need to be sacrificed during surgery can alter the approach to resection of an aneurysm. This anatomical information may permit more informed selection for a therapeutic procedure (surgery versus endovascular coiling) and in planning the treatment approach. For the detection of cerebral aneurysms, a meta-analysis of eight studies demonstrated that CTA had a pooled sensitivity of 99% and a specificity of 94% on a per-patient basis. On a per-aneurysm basis, the pooled sensitivity was 96% and the specificity was 91% (Feng, 2016). Interrater agreement has been noted to be high when evaluating aneurysm features, such as location, side, maximum diameter, and dome of the intracranial aneurysm. The level of agreement has been observed to be lower during assessment of neck diameter, presence of multiple aneurysms, and aneurysm morphology. The degree of interrater agreement increases with rater seniority emphasizing the importance of interpretation experience (Maldaner et al., 2017). Phillipp et al. (2017) conducted a large single-center retrospective evaluation demonstrating a lower sensitivity of 57.6% for smaller aneurysms less than 5 mm and 45% for aneurysms originating from the ICA. The limited sensitivity of conventional CTA for the detection of very small aneurysms and aneurysms adjacent to the skull can be significantly improved by using subtracted CTA, which offers bone-free visualization. Chen et al. (2017) evaluated subtracted 320 detector-row volumetric CTA for the detection of small aneurysms less than 3 mm and found sensitivity, specificity, and accuracy were 96.9%, 99.2%, and 98.6%, respectively, on a per-aneurysm basis. In contrast to typical aneurysms located near the base

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C Fig. 41.6 Right Middle Cerebral Artery Aneurysm Seen on Both Computed Tomographic Angiography (CTA) and Magnetic Resonance Angiography (MRA). A, Coronal section on CTA reveals aneurysm in right middle cerebral artery bifurcation. B, MRA also displays aneurysm with less definition. C, Three-dimensional reconstruction of CTA better defines saccular appearance of this aneurysm.

of the brain, distal aneurysms such as mycotic and oncotic aneurysms may be more difficult to detect on CTA. One study found a lower sensitivity of 45.5% and a specificity of 90.0%, indicating DSA should be considered when strong clinical suspicion exists for such aneurysms (Walkoff et al., 2016). For patients presenting with a nontraumatic subarachnoid hemorrhage and a negative CTA, causative vascular pathology has been identified with subsequent DSA in 9%–13% of cases (Heit et al., 2016). However, in specific cases of perimesencephalic subarachnoid hemorrhage, which are rarely associated with a ruptured aneurysm, CTA has been noted to have a NPV as high as 100%, suggesting that follow-up DSA may not be warranted in these patients (Mortimer et al., 2016). Postoperative aneurysms typically require follow-up imaging to exclude the presence of residual aneurysm, new aneurysmal growth, or recanalization. For the detection of treated aneurysms, one meta-analysis found that CTA had a sensitivity and specificity of 92.6% and 99.3%, respectively, using multidetector CTA. Although DSA remains the gold standard, CTA may present a promising, cost-effective, noninvasive alternative for long-term evaluation (Thaker et al., 2011). However, Pradilla et al. (2012) noted that, in a tertiary center, CTA had limited accuracy, particularly with small aneurysms, with a 20.5% false-positive rate most often in the anterior communicating artery or basilar artery bifurcation regions. Additionally, they noted a 21.6% false-negative rate most commonly in the cavernous segment ICA and MCA regions. There is an increasing utilization of flow diversion and intrasaccular embolization devices for the treatment of intracranial aneurysms, which pose new challenges for follow-up evaluation with CTA due to increased metallic artifacts and limited visualization of aneurysmal contrast opacification. Several small studies have noted technical feasibility and reliability in using this modality for subsequent assessment, but further prospective investigation is warranted (Raoult et al., 2018; Saake et al., 2012).

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A common sequela of aneurysmal subarachnoid hemorrhage is the development of cerebral vasospasm. TCDs are more commonly employed for surveillance, while DSA remains the gold standard for confirming this condition. However, CTA may offer high diagnostic accuracy as one meta-analysis demonstrated a pooled sensitivity of 79.6% and a specificity of 93.1% (Greenberg et al., 2010). This modality may offer a sufficient alternate means of evaluation, especially for patients who may not have sufficient bone windows for ultrasound evaluation. Cerebral vascular malformations. A cerebral arteriovenous malformation (AVM) requires DSA for accurate spatial and temporal assessment of blood flow to the feeding arteries, nidus, and draining veins. CTA has been found to have sensitivities of 87% and 96% for ruptured and unruptured AVMs, respectively. For large AVMs (>3 cm), the overall sensitivity was found to be 100%. Importantly, the sensitivity for identifying associated aneurysms was 88%, making this a useful adjunct imaging modality (Gross et al., 2012). The use of 4D CTA allows for improved accuracy in the diagnosis and classification of shunting patterns using the Spetzler-Martin grading system for AVMs. Moreover, cross-sectional imaging and perfusion data obtained from this modality may assist in treatment planning (Willems et al., 2011). Limited data exist for CTA in the identification of a dural arteriovenous fistula (DAVF), but recent investigations have demonstrated that 4D CTA may correctly reveal the angioarchitecture and differentiate the various patterns of venous drainage. (Beijer et al., 2013). Tian et al. (2015) reported that 4D CTA may be used for the follow-up assessment of patients who underwent transarterial DAVF embolization. Despite differences in temporal and spatial resolutions, the intermodality agreement between 4D CTA and DSA has been found to be excellent in determining shunt location, identification of drainage veins, and fistula occlusion after treatment. This modality may

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Fig. 41.7 Left Internal Carotid Artery (ICA) Aneurysm. Comparison of computed tomographic angiography (CTA) postprocessed images with catheter angiography. A, Catheter angiography lateral view, following left ICA injection, shows aneurysm (arrow) originating from supraclinoid portion of ICA. B, CTA axial source image reveals lobulated aneurysm (arrow). C–E, CTA three-dimensional (3D) volume-rendered images with transparency feature for user-selected tissue regions (called 4D angiography). C, Lateral view from left side of patient demonstrates relationship of the aneurysm, measuring 14 mm from neck to dome, to the anterior clinoid process. D, View of aneurysm (arrow), skull base, and circle of Willis from above. E, Same view as D of aneurysm (arrow) but edited to remove most of skull base densities and improve visibility of vessels.

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offer a potentially feasible alternative for follow-up evaluation. A retrospective review of eight studies evaluating 4D CTA for the detection of both AVMs and DAVFs noted a pooled sensitivity of 77% with a specificity of 100%. The use of 4D CTA offers a practical, minimally invasive alternative for evaluating these cerebrovascular pathologies and may reduce the need for DSA, which carries a risk of important complications (Biswas et al., 2015). Brain death. The absence of cerebral circulation is an important confirmatory test for brain death, and CTA is emerging as an important alternative means of testing. No clear consensus exists regarding the optimal criteria for determining brain death on CTA. Frampas et al. (2009) described a 4-point score with points subtracted based on the lack of opacification of the cortical segments of the MCAs and internal cerebral veins. This method was used to prospectively evaluate 105 patients who were clinically brain dead and was found to have a sensitivity of 85.7% and a specificity of 100%. A meta-analysis evaluating 12 studies determined that if the CTA criterion for brain death was complete lack of opacification of intracranial vessels, then the pooled sensitivity was 62% for the venous phase and 84% for the arterial phase imaging. The sensitivity of CTA was higher when the criterion for brain death included the absence of opacification of internal cerebral veins, either alone (99%) or in combination with lack of flow to the distal MCA branches (85%; Kramer et al., 2014). This appears to be a possible alternative means of detecting cerebral circulatory arrest, and given that it is a fast and noninvasive technique, it may become a useful confirmatory test (Escudero et al., 2009; Frampas et al., 2009).

MAGNETIC RESONANCE ANGIOGRAPHY Methods Numerous techniques are used in the acquisition of MRA images. In general, TOF-MRA and phase-contrast (PC) MRA do not use a contrast bolus and generate contrast between flowing blood in a vessel and surrounding stationary tissues. In 2D TOF-MRA, sequential tissue sections (typically 1.5 mm thick and approximately perpendicular to the vessels) are repeatedly excited, and images are reconstructed from the acquired signal data. This results in high intravascular signal and good sensitivity to slow flow. In 3D TOF-MRA, slabs that are a few centimeters thick are excited and partitioned into thin sections less than 1 mm thick to become reconstructed into a 3D data set. A 3D TOF-MRA has better spatial resolution and is more useful for imaging tortuous and small vessels, but because flowing blood spends more time in the slab than that in a 2D TOF-MRA section, a vessel passing through the slab may lose its vascular contrast upon exiting the slab. In TOF-MRA, stationary material with high signal intensity, such as subacute thrombus, can mimic blood flow. PC-MRA is useful in this situation because the high signal from stationary tissue is eliminated when the two data sets are subtracted to produce the final flow-sensitive images. This technique provides additional information that allows for delineation of flow volumes and direction of flow in various structures from proximal arteries to the dural venous sinuses. In the 2D PC-MRA technique, flow-encoding gradients are applied along two or three axes. A projection image displaying the vessel against a featureless background is produced. Compared with the 2D techniques, 3D PC-MRA provides higher spatial resolution and information on flow directionality along each of three flow-encoding axes. The summed information from all three flow directions is displayed as a speed image, in which the signal intensity is proportional to the magnitude of the flow velocity. The data set in TOF-MRA or PC-MRA may be used to visualize the course of vessels in 3D by mapping the hyperintense signal from the vessel-containing pixels onto a desired viewing plane using a MIP algorithm, thus producing a projection image.

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Fig. 41.8 Three-dimensional contrast-enhanced magnetic resonance angiography of the cerebrovascular system.

MIP images are generated in several viewing planes and then evaluated together to view the vessel architecture. A presaturation band is applied and represents a zone in which both flowing and stationary nuclei are saturated by a radiofrequency pulse that is added to the gradient recalled echo (GRE) pulse sequence. The downstream signal of a vessel that passes through the presaturation zone is suppressed because of the saturation of the flowing nuclei. Presaturation bands may be fixed or may travel, keeping the same distance from each slab as it is acquired. In general, the placement of presaturation bands can be chosen so as to identify flow directionality and help distinguish arterial from venous flow. Contrast-enhanced MRA (CE-MRA) uses scan parameters that are typical of 3D TOF-MRA but uses gadolinium to overcome the problem of saturation of the slow-flowing blood in structures that lie within the 3D slab (Fig. 41.8). The scan time per 3D volume is 5–10 minutes, and data are acquired in the first 10–15 minutes after the bolus infusion of a gadolinium contrast agent (0.1–0.2 mmol/kg). Presaturation bands usually are ineffective at suppressing the downstream signal from vessels when gadolinium is present. In 3D CE-MRA, the total scan time per 3D volume (usually about 30–50 partitions) is reduced to 5–50 seconds (Fain et al., 2001; Turski et al., 2001). Data are acquired as the bolus of the gadolinium contrast agent (0.2–0.3 mmol/kg and 2–3 mL/ sec infusion rate) passes through the vessels of interest, taking advantage of the marked increase in intravascular signal (first-pass method). Vessel signal is determined primarily by the concentration of the injected contrast, analogous to conventional angiography. Because 3D CE-MRA entails more rapid data acquisition, and hence higher temporal resolution, than TOF-MRA, spatial resolution may be reduced. The most common approaches to synchronizing the 3D data acquisition

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with the arrival of the gadolinium bolus in the arteries are measurement of the bolus arrival time for each patient using a small (2 mL) test dose of contrast followed by a separate synchronized manual 3D acquisition by the scanner operator (Fain et al., 2001). Another method rapidly and repeatedly acquires 3D volumes (50% stenosis (Nael et al., 2014). Dynamic 3D CE-MRA may play a prominent future role in evaluating intracranial arterial steno-occlusive disease, but the accuracy, reproducibility, and reliability of CE-MRA measurements compared with those of DSA and TOF-MRA warrant further delineation. Subclavian steal syndrome. Subclavian steal syndrome describes the reversal of normal direction of flow in the vertebral artery ipsilateral to a severe stenosis or occlusion occurring between the aortic arch and vertebral artery origin. DSA remains the standard in visualizing disease in the great vessels, along with abnormal retrograde filling of the affected vertebral artery. Given the invasive nature of DSA, Doppler sonography is often used, but this study may be limited by lack of visualization of the relevant pathology in the subclavian artery. Therefore, MRA offers a reliable comprehensive means to test patients with suspected subclavian steal syndrome. PC-MRA methods encode direction of flow and can accurately depict subclavian stenosis along with reversal of flow in the vertebral artery. Although TOFMRA does not possess true flow-encoded information, flow direction can be deduced with suppression of flow from a single direction by a saturation pulse that allows for selective arterial or venous MRI, with reversal of flow presenting as a flow void. This finding may also be seen with severe stenosis or occlusion but may be distinguished by anatomical imaging of vessel patency, such as with 3D CE-MRA.

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Fig. 41.15 Stent Device in the Distal Left Vertebral Artery. A, Coronal time-of-flight magnetic resonance image demonstrates loss of enhancement in the distal portion of the stent placement, suggesting a severe stenosis. B, Axial images of the neck after contrast administration is unable to accurately determine the degree of residual luminal narrowing. Widening the window settings results in overestimation of stenosis, and a later digital subtraction angiography demonstrated only mild stenosis.

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However, 3D CE-MRA has a potential disadvantage in the lone evaluation of subclavian steal syndrome because it does not possess inherent flow-encoded information. However, the low-resolution 2D TOF localizer acquisition that is often performed beforehand has been shown to provide the same information as a formal TOF-MRA sequence (Sheehy et al., 2005). Acute ischemic stroke. MRA is considered less accurate than CTA and DSA for the evaluation of occlusive intracranial disease. However, when combined with the detailed parenchymal anatomy on brain MRI, significant information may be obtained to better prognosticate and guide further treatment (Marks et al., 2008; Torres-Mozqueda et al., 2008). TOF-MRA, rather than CE-MRA, is more commonly utilized

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B Fig. 41.16 Proximal Middle Cerebral Artery (MCA) Stenosis (Same Patient as in Fig. 41.4). A, Coronal projection magnetic resonance angiogram was produced from the axial source images shown in Fig. 41.4. Coronal view shows better than the axial view (Fig. 41.4, C) that there is stenosis (arrows) involving both M2 branches of the MCA. B, Catheter angiography confirms the presence of both stenoses (arrows).

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for patients with acute stroke and has a sensitivity and specificity of 81% and 98%, respectively, for the detection of occlusion (Bash et al., 2005). However, the use of CE-MRA may be preferred as it has been noted to be superior in localizing vessel occlusion within a shorter acquisition time while providing a larger coverage, including extracranial vessels, and a more accurate assessment of collateral status (Boujan et al., 2018). The use of dynamic MRA for acute ischemic stroke remains under investigation but has shown promise as an accurate surrogate of collateral circulation seen on conventional angiography. This modality offers a fast and reliable means to assess cerebral hemodynamics and collateral circulation in patients with acute ischemic stroke that may be of benefit for those patients undergoing screening for potential thrombectomy treatment (Hernández-Pérez et al., 2016). Overall, MRA is implemented less often for stroke patients who present in early time windows amenable for acute intervention due to its prolonged imaging time relative to CTA. However, advances are being made to optimize rapid combined MRI and MRA stroke protocols, making this an increasingly used modality for potential thrombolytic or thrombectomy candidates. Cerebral aneurysms. MRA has become increasingly used for noninvasive screening and surveillance of aneurysmal disease (Fig. 41.17). The most thoroughly investigated MRA technique for cerebral aneurysms is 3D TOF-MRA, but its main disadvantages are long scanning times, limitations in detecting very small aneurysms, difficulty establishing the relationship of the aneurysm to adjacent (and surgically important) osseous anatomy, and occasional uncertainty in distinguishing between patent lumen, high-grade stenosis, and occlusion. In general, noninvasive imaging evaluation includes a review of T1- and T2-weighted (fast) spin-echo images and T2*weighted gradient echo images, in addition to the source images and MIP images from the MRA acquisition. A 2017 meta-analysis of 18 studies comprising 3463 patients found that TOF-MRA demonstrated a pooled sensitivity and specificity of 89% and 94%, respectively. Additionally, the sensitivity for aneurysms greater than 3 mm is higher (89%) compared with the sensitivity for detecting smaller aneurysms ≤3 mm (78%). Unruptured aneurysms are more likely to be detected than aneurysms on studies with subarachnoid hemorrhage present (Haifeng et al., 2017). False-positive and false-negative aneurysms are more commonly depicted at the skull base and MCA. False-positive aneurysms are often attributable to infundibula and arterial loops (Cho et al., 2011). The addition of 3D reconstructions has been shown to increase diagnostic performance, and studies performed on 3 T demonstrated a trend toward

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Fig. 41.17 Anterior Communicating Artery Aneurysm. A, A three-dimensional time-of-flight magnetic resonance angiogram on 1.5 T reveals a lobulated, saccular aneurysm arising from the junction of the A1 and A2 segments. B, Digital subtraction angiogram prior to coil embolization also demonstrates this anterosuperiorly directed aneurysm.

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Neurological Investigations and Interventions In addition to screening, MRA imaging has emerged as a common noninvasive means for surveillance after endovascular treatment for detecting aneurysm recurrences, although the data remain mixed regarding its accuracy (Fig. 41.18). One meta-analysis evaluated 16 studies that compared 1.5 T TOF-MRA and 1.5 T CE-MRA with DSA in the follow-up of coiled intracranial aneurysms. Pooled sensitivity and specificity of TOF-MRA for the detection of residual flow within the aneurysmal neck or body were 83.3% and 90.6%, respectively. Pooled sensitivity and specificity of CE-MRA for the detection of residual flow were 86.8% and 91.9%, respectively, but they were not found to be significantly different (Kwee and Kwee, 2007). A prospective analysis was performed to compare TOF-MRA and CE-MRA at 1.5 T and 3 T with a reference standard of DSA in the evaluation of previously coiled intracranial aneurysms. For the detection of any aneurysm remnant, the sensitivity was 90%, 85%, 88%, and 90% for 1.5 T TOF, 1.5 T CE, 3 T TOF, and 3 T CE-MRA, respectively. These sensitivities dropped to 50%, 67%, 50%, and 67%, respectively, for the detection of only larger (class 3 and 4) aneurysm remnants because several of these remnants were underclassified as smaller remnants by MRA. CE-MRA at 1.5 T and 3 T had a better sensitivity for larger remnants than TOFMRA, which may be related to greater flow-related artifacts within larger aneurysm remnants on TOF-MRA compared with the luminal

better accuracy (Sailer et al., 2014). For patients presenting with subarachnoid hemorrhage, 3 T TOF-MRA with 3D volume rendering was found to have a sensitivity of 97.6% and a specificity of 93.1% compared with DSA. For the prediction of the correct treatment planning strategy based on aneurysm anatomy, MRA demonstrated a sensitivity of 94% and a specificity of 100%, suggesting that it may serve both as a useful screening and treatment planning tool (Chen et al., 2012). Compared with TOF MRA, CE-MRA is generally considered more accurate in assessing the sac shape, aneurysm neck detection, and visualization of branches originating at the sac or neck (Cirillo et al., 2013). When compared with DSA, one study found that the sensitivity was higher in CE-MRA (96%) compared with TOF-MRA (92%) with an identical specificity of 98% (Levent, 2014). Although MRA demonstrates similar sensitivity and specificity to CTA for detection of intracerebral aneurysms ≥5 mm in diameter, they have lower sensitivity for aneurysms less than 5 mm (Villablanca et al., 2002). Despite the lower sensitivity of MRA for smaller aneurysms, the results of the International Study of Unruptured Intracranial Aneurysms (ISUIA; Wiebers et al., 2003) suggest that this may not significantly impact management of these aneurysms during initial screening because small incidental aneurysms, especially in the anterior circulation, have a lower rupture risk and are more likely to be monitored.

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Fig. 41.18 Right Ophthalmic Artery Aneurysm Following Coil Embolization. A, Computed tomographic angiography source image nondiagnostic for residual lumen due to streak artifacts. B, Three-dimensional time-of-flight magnetic resonance angiogram (3D TOF-MRA) axial source image at level of aneurysm dome reveals central and eccentric hypodensity due to packed coils and peripheral hyperintensity due to flow-related enhancement in residual lumen. C, 3D TOF-MRA axial source image at level of aneurysm neck also shows evidence of flow through patent neck remnant (arrow). D, Coronal maximum-intensity projection image demonstrates continuity of flow into neck and dome remnants of coiled aneurysm (arrows). (From Bowen, B.C., 2007. MR angiography versus CT angiography in the evaluation of neurovascular disease. Radiology 245, 357–361.)

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contrast-filling characteristics of aneurysms on CE-MRA. Specificities of these four MRA techniques for detecting any aneurysm remnant were 52%, 65%, 52%, and 64%, respectively. Specificities improved to 85%, 84%, 85%, and 87%, respectively, for the detection of larger (class 3 and 4) aneurysm remnants, reflecting the difficulty in detecting smaller remnants with MRA. Regarding the detection of any aneurysm growth since previous comparison angiograms, sensitivities for these MRA techniques were 28%, 28%, 33%, and 39%, respectively, and specificities were 93%, 95%, 98%, and 95% (Kaufmann et al., 2010). Artifacts from coil embolization are generally smaller on 3 T MRA versus 1.5 T MRA because a shorter echo-time at 3 T negates artifact enlargement. These artifacts may potentially lead to artificially smaller aneurysm remnants on 1.5 T MRA that should be considered when imaging treated patients (Schaafsma et al., 2014). Although CE-MRA is more likely than TOF-MRA to classify larger aneurysm remnants appropriately, TOF-MRA better identifies the location of coil masses and may be more advantageous if suboptimal CE-MRA contrast bolus is given. Therefore, the advantage of CE-MRA over TOF-MRA remains uncertain, and consideration for both examinations may be made in the follow-up of patients with coiled intracranial aneurysms. Lavoie et al. (2012) found that the sensitivity on MRA for treated aneurysms remains limited for aneurysms 4.0 mm) categories. The posterolateral approach is usually optimal for measurements of plaque formation and residual lumen because plaques most often occur on the posterior wall of the carotid bifurcation and ICA, and B-mode imaging is most accurate when the sound beam is at 90 degrees to the interface being imaged.

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Fig. 41.25 Atherosclerotic Plaque. Longitudinal B-mode image of an atherosclerotic plaque in the region of the carotid bifurcation and proximal internal carotid artery, with possible crater formation (arrow).

High-resolution B-mode imaging also has a unique ability to evaluate the specific features of atherosclerotic plaques (Fig. 41.25; Tegeler et al., 2005). Identifiable characteristics include the distribution of plaque (concentric, eccentric, length), surface features (smooth, irregular, crater), echodensity presence of any calcification producing acoustic shadowing, and texture (homogeneous, heterogeneous, or intraplaque hemorrhage). The presence of hypoechoic plaques and the presence of plaques that are quite heterogeneous with prominent hypoechoic regions (complex plaque) identify an increased risk of stroke. Highresolution B-mode imaging is more accurate than Doppler ultrasound testing for defining atherosclerosis of the vessel wall early in the course of the disease. Measurement of the intima-media thickness, which increases in the early stages of plaque formation, has been correlated with the risk of cardiovascular disease and has been used as a surrogate endpoint for clinical therapeutics (Polak, 2005; van den Oord et al., 2013). The sensitivity of B-mode imaging for detection of surface ulceration is approximately 77% in plaques causing less than 50% linear stenosis and 41% for plaques causing more than 50% linear stenosis, with no significant differences between B-mode carotid imaging and arteriography. Although associated with a somewhat worse outcome, surface irregularity or crater formation appears to be a less important morphological risk factor than echodensity and heterogeneity. Advantages of CFI include rapid determination of the presence and direction of blood flow, with more accurate placement of the Doppler sample volume and determination of the angle of insonation. Absence of color filling in what appears to be the vessel lumen provides clues about the presence of a hypoechoic plaque, and the contour of the color column can provide information about surface features. If a crater or ulcer is open to the lumen, color further details the surface architecture. Newer instruments with sensitive CFI designed to detect very low-flow velocities are able to accurately differentiate critical stenosis from total occlusion (87%–100% sensitivity, 84% specificity vs. angiography), negating the need for conventional angiography (Sitzer et al., 1996). The addition of CFI improves the understanding of many unusual anatomical configurations, such as kinks or coils. Although difficult to quantify accurately, CFI probably adds approximately 5% to the overall diagnostic accuracy of carotid duplex ultrasound. The addition of PDI offers more potential to improve the accuracy in some difficult situations. In the setting of high-grade stenosis, PDI improves the identification of stenosis and the measurement of residual lumen and may improve the visualization of plaque surface features, even in the presence of calcification. Conventional criteria for reporting carotid stenosis use flow velocity to estimate the linear percent stenosis. However, increased

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Fig. 41.26 Volume Flow Rate. Measurement of volume flow rate using color velocity imaging quantification with a color M-mode display of the flow velocities across the common carotid artery and tracking of the vessel diameter. Flow volume is in milliliters per minute.

flow velocity may be seen in other conditions, such as a hyperperfusion state seen in anemia that might be misconstrued as stenosis. To avoid such mistakes, various methods have been devised to evaluate volume flow rate in the extracranial cerebral vessels. Processing techniques, such as color velocity imaging quantification (CVI-Q), may be implemented, and normal volume flow rate values (330 mL/min for women and 375 mL/min for men) have been defined. Use of the CCA volume flow rate in patients with carotid stenosis reveals characteristic decreases in the rate with progressive stenosis. In some laboratories, measurement of CCA volume flow rate is a standard part of the carotid evaluation for patients whose flow velocity suggests 75% or greater carotid stenosis (Fig. 41.26); this technique may better delineate hemodynamic changes (Tan et al., 2002). There appears to be an acceptable correlation between results of CVI-Q and Doppler-based methods (Likittanasombut et al., 2006), and diminished extracranial cerebral volume flow rate may identify an increased risk for recurrent stroke (Han et al., 2006). Contrast-enhanced ultrasound (CE-US) is a more recent technique for the evaluation of high-risk atherosclerotic carotid lesions. The high temporal and spatial resolution capabilities allow better distinction of macrovascular morphology and the visualization of intraplaque neovascularization. The contrast agents administered for CE-US are approved by the US Food and Drug Administration (FDA) for use in cardiac imaging but currently remain off-label for use in the carotid artery. Using CTA as a reference, ten Kate et al. (2013) noted that CE-US had higher sensitivity (88% vs. 29%) than color Doppler ultrasound. Three-dimensional carotid ultrasound is another emerging technique that utilizes postprocessing imaging software to semiautomatically reconstruct 3D plaque volume and surface identified in B-mode and with the aid of color (Makris et al., 2011). Further applications of these techniques remain under investigation. The optimal noninvasive imaging method for determining the severity of carotid artery stenosis remains uncertain. MRA and CTA are being used with rapidly increasing frequency to determine the degree of stenosis. Although duplex carotid ultrasound should not be used as the sole method for definitive diagnosis of carotid disease, this inexpensive imaging technique remains a valid screening tool. A systematic review of published studies comparing carotid ultrasound with DSA showed that for distinguishing severe stenosis (70%–99%), duplex carotid ultrasound had a pooled sensitivity of 86% and a pooled specificity of 87%. For recognizing occlusion, duplex carotid ultrasound had a sensitivity of 96% and a specificity of 100% (Nederkoorn et al., 2003). Another study found high

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concordance rates among CTA, contrast-enhanced MRA, and ultrasound for patients with asymptomatic carotid stenosis (Nonent et al., 2004). However, a study comparing ultrasound and MRA to DSA determined that ultrasound alone would have misassigned 28% of patients to receive carotid endarterectomy (CEA), whereas ultrasound combined with CE-MRA reduced this misassignment rate to 17% (Johnson et al., 2000).

Vertebral Ultrasonography Because pc cerebrovascular disease is quite common, study of the vertebral arteries is considered part of the routine extracranial duplex ultrasound examination. The same techniques described for use in the carotid arteries can be used to study the vertebral arteries and the proximal subclavian or innominate arteries. As such, there should be duplex Doppler and B-mode imaging of these arterial segments. CFI is also helpful for identification and interrogation of the vertebral arteries. The vertebral artery can virtually always be evaluated in the pretransverse and intertransverse cervical segment of C5–C6, whereas the origin can only be studied on the right in 81% of cases and on the left in 65% of cases. Because there is mostly a low-resistance distal vascular bed, the vertebral artery usually shows a low-resistance Doppler spectral pattern similar to that seen with the ICA. Unlike the carotid arteries, there are no widely accepted criteria for stenosis in the extracranial vertebral artery. As with the carotid system, spectral analysis provides insight into proximal and distal disease. Another confounding factor is contralateral occlusive disease, associated with increased carotid volume flow, which may result in an overestimation of the severity of stenosis. One study noted that ultrasound evaluation of the vertebral arteries had a sensitivity and specificity of 40.7% and 100%, respectively, for the detection of symptomatic atherosclerotic disease in stroke patients. The low sensitivity likely precludes this modality from becoming a sufficient screening tool, but this study may serve as a reasonable alternative for monitoring pc disease in patients who may have difficulty undergoing CT or MR imaging (Tábuas-Pereira et al., 2017). Given the variable factors associated with carotid duplex sonography, it has been recommended that each laboratory validate its own Doppler criteria for clinically relevant stenosis and undergo certification by an independent organization, such as the Intersocietal Commission for Accreditation of Vascular Laboratories Essentials and Standards for Accreditation in Noninvasive Vascular Testing. Studies have shown that the accuracy of duplex ultrasound examination is much better from accredited versus nonaccredited laboratories (Latchaw et al., 2009).

Transcranial Doppler Ultrasonography Most commercially available TCD ultrasonography instruments use a low-frequency 2-MHz probe to allow insonation through the cranium. These pulsed-wave Doppler instruments have an effective insonation depth range of 3.0–12.0 cm or more that can be evaluated by increments of 2–5 mm. At an insonation depth of 50 mm, the sample volume is usually 8–10 mm axially and 5 mm laterally. TCD probes also differ from the 4- to 10-MHz transducers used to monitor the progress of intraoperative neurosurgical procedures (Unsgaard et al., 2002). Advantages of TCD include the maneuverability of the relatively small probes, the Doppler sensitivity, and—compared with transcranial color-coded duplex (TCCD) and MRA—the relatively low price of instruments. Routine TCD testing relies on three natural acoustic windows to study the basal segments of the main cerebral arteries. Insonation through the temporal bone window allows detection of flow through the MCA M1 segment and the anterior cerebral artery A1 segment. Normal blood flow direction is toward the probe in the MCA and

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away from it in the anterior cerebral artery. The supraclinoid ICA is also detected but may occasionally be difficult to distinguish from the MCA. Depending on the position of the window, the probe usually has to be tilted frontally to detect these vessels. A posterior (or occipital) tilt of the probe enables insonation of the PCAs. The occipital window takes advantage of the foramen magnum’s opening into the skull. Flow in the distal vertebral artery and proximal to mid-portions of the basilar artery can be detected; its direction is away from the probe in these arterial segments. A considerable degree of natural variation occurs in the position and caliber of these arteries, making insonation occasionally difficult. The ophthalmic artery and carotid siphon can be studied through the orbital window. Flow in the ophthalmic artery is toward the probe and has a high resistance pattern. Flow in the ICA siphon can be either toward or away from the probe, depending on the insonated segment. The power output of the instrument must be decreased when insonating through the orbital window because prolonged exposure to high-intensity ultrasound has been associated with cataract formation. Flow velocities change with age and differ among men and women. Normal values are available. Repeated measurements of flow velocities are highly reproducible. Thus, based on the general knowledge of the location of intracranial arteries and flow direction, a comprehensive map of the basal arteries can be generated. This map is clinically useful because common pathological conditions affecting the intracranial arteries (e.g., atherosclerosis, sickle cell disease, vasospasm associated with aneurysmal subarachnoid hemorrhage) often affect arterial segments that can be insonated. Convexity branches of the cerebral arteries are beyond the reach of TCD.

Transcranial Color-Coded Duplex Ultrasonography Examinations performed with 2.25-MHz phased array and 2.5MHz 90-degree sector transducers enable color-coded imaging of intracranial arterial blood flow in red and blue, respectively, indicating flow toward and away from the probe. The main advantages of TCCD ultrasonography is the ability to visualize and positively identify the insonated vessel, thus increasing the ultrasonographer’s confidence, and the ability to correct for the angle of insonation. In addition, TCCD provides a limited B-mode image of intracranial structures.

Applications

Acute Ischemic Stroke TCD studies obtained within hours from the onset of symptoms of stroke in the carotid territory may reveal stenosis or occlusion of the distal intracranial ICA or proximal MCA in 70% of patients. When compared with DSA, TCD is more than 85% sensitive and specific in detecting supraclinoid ICA or MCA M1 segment lesions. The use of contrast-enhanced color-coded duplex sonography can be especially useful in this context. The use of TCD in the early hours of stroke may also provide important prognostic information. Patency of the MCA by TCD testing within 6 hours of the onset of stroke symptoms is an independent predictor of a better outcome (Allendoerfer et al., 2006). Transcranial power motion-mode Doppler (PMD-TCD) is a technique that along with spectral information simultaneously displays real-time flow signal intensity and direction over 6 cm of intracranial space. One study compared PMD-TCD with CTA and found a sensitivity of 81.8% and a specificity of 94% for detecting an acute arterial occlusion. The sensitivity for detecting MCA occlusions was 95.6%, and the specificity was 96.2%. For the anterior circulation, PMD-TCD demonstrated a sensitivity of 100% and a specificity of

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94.5%. For the pc, sensitivity was 57.1% and specificity was 100% (Brunser et al., 2009). TCD can also help in monitoring the effect of thrombolytic agents. Testing before and after the administration of tissue plasminogen activator (tPA) can assess the agent’s efficacy in obtaining arterial patency and ascertain continued patency during the days after treatment. Ultrasound energy has also been observed to accelerate enzymatic fibrinolysis, possibly by allowing increased transport of drug molecules into the clot and promoting the motion of fluid throughout the thrombus. This observation has led to studies that allow for realtime monitoring of vessel recanalization while potentially providing additional therapeutic benefit from the ultrasound energy (Alexandrov et al., 2004). One meta-analysis found that complete recanalization rates were higher in patients receiving a combination of TCD with IV tPA than in patients treated with IV tPA alone (37.2% vs. 17.2%; Tsivgoulis et al., 2010). Administration of microbubbles and/or lipid microspheres remains under investigation and may help transmit energy momentum from an ultrasound wave to residual flow to promote further recanalization, thereby enhancing the effect of ultrasound on thrombolysis (Alexandrov et al., 2008; Molina et al., 2009). Early studies initially noted increased rates of symptomatic intracranial hemorrhage, highlighting the need to determine the minimum and safe amounts of ultrasound energy necessary to enhance thrombolysis (Eggers et al., 2008; Rubiera and Alexandrov, 2010). Several studies have demonstrated equivalent ICH rates, but additional operator-independent devices, different microbubble-related techniques, and other means of improving sonothrombolysis are being evaluated (Barreto et al., 2013; Bor-Seng-Shu et al., 2012). Investigations remain ongoing for more conclusive evidence of efficacy, while rapid advancements in the designs of therapeutic TCD devices may herald a new therapeutic option for acute ischemic stroke patients treated with IV thrombolysis.

Recent Transient Ischemic Attack or Stroke Compared with other available methods, ultrasound testing offers a safe, accurate, noninvasive, and less expensive method for evaluating extracranial cerebrovascular disease. It is considered the initial test of choice for identifying significant carotid stenosis in patients with recent transient ischemic attack (TIA) or stroke. For the carotid territory, this should include duplex ultrasonography, with or without CFI. Reports should address the severity of stenosis based on Doppler flow-velocity measurements. There also must be information provided about the presence of any plaque, as well as the morphology, based on high-resolution B-mode imaging. Additional helpful ultrasound tools include PDI and volume flow-rate measurement. Results of carotid ultrasound testing must then be integrated with other available testing modalities if additional information is needed. At present, this often means a combination of ultrasound and MRA or CTA, with DSA reserved for those in whom the results of the preceding tests are technically inadequate, equivocal, or contradictory. The combination of ultrasound and MRA is more cost-effective than the use of routine DSA in this setting. However, the best algorithm for evaluation may vary, depending on the services and expertise available at each medical center. MCA or basilar artery occlusion is associated with an absence or severe reduction of Doppler signal at the appropriate depth of insonation at a time when signals from the other ipsilateral basal cerebral arteries are detectable. Follow-up studies often show spontaneous recanalization of previously occluded segments. The latter can be detected within hours from the onset of symptoms, with the majority of symptomatic occlusions being recanalized within 2 days and followed by a period of hyperperfusion.

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Collateral flow patterns associated with severe cervical carotid stenosis or occlusion can also be detected by TCD. They include retrograde flow of the ophthalmic artery and anterior or posterior communicating artery flow toward the hemisphere distal to the stenosed or occluded ICA. Among patients with symptomatic carotid occlusions, one study found that compared with DSA, TCD detection of collateral flow via the major intracerebral collateral branches had a sensitivity of 82% and a specificity of 79% in the anterior portion of the circle of Willis. In the posterior communicating artery, TCD demonstrated a sensitivity of 76% and a specificity of 47% (Hendrikse et al., 2008b). Lesions causing stenosis of the V4 segment of the vertebral artery and the proximal basilar artery can be imaged by TCD. Focal increases of the peak-systolic and mean velocities to 120 cm/sec and 80 cm/sec or more, respectively, at depths of insonation corresponding to these arterial segments are considered significant. Velocities often exceed 200 cm/sec, with lesions causing more than 50% stenosis. Compared with DSA, the sensitivity of TCD is approximately 75% in detecting vertebrobasilar stenotic lesions, and its specificity exceeds 85%. Frequent variation in the size and course of the vertebrobasilar trunk and its contribution of collateral flow to the anterior cerebral circulation are the main reasons for these relatively low figures. Contrast media and TCCD imaging can be particularly helpful in this setting (Stolz et al., 2002). MESs detected by TCD correspond to gaseous microbubbles or emboli composed of platelets, fibrinogen, or cholesterol moving in intracranial arteries. Such MES can be detected spontaneously or with provocative stimuli, such as the Valsalva maneuver. In patients with extracranial carotid disease, these signals are associated with a history of recent TIAs or cerebral infarction in the distribution of the insonated artery, and they correlate with the presence of ipsilateral severe stenosis and plaque ulceration. They are detected mainly during the week following symptoms of cerebral ischemia and resolve afterward. MES can also be detected in subjects with cardiac prosthetic valves but often correspond to gaseous microbubbles in that setting. They are less common in adequately anticoagulated patients with atrial fibrillation. The clinical impact of microembolus detection studies remains limited at this time. The presence of these signals in an arterial territory is useful in identifying proximal “active” lesions. This is especially relevant when a symptomatic patient has more than one potential lesion, such as cervical carotid stenosis and atrial fibrillation, or a suboptimal history. In this situation, laboratory data can help identify the specific cause of cerebral infarction. In addition, because the presence of MES is predictive of future cerebral ischemic events in the insonated artery’s territory, detecting these signals may affect therapeutic decisions. In the future, microembolus detection studies may be useful in monitoring the effect of antithrombotic agents (Markus et al., 2010). Microemboli monitoring is also of interest in the context of potential carotid revascularization procedures. MESs have been reported in 43% of patients with symptomatic carotid stenosis and 10% of patients with asymptomatic carotid stenosis. MESs were reported in 25% of the patients with symptomatic versus 0% of patients with asymptomatic intracranial stenosis. The presence of MES has been found to be associated with a higher risk of ischemic events in patients with spontaneous carotid artery dissections (Brunser et al., 2017). Among patients with aortic embolism, patients with plaques 4 mm or larger demonstrated MES more frequently than patients with smaller plaques. MES has been shown to be useful for risk stratification in patients with carotid stenosis, but data from published studies remain insufficient to reliably predict future events in patients with intracranial stenosis, cervical artery dissection, and aortic embolism (Best et al., 2016; Ritter et al., 2008).

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Extracranial Stenotic Lesions Ultrasound remains a safe and noninvasive method for monitoring patients with carotid or vertebral artery disorders. Periodic evaluation can be helpful for assessing the progression or regression of existing plaques or the development of new lesions, whether symptomatic or asymptomatic. The timing of follow-up carotid testing must be individualized, depending on the severity and type of lesions and/or the onset of new or recurrent symptoms. The identification of asymptomatic carotid stenosis has become an important clinical mandate since the Asymptomatic Carotid Atherosclerosis Study (ACAS) showed the benefit of CEA in asymptomatic patients with 60%–99% stenosis, when compared with treatment with 325 mg of aspirin daily (Executive Committee for the Asymptomatic Carotid Atherosclerosis Study, 1995). Yet, it is not cost-effective to screen the entire population, even with ultrasound. Asymptomatic individuals with cervical bruits should be studied, even though bruits are often due to another cause. Patients with multiple risk factors probably warrant study, but the clinical utility of this has not yet been confirmed. Practice guidelines are being developed for carotid screening in high-risk individuals to identify stenosis that may need clinical treatment or intervention (Qureshi et al., 2007). If vessel disease is identified, stenosis of less than 50% might be initially restudied in 12–24 months, whereas lesions with 50%– 75% stenosis and uncomplicated plaques might be restudied in 6–12 months. For 50%–75% stenosis with complicated plaque features or for more than 75% stenosis, an initial restudy at 3–6 months is appropriate. Lack of progression for several years should result in lengthened intervals before restudy. When evidence of asymptomatic progression is present, a shorter interval is recommended. The development of

new symptoms should prompt urgent re-evaluation. After CEA, repeat ultrasound is often done at approximately one month after surgery and then yearly to identify potential restenosis. Large population studies, such as the Atherosclerosis Risk in Communities and the Cardiovascular Health Study, have documented the association between risk factors and intima-media thickening in the wall of the carotid artery on B-mode imaging. This may represent an early stage in the development of atherosclerosis; the presence of significant thickening correlates with the risk of heart attack and abnormalities on MRI of the brain. Further investigations remain ongoing regarding the clinical utility of identifying increased intima-media thickness values, but it has been suggested that B-mode imaging for evaluation of intima-media thickness should be used clinically to identify patients at high risk for coronary or cerebrovascular events or to assess responses to risk factor modification (Polak, 2005). The hope is that such early identification of atherosclerotic changes will allow interventions to prevent later development of clinical events.

Intracranial Stenotic Lesions Intracranial atherosclerotic plaques are dynamic lesions that may increase in degrees of stenosis or regress over relatively short periods of time. TCD enables noninvasive monitoring of these lesions. It is often obtained at baseline in conjunction with DSA, CTA, or MRA and is subsequently repeated during the follow-up period (Fig. 41.27). Several studies have found that TCD exhibits good accuracy compared with DSA for the detection of greater than 50% of intracranial stenosis. Zhao et al. (2011) noted that TCD had a

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Fig. 41.27 Monitoring of Intracranial Atherosclerotic Lesions. A, Cerebral angiogram shows an area of stenosis (arrow) in the M1 segment of the right middle cerebral artery. B, The first transcranial Doppler study obtained within 48 hours of angiography shows a corresponding peak-systolic velocity of 188 cm/sec. C, Repeat transcranial Doppler study 34 months later shows a further increase of the peak-systolic velocity to approximately 350 cm/sec. (Reprinted with permission from Schwarze, J.J., Babikian, V., DeWitt, L.D., et al., 1994. Longitudinal monitoring of intracranial arterial stenoses with transcranial Doppler ultrasonography. J Neuroimaging 4, 182–187.)

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sensitivity and specificity of 78% and 93%, respectively, in the MCA, using mean flow velocity greater than 100 cm/sec. Using the criteria of mean flow velocities greater than 80 cm/sec in the basilar and vertebral arteries, TCD demonstrated a sensitivity and specificity of 69% and 98%, respectively. Using peak systolic velocity =120 cm/sec, You et al. (2009) found that TCD had a sensitivity and specificity of 96.7% and 93.9%, respectively, in the carotid siphon. Furthermore, Saqqur et al. (2010) noted that in patients with positional neurological changes, TCD had a 94% sensitivity and a 100% specificity in predicting neurological symptoms with testing using a criteria of mean flow velocity decrease of greater than 25%. While TCD monitoring enables detection of new atherosclerotic plaques, clinical experience is limited, and further prospective investigations are needed to make recommendations regarding the frequency and timing of follow-up studies.

Aneurysmal Subarachnoid Hemorrhage Vasoconstriction of intracerebral arteries is the leading cause of delayed cerebral infarction and mortality after aneurysmal subarachnoid hemorrhage. Vasospasm is clinically detected 3 or 4 days after the hemorrhage and usually resolves after day 12. Although the exact cause of vasospasm remains unknown, its presence correlates with the volume and duration of exposure of an intracranial artery to the blood clot. Laboratory and animal models indicate that blood breakdown products can lead to vasoconstriction. The detection of vasospasm is important because it may potentially be treated with medications, hemodynamic management, and endovascular interventions. These treatments are not without risk, so the ability to detect and monitor vasospasm noninvasively has considerable clinical importance. Although vasospasm can be angiographically detected in 30%–70% of patients with aneurysmal subarachnoid hemorrhage, only 20%–40% develop clinical signs of cerebral ischemia. Thus, the presence of vasospasm is not a sufficient condition for the development of a clinical focal ischemic deficit. Several factors, including the severity of spasm, presence of collateral flow, condition of the patient’s intravascular volume, and cerebral perfusion pressure, are considered mitigating factors. TCD has been widely adopted for the daily monitoring of patients with aneurysmal subarachnoid hemorrhage due to its portability to the bedside and its noninvasive nature. A survey of vascular neurosurgeons and neuroradiologists across 32 countries noted that daily screening for vasospasm was a common practice among US (70%) and non-US (53%) practitioners (Hollingworth et al., 2015). TCD studies show an increase in the flow velocities of basal cerebral arteries, usually starting on day 4 after subarachnoid hemorrhage and peaking by days 7–14 (Fig. 41.28). Although a diffuse increase in velocities is often detected in patients with severe hemorrhage, arterial segments in close proximity to the subarachnoid blood clot usually have the highest velocities. Severe vasospasm in an arterial segment can be associated with reduced regional cerebral blood flow in the artery’s distal territory. There is a linear inverse relationship between the severity of vasospasm and the amplitude of flow-velocity increase in an arterial segment. This is valid until the vasoconstriction is so severe that the flow volume is reduced, flow velocities drop, and the TCD signal becomes difficult to detect. The linear relationship can also be affected by several factors, including the presence of hyperperfusion. Angiographic studies confirm the presence of at least some degree of MCA vasospasm when the mean flow velocities are higher than 100 cm/sec, but values below 120 cm/sec are not usually considered clinically significant. Mean velocities in the range of 120–200 cm/sec correspond to 25%–50% angiographically determined diameter reduction; values exceeding 200 cm/sec correspond to more than 50% luminal narrowing (Sloan et al., 1999). The 200 cm/sec threshold and rapid flow-velocity increases exceeding

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Fig. 41.28 Subarachnoid Hemorrhage. Temporal bone window; depth of insonation of 56 mm. Increased flow velocities indicating moderate to severe vasospasm in the middle cerebral artery M1 segment.

50 cm/sec on consecutive days are associated with subsequent infarction. TCD is also used to monitor the effects of endovascular treatment of vasospasm. Flow velocities decrease after successful angioplasty or papaverine infusion. Persistent increases after treatment indicate either extension of vasospasm to new arterial segments or hyperemia in the treated arterial segment and may constitute a valid reason for repeat cerebral angiography. The accuracy of TCD in detecting vasospasm depends to some degree on the location of the involved arterial segment. A recent meta-analysis of 15 studies noted a pooled sensitivity of 66.7%, with a specificity of 89.5% for the detection of vasospasm in the MCA (Mastantuono et al., 2018). Basilar artery vasospasm is detected with an approximate sensitivity of 75% and specificity of 80% (Sloan et al., 1999). However, for vasospasm of the ACA and PCA, sensitivity of TCD is notably inferior (Sloan et al., 2004). Several factors, including the effects of hyperemia, increased intracranial pressure (ICP) and blood pressure changes, the presence of vasospasm in convexity branches not accessible by TCD, and difficulties in assessing vasospasm by angiography contribute to these findings. Because of these limitations in accuracy, the combined use of TCD and single-photon emission computed tomography (SPECT) or xenon-enhanced CT has been advocated, with the expectation that it will provide a more comprehensive and accurate assessment of the clinical condition. Overall, however, TCD is considered to have acceptable accuracy for the evaluation of vasospasm in aneurysmal subarachnoid hemorrhage. It is a useful tool with limitations that must be taken into consideration in the clinical setting.

Cardiopulmonary Shunt Detection Paradoxical embolism via a right-to-left cardiopulmonary shunt remains an important cause of stroke in younger patients. A patent foramen ovale (PFO) is a common source of right-to-left circulatory shunting that occurs in approximately 25% of the general population. Patients with suspected cerebrovascular ischemia secondary to paradoxical embolism may undergo a TCD “bubble” study. Microparticle contrast agents or simple agitated saline with microbubbles may be

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peripherally injected while continuous TCD monitoring of the MCA is performed for MES detection. The Valsalva maneuver by the patient is often elicited a few seconds after contrast injection to ensure arrival of the microbubbles into the right atrium. This technique increases the right atrial pressure and facilitates the travel of microbubbles into the left atrium if a shunt is present. TCD monitoring is typically performed up to 40 seconds while the patient remains in supine and/ or sitting positions. Larger shunts with higher MES counts are associated with an increased risk of ischemic strokes (Lee et al., 2018a). In comparison with transesophageal echocardiograms, TCD has been shown to have a pooled sensitivity and specificity of 96.1% and 92.4%, respectively, based on a meta-analysis of 35 studies (Katsanos et al., 2016). A more recent study noted a sensitivity and specificity of 100%, confirming that TCD represents an optimal screening test for the detection of cardiopulmonary shunts in younger patients with cryptogenic strokes (Palazzo et al., 2019). When acoustic bone windows are absent, TCD monitoring in the cervical internal carotid arteries or vertebral arteries has been demonstrated to be a valid substitute (Perren et al., 2016).

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Cerebrovascular Reactivity Cerebrovascular reactivity testing evaluates the presence of abnormal cerebral hemodynamic changes to potentially identify patients at an increased risk of recurrent stroke. Both IV acetazolamide administration and carbon dioxide inhalation are used to assess cerebrovascular reactivity. In patients with exhausted cerebrovascular reactivity reserves, flow velocities fail to adequately increase after the IV administration of acetazolamide or have a decreased response to hypercapnia and hypocapnia. Multiple studies have demonstrated that an impaired TCD cerebrovascular reactivity in patients with severe ICA stenosis or occlusion is independently associated with an increased risk of ipsilateral ischemic events (Reinhard et al., 2014). Further investigation is necessary to determine whether such testing can reliably identify patients who might benefit from a revascularization procedure.

Sickle Cell Disease An occlusive vasculopathy characterized by a fibrous proliferation of the intima often involves the basal cerebral arteries of patients with sickle cell disease. Cerebral infarction is a common complication of this vasculopathy and has a frequency of approximately 5%–15%. As in all patients with anemia, flow velocities are diffusely increased in individuals with sickle cell anemia. Additional focal velocity increases in the basal cerebral arteries can be detected in some subjects. A time-averaged mean of the maximum velocity of 200 cm/sec or greater in the distal ICA and proximal MCA identifies neurologically asymptomatic children at an increased risk for first-time stroke (Adams et al., 1998). In addition to standard insonation techniques with the TCD probe, extending the submandibular approach to include infrasiphon portions of the ICA increases the sensitivity to better identify sickle cell patients with potential sources of cerebral infarction (Gorman et al., 2009). Periodic red blood cell transfusion is associated with a 90% reduction in the rate of stroke. Expert guidelines from the National Heart, Lung, and Blood Institute strongly recommend that children with sickle cell disease between ages 2 and 16 receive annual TCD examinations (Yawn et al., 2014). Discontinuation of transfusion therapy can result in a reversal of abnormal blood-flow velocities and stroke (STOP 2 Trial, 2005). A 2012 review determined that treating children with transfusions based on TCD results was both clinically effective and cost-effective (Cherry et al., 2012). Despite national recommendations and

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B Fig. 41.29 Raised Intracranial Pressure. Reverberating flow pattern (A) and small systolic spikes (B) seen in a patient with markedly increased intracranial pressure.

its proven efficacy, TCD screening rates continue to remain low and underutilized (Reeves et al., 2016).

Brain Death A characteristic pattern of changes can be detected by TCD in patients with increased ICP. Early findings consist of a mild decrease in the diastolic flow velocity and an increase in the difference between peak-systolic and end-diastolic velocities. When ICP increases further and reaches the diastolic blood pressure level, flow stops during diastole, and the corresponding flow velocity drops to zero; flow continues during systole, and spiky systolic peaks are observed. A further increase in ICP is associated with a reverberating flow pattern, with forward flow in systole and retrograde flow in diastole (see Fig. 41.28). The net volume of flow decreases and can reach zero. At cerebral perfusion pressure values close to zero, either small systolic spikes are observed (Fig. 41.29) or no signal at all is detected. This corresponds to a complete arrest of flow as demonstrated by cerebral angiography. The pattern of TCD changes is not specific to a particular neurological disease and can occur in a variety of conditions associated with increased ICP. These changes are also observed in patients clinically diagnosed as brain dead. Multiple case series have generally reported good correlations between TCD confirmation of cerebral circulatory arrest and clinical confirmation of brain death. Furthermore, this study remains useful as an ancillary test for brain death confirmation because it is safe, noninvasive, and easily performed at the bedside. A 2016 meta-analysis of 22 studies noted a sensitivity of 76% and a specificity of 74.3% for TCD assessment when compared with clinical brain death criteria (Chang et al., 2016). Although TCD is helpful in detecting cerebral circulatory arrest, it cannot be recommended as the sole diagnostic test for the diagnosis of brain death. The latter must be established based on the clinical presentation and neurological

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Fig. 41.30 Carotid Endarterectomy. At clamp insertion, the peak-systolic flow velocity decreases from approximately 175 cm/sec to 35 cm/sec.

examination findings. TCD and other laboratory tests can help confirm the clinical impression.

Periprocedural Monitoring CEA and carotid artery stenting (CAS) remain important interventions for certain cases of asymptomatic and symptomatic carotid stenosis. Monitoring is often performed to identify and correct periprocedural events that can lead to cerebrovascular complications. Monitoring tests currently in use for CEA include electroencephalography. These tests are useful in detecting cerebral hypoperfusion or its consequence, cerebral ischemia, and investigations remain ongoing to determine their effectiveness in reducing the perioperative stroke rate. TCD monitoring during CEA shows a consistent pattern of flow-velocity changes in the ipsilateral MCA. The most significant changes occur at the time of carotid clamping, with persistent and severe flow-velocity decreases to less than 15% of pre-clamp values in up to 10% of patients (Fig. 41.30). Patients with velocities decreasing to this level usually are considered candidates for shunting. Although definitive TCD criteria for shunting have not yet been established, a post-clamp peak-systolic or mean flow-velocity decrease to less than 30% of the pre-clamp value is often considered an acceptable criterion. A 2017 meta-analysis noted that MCA velocity changes on intraoperative TCD had a pooled specificity and sensitivity of 84.1% and 49.7%, respectively, for the prediction of perioperative strokes (Udesh et al., 2017). TCD monitoring also has the unique capability of detecting microembolism as it occurs. This provides a considerable edge to TCD when compared with other monitoring techniques because the majority of

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Fig. 41.31 Carotid Endarterectomy. At clamp release, flow velocities are restored, and microembolic signals are seen.

perioperative infarcts are thought to be secondary to cerebral embolism. Microemboli are detected at specific stages of surgery; dissection, clamp insertion and release, and the immediate postoperative period are the high-risk periods (Fig. 41.31). The presence of solid and gaseous microemboli in patients undergoing CEA and/or carotid stenting has been associated with procedure-related acute ipsilateral ischemic strokes on MRI and postoperative cognitive decline (Skjelland et al., 2009). One study evaluating patients who underwent CEA under TCD monitoring found that low MCA mean blood-flow velocity (≤28 cm/sec) during carotid dissection was significantly associated with new postoperative neurological deficits in patients with 10 or greater MES during carotid dissection. This combined evaluation resulted in improved specificity and PPV when compared with either criterion used alone (Ogasawara et al., 2008). TCD remains a relative newcomer to the field of periprocedural monitoring and provides useful information for potentially averting cerebrovascular complications. The complete reference list is available online at https://expertconsult. inkling.com/.

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42 Functional and Molecular Neuroimaging Karl Herholz, Stefan Teipel, Sabine Hellwig, Sönke Langner, Michel Rijntjes, Stefan Klöppel, Cornelius Weiller, Philipp T. Meyer

OUTLINE Functional Neuroimaging Modalities, 576 Functional Magnetic Resonance Imaging, 576 Arterial Spin Labeling, 577 Positron Emission Tomography, 577 Single-Photon Emission Computed Tomography, 578 Clinical Applications, 579 Overview of Dementia, 579 Alzheimer Disease, 579 Mild Cognitive Impairment, 584 Dementia with Lewy Bodies, 584

Frontotemporal Lobar Degeneration, 585 Vascular Dementia, 586 Parkinsonism, 586 Brain Tumors, 589 Epilepsy, 592 Presurgical Brain Mapping, 594 Paraneoplastic and Autoimmune Disorders, 596 Ischemic Stroke, 598 Coma and Consciousness, 599

Structural imaging modalities such as computed tomography (CT) and magnetic resonance imaging (MRI) are essential techniques for evaluating various central nervous system (CNS) disorders, providing superb structural resolution and tissue contrast. On the other hand, functional and molecular imaging modalities—such as functional MRI (fMRI), positron emission tomography (PET), and single-photon emission computed tomography (SPECT)—visualize brain functions that are not necessarily related to brain structure, most notably cerebral blood flow (CBF), metabolism, receptor binding, and pathological deposits. The techniques are particularly valuable for mapping brain functions or depicting disease-related molecular changes that occur independently of or before structural changes. The principles of fMRI, PET, and SPECT and their applications in clinical neurosciences are discussed in this chapter. Regarding applications of PET and SPECT, the focus is on dementia, parkinsonism, brain tumors, epilepsy, and autoimmune encephalitis. These applications are particularly well established and important in clinical practice. Localization of brain function as a main focus of fMRI research is utilized in presurgical mapping, whereas fMRI research is increasingly also addressing functional brain networks and their changes in neurological diseases.

FUNCTIONAL NEUROIMAGING MODALITIES Functional Magnetic Resonance Imaging Today, fMRI is a standard technique in neuroscience brain imaging. It relates to the blood oxygen level–dependent (BOLD) effect, which is due to a transient and local excess of oxygenated blood resulting from changes in regional CBF and neuronal activity. Oxygenated hemoglobin is used here as an intrinsic contrast agent and serves as a surrogate marker of neuronal oxygen consumption and activity.

One approach to studying the integrity of functional neuronal networks uses experimental stimuli (e.g., words that have to be read) either in a block design (series of words for 20–30 seconds alternating by rest blocks of similar length over several minutes) or event-related tests (≈30–40 stimuli of each type presented in a counterbalanced order, each followed by some baseline period). Experiments are often conducted with multiple subjects, which requires stereotactic normalization into a standard space. Time series are analyzed using univariate analyses within the general linear model (GLM), enabling inferences on local effect sizes. Resulting visualizations illustrate regions with task-specific statistically significant differences in brain activation. More recently multivariate analyses, such as partial least squares, enable inferences on network connectivity on the whole-brain level. Complementary approaches use graph theory analysis to elucidate the network features during task condition or resting state (see later) and their alteration through brain disease or assessment of effective connectivity using causal inference modes, such as dynamic causal modeling, Granger causality, or Bayesian learning networks. Parallel to task-related MRI, resting-state fMRI (Rs-fMRI) has been developed for applications in dementia research (Fox et al., 2005; Thomas et al., 2014). Analysis of spontaneous fluctuations of the BOLD signal during resting-state conditions has revealed consistent networks of intrinsic connectivity that partly map with functional networks activated during task performance, such as motor networks, language networks, attention networks, or deactivated during task performance, such as the default mode network (DMN) involving medial temporal lobe, superior parietal, and prefrontal lobe areas. Analysis of resting-state intrinsic connectivity networks typically involves analysis of correlations with seed regions or network analysis using multivariate techniques such as independent component analysis. Rs-fMRI analyses have been used in the analysis of prodromal or manifest

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Arterial Spin Labeling Arterial spin labeling (ASL) is an MRI technique that provides estimates of cerebral perfusion at the tissue level noninvasively and without the administration of contrast media. The main physiological parameter that can be measured by ASL is the CBF. ASL imaging techniques provide quantitative parametric imaging maps of CBF for visual and region-of-interest (ROI)–based analysis (Grade et al., 2015; Haller et al., 2016). ASL was first introduced in the early 1990s (Detre et al., 1992; Williams et al., 1992). However, its main drawback is its inherent low signal-to-noise ratio (SNR; Golay et al., 2004). Although ASL is possible with 1,5 tesla (T) MR systems, low SNR increases the necessary scan time and therefore makes the technique sensitive to motion artifacts. Recent advances in coil technology and increasing field strength of the MR systems have led to a rapidly growing interest in ASL in clinical and preclinical imaging (Haller et al., 2016). In contrast to other MR-based techniques for the evaluation of tissue perfusion (e.g., dynamic contrast-enhanced MRI [DCE-MRI]), ASL uses the water molecules of the blood as an endogenous contrast agent to estimate tissue perfusion. ASL is based on the strategy of magnetically labeling the protons in blood molecules before they flow into the tissue of interest. According to the spin labeling technique used, ASL can be divided into three different types: pulsed ASL (PASL), pseudo-continuous ASL (pCASL), and continuous ASL (CASL). Currently the most used types of ASL are pCASL and PASL. Important technical parameters for ASL acquisition are positioning of the labeling plane below the brain, labeling duration, and the postlabeling delay (PLD) or inflow-time of the postlabeling period. This delay describes the time between the end of the labeling period and the start of the imaging period. It describes the time allowed for the labeled blood to enter the tissue of interest within the imaging volume. The PLD depends on the blood velocity, which is correlated with the subject’s age. Because older patients have a decreased velocity, the recommended PLD is 1500 ms for pediatric patients and 1800 and 2000 ms for healthy adults below and above 70 years of age, respectively. For adult patients, a PLD of 2000 ms is recommended. There is also a need for background suppression and prevention of patient motion during image acquisition to reduce noise and artifacts masking the signal difference, thus subsequently hindering image analysis. Image readout of ASL was traditionally based on fast echo planar imaging (EPI) techniques. Recently more advanced three-dimensional (3D) acquisition techniques have been proposed (e.g., 3D gradient and spin echo [GRASE] or 3D rapid acquisition relaxation enhanced [RARE] techniques). Compared with two-dimensional (2D) techniques, 3D readout has superior SNR and allows the acquisition of the entire volume of interest within one shot, thus reducing the slice-dependent variations of the perfusion signal observed in 2D techniques (Vidorreta et al., 2013).

Positron Emission Tomography The concept of modern PET was developed during the 1970s (Phelps et al., 1975). The underlying principle of PET and also of SPECT is to image and quantify a physiological function or molecular target of interest in vivo by noninvasively assessing the spatial and temporal distribution of the radiation emitted by an intravenously injected or inhaled target-specific probe (radiotracer). Importantly, PET and

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SPECT tracers are administered in a nonpharmacological dose (micrograms or less), so they neither perturb the underlying system nor cause pharmacological effects. Because of their ability to enable the visualization of molecular targets and functions on a macroscopic level with unsurpassed sensitivity down to a picomolar concentration, PET and SPECT are also called molecular imaging techniques. (See Cherry, 2003, for a textbook on PET and SPECT physics.) (See Table 42.1 for a glossary of PET and SPECT tracers.) In the case of PET, a positron-emitting radiopharmaceutical is injected or inhaled by the subject. The emitted positron travels a short distance in tissue (effective range 95%), with diagnostic sensitivity depending on the inclusion of either patients with clinically well-established diagnoses (97%, ET vs. neurodegenerative parkinsonism; Benamer, Patterson et al., 2000) or patients with clinically “uncertain” parkinsonian syndromes (CUPS) or tremor (78%; Marshall, Reininger et al., 2009). The lower apparent sensitivity in the latter study was due to the inclusion of patients with scans without evidence of dopaminergic

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deficit (SWEED) who were clinically diagnosed with neurodegenerative parkinsonism. Lower rates of SWEED (10%–15%) have also been observed in clinical therapy trials including clinically certain cases; but accumulating evidence (e.g., stable clinical and imaging follow-up, no response to dopaminergic treatment) suggests that SWEED patients do not suffer from neurodegenerative parkinsonism (Mareket al., 2014). Larger studies also underline the diagnostic value of [123I]FP-CIT SPECT in secondary parkinsonism-like schizophrenia and possible drug-induced parkinsonism (normal DAT binding; Tinazzi et al., 2014) or vascular parkinsonism (normal, homogenously reduced, or focal DAT defects; Benitez-Rivero et al., 2013). The actual clinical impact of DAT imaging on the management of patients with CUPS was highlighted by multicenter studies (Catafau et al., 2004; Kupsch et al., 2012). For instance, in one of these studies (Catafau et al., 2004), 36% and 54% of patients with clinically suspected decreased and normal nigrostriatal intergrity showed a normal and pathological [123I] FP-CIT SPECT, respectively, which led to changes in the clinical management in 72% of cases.

Differential Diagnosis of Neurodegenerative Parkinsonism However, DAT imaging does not allow for a reliable differential diagnosis between PD, MSA, PSP, and CBD (Meyer and Hellwig, 2014). Instead, [18F]FDG PET has gained acceptance as the method of choice. It surpasses the diagnostic accuracies of other commonly used techniques such as the imaging of cardiac sympathetic innervation (e.g., using [123I]metaiodobenzylguanidine ([123I]MIBG) scintigraphy) or

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Fig. 42.9 Upper panel, Physiological striatal [18F]FDOPA (FD) uptake, VMAT2 ([11C]DTBZ), and DAT ([11C]-methylphenydate, MP ) binding in a healthy control. Lower panel, Asymmetrical reduction of uptake in a patient with PD, with activity reduction of all three tracers in the posterior putamen and relative sparing of the caudate nucleus. (Courtesy Vijay Chandran and A. Jon Stoessl, University of British Columbia, Canada.)

of striatal dopamine D2/D3 receptors (e.g., using [123I]iodobenzamide ([123I]IBZM); Meyer and Hellwig, 2014). Assessment of regional CBF changes with SPECT may also be used for this purpose (e.g., Eckert et al., 2007). However, since [18F]FDG PET is technically superior and also widely available, the focus here is on [18F]FDG PET. [18F]FDG PET shows disease-specific alterations of cerebral glucose metabolism (e.g., Eckert et al., 2005; Juh et al., 2004; Hellwig et al., 2012; Teune et al., 2010). In scans of PD patients, major abnormalities may not appear initially. On closer inspection and especially on voxel-based statistical analyses, PD is characterized by a posterior temporoparietal, occipital, and sometimes frontal hypometabolism (especially in PD with MCI and PDD) and relative hypermetabolism of putamen, globus pallidus, sensorimotor cortex, pons, and cerebellum (Fig. 42.10). Interestingly, temporo-parieto-occipital hypometabolism may also been seen in nondemented PD patients (Hellwig et al., 2012; Hu et al., 2000), indicating an increased risk of subsequent development of PDD (see “Dementia and Mild Cognitive Impairment,” earlier). Conversely, MSA patients show a marked hypometabolism of striatum (posterior putamen; especially in MSA-P), pons, and cerebellum (especially in MSA-C; Fig. 42.11). In PSP, regional hypometabolism is consistently noted in medial, dorsolateral, and ventrolateral frontal areas (pronounced in anterior cingulate gyrus as well as supplementary motor and premotor areas), caudate nucleus, (medial) thalamus and upper brainstem (Fig. 42.12). Recently proposed MDS-PSP criteria set

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a framework to diagnose several PSP-predominant types (Hoglinger et al., 2017), which can be expected to also differ on [18F]FDG PET. For example, respective functional domains have been linked to predominant regional hypometabolism of bilateral anterior cingulate gyrus (vertical gaze palsy; Amtage et al.,2014), thalamus (repeated unprovoked falls; Zwergal et al., 2011), midbrain (gait freezing; Park et al., 2009) and left medial and dorsolateral frontal lobe (nonfluent aphasia; Roh et al., 2010). Finally, CBD is characterized by a usually highly asymmetric hypometabolism of frontoparietal areas (particularly parietal), motor cortex, middle cingulate gyrus, striatum and thalamus contralateral to the most affected body side (Fig. 42.13). The aforementioned results gained from categorical comparisons fit the results gained from spatial covariance analyses. These were employed to detect abnormal disease-related metabolic patterns in PD, MSA, PSP, and CBD, which were demonstrated to be highly reproducible and to correlate with disease severity and duration; thus they allow for prospective discrimination between cohorts (Eckert et al., 2008; Ma et al., 2007; Niethammer et al., 2014; Poston et al., 2012). The expression of two distinctive spatial covariance patterns characterizes PD: one related to motor manifestations (PDRP) and one to cognitive manifestations (PDCP). The PDRP is already significantly increased in the ipsilateral (“presymptomatic”) hemispheres of patients with hemiparkinsonism (Tang et al., 2010a). Finally, using [18F]FDG PET and CBF SPECT, it was demonstrated that PDRP is also increased in REM sleep behavior

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al., 2005; Garraux et al., 2013; Hellwig et al., 2012; Juh et al., 2004; Tang et al., 2010b; Tripathi et al., 2013). Consistently, a preliminary meta-analysis of currently available studies with inclusion of multiple disease groups yielded a diagnostic sensitivity and specificity for visual PET readings—supported by voxel-based statistical analyses— for the diagnosis of APS of 91.4% and 90.6%, respectively. Diagnostic specificity of [18F]FDG PET for diagnosing MSA, PSP, and CBD was consistently shown to be high (>90%, as requested for a confirmatory test), whereas sensitivity was more variable (>75%; Meyer et al., 2017). However, given the clinical and imaging ambiguity, it may be advisable to use a combined PSP/CBD tauopathy category for PET readings, which reaches a sensitivity and specificity of 87% and 100%, respectively (Hellwig et al., 2012).

Additional Observations in Parkinson Disease Using Other Positron Emission Tomography Imaging Methods

Fig. 42.10 [18F]FDG positron emission tomography (PET) in Parkinson disease (PD) is typically characterized by (relative) striatal hypermetabolism. Temporoparietal, occipital, and sometimes frontal hypometabolism can be observed in a significant fraction of PD patients without apparent cognitive impairment. Cortical hypometabolism can be fairly pronounced, possibly representing a risk factor for the subsequent development of Parkinson disease with dementia (PDD). Upper panel, Transaxial PET images of [18F]FDG uptake. Lower panel, Results of voxel-based statistical analysis using Neurostat/3D-SSP. Given are right and left lateral (RT.LAT and LT.LAT), superior (SUP), and posterior (POST) views (see Fig. 42.1 for additional details). (From Neurostat/3D-SSP analysis based on Minoshima, S., Frey, K.A., Koeppe, R.A., Foster, N.L., Kuhl, D.E., 1995. A diagnostic approach in Alzheimer’s disease using three-dimensional stereotactic surface projections of fluorine-18-FDG PET. J Nucl Med. 36 [7], 1238–1248.)

disorder, being a significant predictor of phenoconversion to PD or DLB (Holtbernd et al., 2014). Thus covariance patterns of cerebral glucose metabolism represent very interesting biomarkers for early diagnosis and therapy monitoring in parkinsonism (Hirano et al., 2009). PSP and CBD may be considered to represent different manifestations of a disease spectrum with several common clinical, pathological, genetic, and biochemical features (Kouri et al., 2011). This issue becomes even more complex if one considers that FTD is often caused by PSP and CBD pathology (see earlier; Kertesz et al., 2005). Consequently the clinical diagnosis of CBD is notoriously inaccurate (Ling, et al., 2010; Wadia and Lang, 2007 ) and imaging results in patients with clinically diagnosed PSP and CBD may be very similar. For instance, findings can be fairly asymmetric not only in CBD but also in PSP, whereby an asymmetric PSP presentation is related to an asymmetric metabolism in motor cortex, cingulate gyrus, and thalamus (Amtage et al., 2014). However, the aforementioned group analysis (Amtage et al., 2014) and the few available studies with postmortem verification (Zalewski et al., 2014) imply that asymmetric frontoparietal hypometabolism is suggestive of CBD. Taken together, these observations indicate that additional studies with postmortem verification are needed to define reliable PET criteria, particularly in tauopathies. Several larger, in part, prospective studies have investigated the applicability of [18F]FDG PET for the differential diagnosis of parkinsonism. They unanimously found a very high accuracy (>90%) of [18F]FDG PET for the distinction between PD and APS, which was largely independent of analytic methods, patient groups (with or without CBD and/or PDD/DLB), and symptom duration (Eckert et

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Postural instability and gait disturbances in PD are less responsive to dopaminergic therapy. PET studies show an association of these features with cholinergic dysfunction. PD patients with falls have lower thalamic cholinergic activity than nonfallers despite comparable nigrostriatal dopaminergic activity (Bohnen et al., 2009). Reduction in gait speed correlates with a reduction in cortical cholinergic activity (Bohnen et al., 2013). Amyloid deposits have also been associated with postural instability and gait dysfunction (Muller et al., 2013). PET has been used to investigate depression in PD, with surprising results. Using the selective serotonin transporter (SERT) ligand [11C]DASB, Guttman and colleagues demonstrated widespread reductions in SERT in PD patients compared with healthy controls, compatible with loss of serotonergic fibers (Guttman et al., 2007). In PD patients with depression, however, SERT binding was increased, particularly in dorsolateral and prefrontal cortex (Boileau et al., 2008); SERT binding correlated with clinical ratings of depression. Although not anticipated, this finding is reminiscent of major depression, where SERT binding is increased in those subjects with negativistic dysfunctional attitudes (Meyer et al., 2004). Additional studies are warranted.

Brain Tumors Gliomas are the most frequent intraparenchymal tumors of the brain. Their histological classification and grading have recently been revised, now also including prognostically relevant molecular markers (International Agency for Research on Cancer et al., 2016). Most imaging studies have been conducted prior to this revision, but the main results still remain valid. As in other malignancies, increased glucose metabolism is associated with proliferative activity and aggressiveness in brain tumors. In fact, the imaging of brain tumors was the first oncological application of [18F]FDG PET (Di Chiro et al., 1982). However, opposed to other body regions, the use of [18F]FDG PET in brain tumor imaging is compromised by lack of contrast due to the high physiological uptake of [18F]FDG in normal gray matter. Thus accurate tumor delineation is not feasible with [18F]FDG PET alone and PET/MRI coregistration is mandatory for [18F]FDG PET interpretation. Due to this limitation of [18F]FDG PET, other radiotracers with little physiological brain uptake—in particular, amino acid tracers [18F]FET, [18F]FDOPA and [11C]MET—are increasingly used (Herholz et al., 2012). However, virtually all other imaging methods depend on changes of transport at the blood–brain barrier (BBB), and [18F]FDG is the only tracer mainly reflecting tumor metabolism. Since cerebral uptake of amino acid tracers is mediated by the carrier (i.e., largely independent of a BBB leak), these tracers allow for a high tumor-to-brain contrast and accurate

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Fig. 42.11 [18F]FDG positron emission tomography (PET) in multiple system atrophy (MSA). In contrast to Alzheimer disease (AD), striatal hypometabolism is commonly found in MSA (see left striatum), particularly in those patients with striatonigral degeneration (SND, or MSA-P). In patients with olivopontocerebellar degeneration (OPCA or MSA-C), pontine and cerebellar hypometabolism is particularly evident. Upper panel: Transaxial PET images of [18F]FDG uptake. Lower panel: Results of voxel-based statistical analysis using Neurostat/3D-SSP. Given are right and left lateral (RT.LAT and LT.LAT), superior (SUP), and inferior (INF) views (see Fig. 42.1 for additional details).

tumor delineation even in the majority of low-grade gliomas (LGGs) without contrast enhancement on CT or MRI. High-grade gliomas (HGGs; WHO grades III–IV) show a significantly higher [18F]FDG uptake than LGGs; (WHO grades I–II) and normal white matter (Figs. 42.14 and 42.15; Delbeke et al., 1995; Meyer et al., 2001; Padma et al., 2003). Oligodendrogliomas show higher uptake of astrocytomas of the same grade (Derlon et al., 2000). Common causes of false-positive [18F]FDG PET scans include brain abscesses, inflammatory changes, pituitary adenomas, and childhood brain tumors (e.g., juvenile pilocytic astrocytomas, choroid plexus papillomas, and gangliogliomas). Nevertheless, [18F]FDG PET may also be a helpful method for tumor grading in childhood CNS tumors (Borgwardt et al., 2005). [18F]FDG uptake is also a predictor of overall survival in patients with gliomas (Alavi et al., 1988; De Witte et al., 2000; Kim et al., 1991; Padma et al., 2003; Patronas et al., 1985). Primary CNS lymphoma (PCNSL) usually show very high [18F]FDG uptake, even exceeding normal gray matter, making [18F]FDG PET a powerful method for the detection of cerebral lymphoma (Fig. 42.16). Moreover, [18F]FDG uptake was found to be an independent predictor of progression-free survival in PCNSL (Kasenda et al., 2013). Some limitations of FDG in gliomas can be overcome by PET studies using large neutral amino acid tracers like [18F]FET and [11C] MET, which are transported by the symmetric A-type carrier and avidly taken up by most LGG (∼80%) and virtually all HGG (>90%) tumors, while physiological brain uptake is low (see Figs. 42.14 and 42.15). [18F]FDOPA can also be used as an amino acid for glioma imaging, but high physiological uptake in the basal ganglia due to

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conversion and storage as [18F]fluoro-dopamine must be considered when scans are being interpreted (Bell et al., 2015). Amino acids such as [18F]fluciclovine, transported by the asymmetric ASC transporter, provide even better contrast because of their very low uptake in normal brain (Tsuyuguchi et al., 2017); however, total uptake in tumors is also lower than with FET and MET. Amino acid PET is very highly sensitive in detecting and delineating gliomas (Galldiks and Langen, 2015). A recent meta-analysis described the high accuracy of [18F]FET PET in differentiating between neoplastic and nonneoplastic brain lesions (sensitivity 82%, specificity 76%; Dunet et al., 2012). In rare instances false-positive findings can be caused by acute inflammatory processes, focal status epilepticus, gliosis, surrounding hematomas, and reperfused ischemia (Hutterer et al., 2013). It has been shown that amino acid PET significantly improves biopsy planning and tumor delineation for surgical resection compared with MRI or [18F]FDG PET, with amino acid PET typically showing larger tumor volumes (Pauleit et al., 2009; Pirotte et al., 2004, 2006; see Fig. 42.15). Furthermore, complete resection of tissue with increased PET tracer uptake ([11C]MET or [18F]FDG) was associated with better survival in HGG, whereas resection of areas with contrast enhancement on MRI was not (Pirotte et al., 2009). Concerning grading, most studies showed a higher amino acid uptake of HGG compared with LGG. However, considerable overlap between groups prohibits a reliable distinction. This situation is further complicated by the observation that oligodendrogliomas show higher amino acid uptake than corresponding astrocytomas (Glaudemans et al., 2013; Herholz et al., 2012). Consequently the prognostic value of

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Fig. 42.12 [18F]FDG positron emission tomography (PET) in progressive supranuclear palsy (PSP). Typical finding in PSP include bilateral hypometabolism of mesial and dorsolateral frontal areas (especially supplementary motor and premotor areas). Thalamic and midbrain hypometabolism is usually also present. In line with overlapping pathologies in frontotemporal dementia (FTD) and PSP, patients with clinical FTD can show a PSP-like pattern and vice versa (see Fig. 42.3). Upper panel, Transaxial PET images of [18F]FDG uptake. Lower panel, Results of voxel-based statistical analysis using Neurostat/3D-SSP. Given are right and left lateral (RT.LAT and LT.LAT) and mesial (RT.MED and LT.MED) views (see Fig. 42.1 for additional details). (From Neurostat/3D-SSP analysis based on Minoshima, S., Frey, K.A., Koeppe, R.A., Foster, N.L., Kuhl, D.E., 1995. A diagnostic approach in Alzheimer’s disease using three-dimensional stereotactic surface projections of fluorine-18-FDG PET. J Nucl Med. 36 [7], 1238–1248.)

amino acid uptake is inferior to [18F]FDG PET in mixed populations (Pauleit et al., 2009). However, the initial uptake and kinetic course of [18F]FET uptake was found to be highly predictive of tumor grade (Calcagni et al., 2011; Popperl et al., 2006): HGGs usually show an early peak with a subsequent decrease of [18F]FET uptake, whereas LGGs commonly show a delayed and steadily increasing [18F]FET uptake. These kinetic patterns were also found to predict malignant transformation and prognosis in patients with LGG (Galldiks et al., 2013; Jansen et al., 2014). Within groups of LGG, lower amino acid uptake is also associated with a better prognosis (Floeth et al., 2007; Smits et al., 2008). There is often considerable heterogeneity within gliomas with regard to local tumor proliferation and malignancy. PET can localize the most malignant tumor parts, which should be selected for histological assessment by biopsy in order to provide accurate tumor grading (Goldman and Pirotte, 2011). Planning radiation therapy is another important application. Clinical trials will investigate whether amino acid PET for the definition of gross tumor volume and for radiation treatment can improve outcome (Oehlke et al., 2016). This is particularly relevant after surgery, when the specificity of MRI is compromised by postoperative changes (Grosu et al., 2005; Hirata et al., 2018). Hypoxic tumor tissue is resistant to radiation therapy. Research studies have demonstrated that PET with tracers based on agents that bind to hypoxic tissue, such as [18F]FMISO, can identify hypoxic tissue in gliomas and thus potentially guide radiotherapy (Bekaert et al., 2017). Differentiation between benign treatment-associated changes (radiation necrosis and pseudoprogression in particular) and residual

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Fig. 42.13 [18F]FDG positron emission tomography (PET) in corticobasal degeneration (CBD). In line with the clinical presentation, CBD is characterized by a highly asymmetrical hypometabolism of frontoparietal areas (including the sensorimotor cortex; often most pronounced parietal), striatum, and thalamus. Upper panel, Transaxial PET images of [18F]FDG uptake. Lower panel. Results of voxel-based statistical analysis using Neurostat/3D-SSP. Given are right and left lateral (RT.LAT and LT.LAT) and superior (SUP) views (see Fig. 42.1 for additional details). (From Neurostat/3D-SSP analysis based on Minoshima, S., Frey, K.A., Koeppe, R.A., Foster, N.L., Kuhl, D.E., 1995. A diagnostic approach in Alzheimer’s disease using three-dimensional stereotactic surface projections of fluorine-18-FDG PET. J Nucl Med. 36 [7], 1238–1248.)

Fig. 42.14 [18F]FDG and [18F]FET positron emission tomography (PET) in a left frontal low-grade oligodendroglioma (World Health Organization grade II). [18F]FDG uptake (middle) of low-grade gliomas is usually comparable to white-matter uptake, prohibiting a clear delineation of tumor borders. In contrast, the majority of low-grade gliomas (particularly oligodendrogliomas) show intense and well-defined uptake of radioactive amino acids such as [18F]FET (right) even without contrast enhancement on MRI (left). (Courtesy Karl-Josef Langen, MD, Institute of Neuroscience and Medicine, Research Center Juelich, Germany.)

or recurrent tumor is of paramount importance. Since the specificity of CT and MRI is compromised by contrast enhancement due to nonneoplastic posttherapeutic changes, PET imaging is frequently used. However, the merit of [18F]FDG PET is controversial, since earlier studies provided highly variable results with sensitivity and specificity ranging from 40% to 100% (Herholz et al., 2012; Langleben et al., 2000). False-negative results are relatively frequent and may occur due to very recent radiation therapy, pretreatment low [18F]FDG uptake (e.g., in LGG or metastases with low [18F]FDG avidity), masking by physiological uptake, and small tumor volumes. Conversely, intense inflammatory reaction after radiation therapy (especially stereotactic) and

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Fig. 42.15 [18F]FDG and [18F]FET positron emission tomography (PET) in a right mesial temporal high-grade astrocytoma (World Health Organization grade III). In contrast to low-grade gliomas, high-grade tumors usually have [18F]FDG uptake (middle) that is distinctly higher than white matter and sometimes even above gray matter, as in this case. Nevertheless, the [18F]FET scan (right) clearly depicts a rostral tumor extension that is missed by [18F]FDG PET, owing to high physiological [18F] FDG uptake by adjacent gray matter. Tumor delineation is also clearer on [18F]FET PET than on magnetic resonance imaging (left). (Courtesy Karl-Josef Langen, MD, Institute of Neuroscience and Medicine, Research Center Juelich, Germany.)

Fig. 42.16 [18F]FDG and [18F]FET positron emission tomography (PET) in a primary central nervous system lymphoma (PCNSL). PCNSL usually show a very intense [18F]FDG uptake (middle), whereas the metabolism of surrounding brain tissue is suppressed by extensive tumor edema (see magnetic resonance image, left). [18F]FET uptake (right) of cerebral lymphoma can also be high. (Courtesy Karl-Josef Langen, MD, Institute of Neuroscience and Medicine, Research Center Juelich, Germany.)

seizure activity may result in false-positive findings. If tumor uptake exceeds the expected background uptake in adjacent brain tissue, it is crucial to carefully evaluate the accuracy of PET/MRI coregistration (Fig. 42.17). Under these conditions, the sensitivity and specificity of [18F]FDG PET in differentiating between tumor recurrence (gliomas and metastases) and radiation necrosis is about 75% to 80% and 85% to 90%, respectively (Chao et al., 2001; Gomez-Rio et al., 2008; Wang et al., 2006; ). As in the case of primary tumors, the shortcomings of [18F]FDG PET may be overcome by amino acid PET (see Fig. 42.17). The reported sensitivity and specificity of amino acid PET range from 75% to 100% and 60% to 100%, respectively (Glaudemans et al., 2013; Galldiks et al., 2012; Nihashi et al., 2013). Finally, PET has also been used successfully to assess response following drug treatment (Roelcke, Wyss et al., 2015), but appropriate PET criteria and the clinical role of PET still requires further definition. The assessment of proliferation is of particular interest in the case of brain tumors. Thymidine-based tracers [11C]thymidine and [18F]fluorothymidine ([18F]FLT) are incorporated into DNA in proliferating tumors and have been used to assess proliferation. However, uptake of these tracers in lesions with an intact BBB is very low, and high uptake is observed only in tumors with BBB damage. Thus dynamic scanning is required to measure tracer incorporation into DNA. This has been used successfully to distinguish between recurrent tumors and radiation necrosis (Spence et al., 2009), but the results were not superior to those from [18F]FDG PET (Enslow et al., 2012).

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Fig. 42.17 [18F]FDG and [18F]FET positron emission tomography (PET) in a recurrent high-grade astrocytoma (World Health Organization grade III). [18F]FDG uptake (middle) is clearly increased above expected background in several areas of suspected tumor recurrence on magnetic resonance image (left), confirming viable tumor tissue. Compared with [18F]FDG PET, [18F]FET PET (right), more clearly and extensively depicts the area of active tumor. (Courtesy Karl-Josef Langen, MD, Institute of Neuroscience and Medicine, Research Center Juelich, Germany.)

[11C]Methionine has also been used for the imaging pituitary tumors and monitoring their treatment, with dopamine receptor ligands as a possible alternative (Bergstrom et al., 1991). More recently there has been considerable interest in imaging of somatostatin receptors (SSTRs) in brain tumors, including meningiomas and gliomas, using 68Ga-DOTA-conjugated peptides such as [68Ga]DOTA-TATE or [68Ga]DOTA-TOC (Rachinger et al., 2015). Interestingly, in meningioma, the expression of SSTRs seems to increase with increasing tumor grade (Barresi et al., 2008; Wang et al., 2013). Thus SSTR PET may serve as a selection criterion for radionuclide treatment with beta-emitting SSTR ligands (e.g., [177Lu] DOTA-TATE or [90Y]DOTA-TOC), but the overall benefit of this theranostic approach still requires further validation (Seystahl et al., 2016). Experimental studies include endothelial receptor imaging and theranostic approaches using longer-lived isotopes such as 66Cu and 89Zr (Jansen et al., 2017). Magnetic resonance spectroscopy (MRS) has been suggested in addition to MRI to help in the characterization of brain tumors by detecting metabolic alterations that may be indicative of the tumor class (Callot et al., 2008). MRS emerged as a clinical research tool in the 1990s; it has not yet entered broad clinical practice, although it is frequently used at some instituations. Of the principal metabolites that can be analyzed, N-acetylaspartate (NAA) is present in almost all neurons. Its decrease corresponds to neuronal death or injury or the replacement of healthy neurons by other cells (e.g., tumor). Cholinecontaining compounds increase whenever there is cellular proliferation. Creatine is a marker of overall cellular density. Myoinositol is a sugar that is present only in glia. Lactate concentrations reflect hypoxic conditions as well as hypermetabolic glucose consumption. The most frequently studied chemical ratios to distinguish tumors from other brain lesions with MRS are choline/creatine, choline/NAA and lactate/ creatine. Specifically, a choline/NAA ratio greater than 1 is indicative of neoplasm. The differentiation between astrocytomas of WHO grades II and III is especially difficult. MRS in conjunction with structural MRI has been used to differentiate cystic tumor from brain abscess (Chang et al., 1998), LGG versus gliomatosis cerebri, and edema versus infiltration (Nelson et al., 2002). Positive responses to radiotherapy or chemotherapy may be associated with a decrease in choline (Lichy et al., 2005; Murphy et al., 2004).

Epilepsy In drug-refractory focal epilepsy, surgical resection of the epileptogenic focus offers an excellent chance of a seizure-free outcome or at least reduced seizure frequency, making epilepsy surgery the treatment of choice in these patients. Accurate localization of the seizure focus as

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CHAPTER 42 Functional and Molecular Neuroimaging a prerequisite for successful surgery is commonly accomplished by a comprehensive presurgical evaluation including neurological history and examination, neuropsychological testing, interictal and ictal electroencephalography (EEG), depth recordings, high-resolution MRI, and video-EEG monitoring. To circumvent the necessity for invasive EEG recordings or to target their location for invasive EEG recordings, [18F]FDG PET and CBF SPECT are often used to gain information about the location of the focus of seizure onset. In contrast to the aforementioned PET and SPECT indications, in which PET is superior to SPECT, both modalities are equally essential and often complementary in the presurgical assessment of patients with drug-refractory focal epilepsy (Goffin et al., 2008). In general, PET and SPECT are of particular diagnostic value if the surface EEG and MRI yield inconclusive or normal results (Casse et al., 2002; Knowlton et al., 2008; Willmann et al., 2007). Several neurotransmitter receptor ligands (most notably [11C]/[18F]flumazenil) have been proposed for imaging in epilepsy. However, their availability is still very restricted and their superiority compared with [18F]FDG PET and ictal SPECT has not been validated (Goffin et al., 2008). Because of their rapid, virtually irreversible tissue uptake, CBF SPECT tracers such as [99mTc]ECD and [99mTc]HMPAO (stabilized form) can be used in combination with video-EEG monitoring to image the actual zone of seizure onset. To do so, the patient is monitored by video EEG and the tracer is administrated as fast as possible after seizure onset or EEG discharges to capture the associated CBF increase. For rapid tracer administration and radiation safety reasons, the radiotracers should be stored in a shielded syringe pump and injected via remote control from the surveillance room. Actual SPECT acquisition can then be done at a later time (preferably within 4 hours after injection), when the patient has recovered and is cooperative. Although ictal SPECT alone may show a well-defined region of hyperperfusion corresponding to the seizure onset zone, it is recommended to acquire an additional interictal SPECT scan (also under EEG monitoring) to exclude seizure activity. By comparing both scans, even areas with low ictal CBF increases or CBF increases from an interictally hypoperfused state to an apparent “normal” perfused ictal state can be reliably defined. In addition to visual inspection, computation of parametric images of CBF changes (e.g., ictal—interictal difference images), which are overlaid onto a corresponding MRI, are optimal for focus localization. Such analyses (most notably subtraction ictal SPECT coregistered to MRI [SISCOM]) significantly improve the accuracy and interrater agreement on localization of the seizure focus with ictal SPECT, particularly in frontoparietal neocortical epilepsy (Lee et al., 2006; O’Brien, et al., 1998; Spanaki et al., 1999 Fig. 42.18). The area with the most intense and extensive ictal CBF increase is commonly assumed to represent the seizure onset zone. However, depending on the time gap between seizure onset and cerebral tracer fixation, ictal SPECT depicts not only the onset zone but also the propagation zone. Therefore accurate knowledge regarding the timing of tracer injection is crucial for the interpretation of ictal SPECT. In patients with temporal lobe epilepsy (TLE), CBF increases may propagate to various cortical areas during seizure progression—including the contralateral temporal lobe, insula, basal ganglia, and frontal lobe—reflecting seizure semiology (Shin et al., 2002). In patients with focal dysplastic lesions, distinct ictal perfusion patterns have been observed with seizure propagation, during which the area of most intense CBF increase may migrate away from the seizure onset zone (Dupont et al., 2006). This underlines the need for rapid tracer injection after seizure onset to localize the actual onset zone. A delay not exceeding 20–45 seconds enables optimal localization results (Lee et al., 2006; O’Brien et al., 1998). At later time points, a so-called postictal switch occurs, leading to hypoperfusion of the

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Fig. 42.18 [18F]FDG positron emission tomography (PET) and ictal [99mTc]ECD SPECT in left frontal lobe epilepsy. This patient’s magnetic resonance imaging (MRI) scan (top row) was normal, whereas [18F] FDG PET showed extensive left frontal hypometabolism (second row). Additional ictal and interictal [99mTc]ECD SPECT scans were performed for accurate localization of seizure onset. Result of a SPECT subtraction analysis (ictal-interictal; blood flow increases above a threshold of 15%, maximum 40%) was overlaid onto MRI and the [18F]FDG PET scan (third and fourth rows, respectively), clearly depicting the zone of seizure onset within the functional deficit zone given by [18F]FDG PET.

onset zone. Within 100 seconds from seizure onset, about two-thirds of ictal SPECT studies can be expected to show hyperperfusion; after that (>100 seconds postictally), hypoperfusion will be observed (Avery et al., 1999). The diagnostic sensitivity of ictal SPECT to correctly localize the seizure focus (usually with reference to surgical outcome) is about 85% to 95% in TLE and 70% to 90% in extratemporal lobe epilepsy (ETLE; Devous et al., 1998; Newton et al., 1995; Weil et al., 2001; Zaknun et al., 2008). Focus localization can also be successful by postictal tracer injection, capturing postictal hypoperfusion. However, localization accuracy will be lower (about 70%–75% in TLE and 50% in ETLE; Devous et al., 1998; Newton et al., 1995). In contrast, interictal SPECT to detect interictal hypoperfusion is insufficient for focus localization (sensitivity about 50% in TLE; of no diagnostic value in ETLE; Newton et al., 1995; Spanaki et al., 1999; Zaknun et al., 2008). In contrast to ictal SPECT, [18F]FDG PET studies are performed in the interictal state to image the functional deficit zone, which shows abnormal metabolism between seizures and is generally assumed also to contain the seizure onset zone. The etiology of this hypometabolism is not fully understood and probably relates to functional (e.g., surround inhibition of areas of seizure onset and propagation as a defense mechanism) and structural changes (e.g., neuronal or synaptic loss due to repeated seizures). Hypometabolism appears to increase with the duration, frequency, and severity of seizures and usually extends

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considerably beyond the actual seizure onset zone, occasionally involving contralateral mirror regions (Kumar and Chugani, 2013). A direct comparison of ictal perfusion abnormalities detected by SISCOM and interictal [18F]FDG PET hypometabolism in TLE patients demonstrated high concordance, suggesting that seizures are generated and spread in metabolically abnormal regions (Bouilleret et al., 2002). To ensure an interictal state, the patient should ideally be seizure free for at least 24 hours before PET and be monitored by EEG after [18F]FDG injection to rule out possible subclinical epileptic activity. Side-to-side asymmetry may be calculated by ROI analysis to support visual interpretation, whereby an asymmetry ≥10% is commonly used as a threshold for regional pathology. Furthermore, voxel-wise statistical analyses are strongly recommended: Visual analysis by an experienced observer is at least as accurate in TLE patients (Fig. 42.19), but accuracy and interobserver agreement of focus localization is considerably improved by additional voxel-wise statistical analyses in ETLE (Drzezga et al., 1999; Fig. 42.20). Finally, PET/MRI coregistration is very helpful for detecting PET abnormalities in regions with apparently normal anatomy (e.g., caused by subtle focal cortical dysplasia, FCD) and to disclose the extent of PET findings in relation to structural abnormalities (e.g., in epileptogenic tumors or tuberous sclerosis; Lee and Salamon, 2009). However, if structural abnormalities and the accompanying hypometabolism are extensive (e.g., infarction, contusion, surgery), ictal SPECT may be preferred to image the area of seizure onset. [18F] FDG PET may nevertheless be helpful to evaluate the functional integrity of the remaining brain regions. In meta-analyses, the sensitivity of [18F]FDG PET for focus lateralization (rather than localization given the extent of hypometabolism) in TLE was reported to be around 86%, whereas false lateralization to the contralateral side of the epileptogenic focus rarely occurs ( TH1 cells, and interacts with Tim-4 on APCs to induce T-cell proliferation (Meyers et al., 2005).

Chemokines Chemokines are a recently discovered and extensively studied group of molecules that aid in leukocyte mobility and directed movement. Chemokines may be grouped into two subfamilies based on the configuration and binding of the two terminal cysteine residues. If the two residues participating in disulfide bonding are adjacent, they are termed the C-C family (e.g., MCP, MIP-1α, RANTES). Those separated by one amino acid, are C-X-C family members (e.g., IL-8), where X indicates a nonconserved amino acid. Two chemokine receptors, CCR-5 and CXCR-4, can act as coreceptors for strains of HIV. Chemokines are produced by a variety of immune and nonimmune cells. Monocytes, T cells, basophils, and eosinophils express chemokine receptors, and these receptor-ligand interactions are critical to the recruitment of leukocytes into specific tissues.

Termination of an Immune Response The primary goal of the immune response is to protect the organism from infectious agents and generate memory T- and B-cell responses that provide accelerated and high-avidity secondary responses on reencountering antigens. It is desirable to terminate these responses once an antigen has been cleared. In parallel, the immune system must constantly function to prevent autoimmune activation and to maintain self-tolerance. A number of systems operate to prevent uncontrolled responses. Here we discuss termination of individual components of the immune response. Following is a discussion of the mechanisms that maintain self-tolerance, many of which are also involved in immune-response termination.

B-Cell Inhibition In most instances, an antigen is cleared either by cells of the reticuloendothelial system or through the formation of antigen–antibody complexes. These complexes can themselves result in the inhibition of B-cell differentiation and proliferation through binding of the Fc receptor to the CD32 (FcγRIIB) receptor on the surface of the B cell.

Immunoglobulin The variable regions of the Ig and the TCR molecule represent novel proteins that can act as antigens. Antigenic variable regions are called idiotopes, and responses against such antigens are called anti-idiotypic. Niels Jerne’s network hypothesis postulates that anti-idiotypic responses serve to regulate the immune response; however, the extent to which this operates is unclear.

T Cells Termination of the T-cell immune response is mediated by several mechanisms including anergy, deletion, and suppressor cell activity. Anergy or functional unresponsiveness occurs when there is insufficient T-cell activation. Repeated stimulation of T cells may lead to activation-induced cell death through apoptosis. Cytokine-mediated regulation can also serve to terminate the immune response, notably by secretion of TH2 and TH3 cytokines. Regulatory cells (discussed in the following section) generally inhibit the immune response through secretion of cytokines, through cytotoxic mechanisms, or by modulation of the function of APCs. A combination of the above-described mechanisms cooperate to maintain self-tolerance, particularly peripheral tolerance, and are discussed later.

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IL-2R

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T cell Proliferation effector function

IL-2 B7

CD28

A Nonprofessional APC MHC

TCR

T cell Anergy

CD28

B Fig. 49.6 A Two-Signal Model of T-Cell Activation. Activation of the T-cell receptor (TCR) by an antigen major histocompatibility complex (MHC) provides signal 1, which is sufficient to induce the T cell to enter the cell cycle and begin blast transformation, which is characterized by an increase in cell size. Signal 2, the costimulatory signal, can be provided to the T cell through interaction of CD28 with molecules of the B7 family found on the surface of bone marrow–derived antigen-presenting cells (APCs). A, In this instance, TCR signals are complemented, enabling the T cell to proliferate, produce cytokines, and develop mature effector functions. B, In the absence of a second signal, T-cell activation is abortive, and the cell becomes anergic. Signal 2 might not be delivered if the APC does not express a costimulatory ligand on its surface, perhaps because a nonprofessional APC, such as an epithelial cell, is presenting antigen. IL, Interleukin.

SELF-TOLERANCE An organism’s ability to maintain a state of unresponsiveness to its own antigens is termed self-tolerance. Self-tolerance is maintained through three principal mechanisms: deletion, anergy, and suppression. Selftolerance may be broadly categorized as either central or peripheral tolerance. Similar mechanisms may also be used to induce tolerance to a foreign antigen or terminate an immune response.

Central Tolerance Bone marrow stem cells migrate to the thymus, thereby becoming thymocytes, or T cells. In this location, T-cell VDJ germline genetic elements recombine to create α and β chains, which in turn form the TCR. Thymocytes then undergo a process of education that involves positive and negative selection. Positive selection of thymocytes occurs in the thymus cortex when the cells are in the double negative stage, CD4− CD8−. The cortex contains dendritic and epithelial cells that present MHC antigens to the developing thymocytes. T cells with receptor having no affinity to MHC will fail to receive signals needed for maturation and will die in situ. Those with low affinity toward MHC survive and become single-positive thymocytes depending on their affinity toward MHC I (CD8+) or MHC II (CD4+). In the thymus medulla, thymocytes that display a high affinity toward self-antigen are deleted by apoptosis, a process called negative selection. Most T-cell education occurs in the thymus; however, extrathymic sites may exist.

Peripheral Tolerance Self-reactive lymphocytes may escape central tolerance; therefore peripheral mechanisms exist to maintain self-tolerance. This is termed peripheral tolerance. Peripheral tolerance is maintained through clonal anergy or clonal deletion. It is not clear to what extent each of these mechanisms functions in maintaining human self-tolerance; however, extensive research has been done to elucidate the mechanisms through which anergy and deletion work. In addition, self-tolerance may be maintained despite the presence of antigen-responsive

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lymphocytes. It is postulated that this is due to the presence of suppressor T cells or other factors that may interfere with a successful lymphocyte response.

Anergy Due to Failure of T-Cell Activation In normal circumstances, an APC presents antigen as a peptide + MHC complex (signal one). In the absence of signal one, the T cell dies because of neglect. If signal one is presented in the absence of costimulatory signals (signal two), the T cell becomes anergic. An example of this situation occurs when an antigen is presented by nonprofessional APCs that lack the appropriate costimulatory molecules (Fig. 49.6). However, when a T cell is activated, it up-regulates the expression of an alternate costimulatory molecule, CTLA-4. CTLA-4 engagement by CD80 and CD86 on the surface of APCs sends a negative signal to the T cell, inhibiting cell growth and proliferation. Animals deficient for CTLA-4 expression on their T lymphocytes have an uncontrolled lymphoproliferative phenotype with autoreactivity (Waterhouse et al., 1995).

Apoptosis Apoptosis is the process in which a cell undergoes programmed cell death. As opposed to necrosis, when interruption of the supply of nutrients triggers cell death, apoptosis may be triggered by various signals including withdrawal of growth factors, cytokines, exposure to corticosteroids, and repeated exposure to antigens. Mediators of apoptosis include the Bcl family of genes, which are mostly antiapoptotic, and the Fas family of genes, which are proapoptotic. Activated T cells also express Fas ligand (CD95L or FasL) and Fas (CD95); ligation of Fas and FasL induces apoptosis of the T cells. Repeated stimulation with an antigen may also induce apoptosis via the Fas/FasL pathway, a process termed activation-induced cell death (AICD). Therefore an autoreactive T lymphocyte may encounter large doses of self-antigen in the periphery and consequently may be deleted by AICD. Mice lacking Fas or FasL develop a lupus-like syndrome (Zhou, et al., 1996), and mutations in the Fas gene were associated with an autoimmune disease with lymphoproliferation in humans (Drappa, et al., 1996).

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THE GUT MICROBIOME

Activated T cell

APC MHC

TCR

Apoptosis FasL Fas Fig. 49.7 Activation of the T cell leads to coexpression of the death receptor Fas (CD95) and its ligand (FasL), resulting in death of the cell and neighboring cells. APC, Antigen-presenting cell; MHC, major histocompatibility complex; TCR, T-cell receptor.

The gut is home to trillions of commensal bacteria, viruses, fungi, and protozoa. Commensal bacteria have co-evolved with humans and homeostasis is maintained with beneficial effects for both (Forbes, Bernstein et al. 2018). The microbiome has a large influence on the immune system, and changes in the microbiome have been reported in many diseases although the exact mechanisms by which these changes affect human health are still unknown. This in an area of active investigation.

IMMUNE SYSTEM AND CENTRAL NERVOUS SYSTEM Immune Privilege in the Central Nervous System

IL-2 is the prototypical growth factor, inducing clonal expansion of antigen-stimulated lymphocytes; paradoxically, disruption of the IL-2 gene leads to accumulation of activated lymphocytes and autoimmune syndromes (Sadlack, et al., 1993). This is because IL-2 induces the transcription and surface expression of Fas ligand (FasL). Interactions of Fas with FasL lead to cell death (Fig. 49.7). Therefore IL-2 plays a dual role in T-cell regulation, reflecting a possible role for cytokine concentration and timing of exposure. Other cytokines that mediate apoptosis and cell death are TNF-α and IFN-γ. Complete absence of either of these cytokines results in deficient T-cell apoptosis, inability to terminate the immune response, and uncontrolled autoimmune disease.

Regulatory T Cells Regulatory T cells (Treg) function to down-regulate CD4 and CD8 T-cell responses. Regulatory T cells can be of the CD4+ or CD8+ subtypes. Regulatory T cells can be generated under similar conditions used to generate anergic cells, and it has been postulated that they are the same entity (Lombardi et al., 1994). Several populations of regulatory or suppressor T cells have been described in humans. CD4+ regulatory T cells were initially identified by expression of CD4 and high levels of CD25 (Baecher-Allan et al., 2001; Dieckmann et al., 2001; Levings et al., 2001; Stephens et al., 2001; Yagi et al., 2004). Most Tregs also express GITR, CD103, CTLA-4, lymphocyte activation gene 3 (LAG-3), and low levels of CD45RB, although no single marker is specific for Tregs. The expression of the transcription factor Foxp3 correlates with regulatory function of CD4+ T cells in mice (Littman and Rudensky, 2010) and deletion of Foxp3 results in loss of suppressive phenotype. In humans, immune dysfunction/polyendocrinopathy/ enteropathy/X-linked (IPEX) syndrome is an autoimmune syndrome consisting of lymphoproliferation lympho-proliferation, thyroiditis, insulin-dependent diabetes mellitus, enteropathy, and other immune disorders. Most cases of IPEX syndrome are caused by mutations in FOXP3. Other types of regulatory T cells include CD8+CD28− T cells (Koide and Engleman 1990), IL-10-producing TH2 cells (Bacchetta, Bigler et al. 1994), and TGF-β-producing TH3 cells (Kitano et al., 2000; Levings et al., 2001; Roncaro and Levings, 2000). In humans, there is little evidence for antigen-specific suppressor cell responses. Regulatory T cells suppress T-cell proliferation through a variety of mechanisms, including the production of immunosuppressive cytokines (TH2 or TGF-β) or through T–T cell interactions, including the expression of inhibitory molecules such as CTLA-4. Regulatory cells play an important role in the control of the immune response in autoimmune disorders, and the function of regulatory T cells may be enhanced by immunomodulatory therapies.

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Immunological reactions in the CNS differ from those in the rest of the body because of its unique architecture, cellular composition, and molecular expression. The CNS has been termed an immunologically privileged site because of the relative improved survival of allografts within this region. Indeed, the same factors that play a role in immunological tolerance in the CNS play a role in immune-mediated diseases involving the CNS, infections of the CNS, tumor survival, and therapies. Important factors relevant to immunological responses in the CNS are: (1) absence of classic lymphatic drainage, limiting the immunological circulation; (2) the BBB, which limits the passage of immune cells and factors; (3) the low level of expression of MHC factors, particularly MHC II in the resident cells of the CNS; (4) low levels of potent APCs, such as dendritic or Langerhans cells; and (5) the presence of immunosuppressive factors such as TGF-β (Wilbanks and Streilein, 1992) and CD200 (Webb and Barclay, 1984). The CNS was long-thought to lack a lymphatic system; however, the recent discovery of lymphatic vessels within the CNS dural sinuses (Aspelund et al., 2015; Louveau et al., 2015). has opened new areas of investigation into the trafficking of cerebral immune cells. Monocytederived CNS resident cells, termed microglia, play an important role in immune surveillance in these areas. The BBB is composed of tight junctions between endothelial cells and a layer of astrocytic foot processes that prevent entry of inflammatory cells and other factors into the CNS. Entry of inflammatory cells across the BBB is facilitated by up-regulation of adhesion molecules ICAM-1 and VCAM-1 on endothelial cells. T cells must be activated before crossing the BBB. Entry is facilitated by expression of receptors for adhesion molecules, including α4-integrin. The CNS houses cells that are capable of antigen presentation under certain conditions in vitro, but to what extent this occurs in vivo remains under debate. In the CNS, endogenous expression of MHC class I and class II on APCs, such as microglia, is low, and in oligodendrocytes and astrocytes it is almost undetectable. Neurons express MHC class I only when damaged and in the presence of IFN-γ (Neumann et al., 1995). Expression of MHC antigens on both microglia and astrocytes is enhanced by the presence of cytokines, TNF-α, and IFN-γ. Under certain conditions, microglial cells may play a role as APCs in the nervous system (Perry, 1994). More recently, populations of perivascular dendritic cells capable of antigen presentation have been identified in rodents (Greter et al., 2005), with analogous populations demonstrated in humans; however, their role in human disease is unclear. Immune privilege in the CNS is also influenced by the constitutive expression of a number of immunoregulatory factors, some of which are common to immune privilege in the anterior chamber of the eye. Anterior chamber immune privilege is due in part to expression of

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CHAPTER 49 Neuroimmunology TGF-β in the aqueous of the eye. In the CNS, TGF-β is produced by astrocytes and microglia and may play a role in down-regulating immune responses locally. Neurons are also capable of producing TGF-β, which in animal models has been shown to facilitate the differentiation of regulatory T cells (Liu, et al., 2006). Increased expression of Fas ligand in the CNS compared with the peripheral nervous system (PNS) may increase apoptosis of T cells, thereby down-regulating the immune response (Moalem et al., 1999). Some CNS tumors express large amounts of TGF-β, which may play a role in protecting them from immune surveillance. CNS tumors may also express Fas or Fas ligand, facilitating protection from immune surveillance. Some populations of neurons express a cell surface marker named CD200. CD200 is a nonsignaling molecule but serves to inhibit activation of cells including microglia and macrophages that express the CD200 receptor (CD200R) (Hoek et al., 2000; Wright et al., 2000). CD200 has been shown to down-regulate inflammatory responses in models of MS (Liu et al., 2010) and uveitis (Broderick et al., 2002, Banerjee and Dick, 2004). Fractalkine (CXCL1) is a chemokine that is constitutively expressed on some populations of neurons. Interaction with its receptor, CX3CR1, present on microglia and NK cells, serves to down-regulate microglial-mediated neurotoxicity both in vitro and in animal models of Parkinson disease and amyotrophic lateral sclerosis (ALS) (Cardona et al., 2006). In the animal model of MS, absence of fractalkine or its receptor resulted in a reduction of NK cells in the CNS and exacerbation of disease, supporting the view that NK cells play an inhibitory role in CNS inflammation (Huang et al., 2006).

Neuroglial Cells and the Immune Response Neuroglial cells including microglia and astrocytes participate in immune responses within the CNS, and there is increasing evidence that these cells play a central role in initiating and propagating immune-mediated diseases of the CNS. Microglia are derived from bone marrow cells during ontogeny (Hickey and Kimura, 1988) and reside within the CNS as three principal types of cells: perivascular microglia, parenchymal microglia, and Kolmer cells, which reside in the choroid plexus. Microglia have mitotic potential and can differentiate from bone marrow–derived cells to perivascular microglia and parenchymal microglia. Compared with macrophages, microglia are relatively radioresistant. Microglia may exist either in a resting (ramified) form or activated or phagocytic forms within the CNS. Activated microglia express higher levels of MHC class II and produce higher levels of proinflammatory cytokines including TNF-α, IL-6, and IL-1, as well as nitric oxide and glutamate. Microglia express chemokine receptors and various PRRs, including TLRs. PRRs recognize PAMPs expressed by a variety of microbes, and interaction results in microglial activation. The primary functions of microglia are immune surveillance for foreign antigens and phagocytic scavengers of cellular debris. Microglia, particularly perivascular microglia, may also participate in antigen presentation within the CNS under certain conditions. Microglia play a role in regulating the programmed elimination of neural cells during brain development and, in some cases, enhance neuronal survival by producing neurotrophic and antiinflammatory cytokines. Microglia may also play a role in neuroregeneration and repair. However, there is overwhelming evidence that microglia play a deleterious role in several neurodegenerative diseases: MS, ALS, Parkinson disease, and HIV-associated dementia. Their role in Alzheimer disease (AD) is less clear. Overactivation of microglia, possibly by microbes or other environmental factors through PRRs, may result in chronic proinflammatory milieu in the CNS, leading to progressive neurodegeneration. Strategies to down-regulate such responses are under investigation (Block et al., 2007).

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Astrocytes play multiple roles in the CNS, including their role in the glia limitans at the BBB and physical support of neuronal and axonal structures, as well as provision of growth factors. Astrocytes secrete cytokines including TGF-β and are also influenced by IL-1 and interferons to divide and express proteins such as costimulatory molecules and TLRs on their surfaces. There is increasing evidence against the role of astrocytes in antigen presentation within the CNS. Astrocytes play a critical role in converting glutamate to glutamine, a less toxic substance, so impairment of astrocyte function may result in increased glutamate-mediated neurotoxicity. Astrocytes also produce chemo-kines, including stromal-derived factor-1 (SDF-1), which plays a significant role in HIV-associated dementia. Cells of the CNS not only respond to inflammatory stimuli but also are also capable of producing cytokines and other inflammatory factors, often directly under the influence of lymphocytes. These observations led to the conclusion that the brain is not an immunologically sequestered organ but that it interacts, produces immunologically active factors, and is closely involved with the systemic immune response.

PUTATIVE MECHANISMS OF HUMAN AUTOIMMUNE DISEASE Why does autoimmune disease occur? It largely results as a culmination of interactions between genetic predisposition, environmental factors, and failure of self-tolerance maintenance mechanisms. Some diseases such as MS are termed immune-mediated because no definitive autoantigen has been demonstrated. Other diseases are clear cases of molecular mimicry such as Gd1b-mediated axonal neuropathy, in which the self-antigen attacked by the immune system is similar to that of an environmental antigen (in this case the Penner O:19 serotype of Campylobacter jejuni). Thus autoimmune diseases may be mediated by heterogeneous mechanisms, and in some cases more than one mechanism may be operating. Autoimmune diseases may be classified as T- or B-cell mediated. Some, such as myasthenia gravis (MG), are mediated through a combination of both. In many B cell–mediated diseases, an autoantigen has been identified, to which the B cell produces autoantibodies. Examples are MG, in which sera from patients contain antibodies to the α subunit of the acetylcholine receptor, and Lambert-Eaton syndrome, in which symptoms are caused by antibodies targeting calcium channels. In contrast to T-cell–mediated diseases, identification of autoantigens in antibody-mediated diseases may be easier, because B cells react to whole proteins, whereas the determinants recognized by T cells tend to be APC-processed small peptides of 10–20 amino acids. Thus for T-cell–mediated diseases such as MS, inflammatory demyelinating polyneuropathy, and polymyositis, there is little evidence demonstrating a causal relationship between an autoantigen and autoimmune disease. In addition, T-cell reactivity to autoantigens does not necessarily guarantee disease, because autoreactivity to some self-antigens is seen in healthy individuals. Thus the only conclusive evidence that can indicate causality between an antigen and T-cell–mediated autoimmune disease would be the reversal of the disease process by removal of the putative autoreactive T-cell repertoire. Although this has been feasible in some animal models, establishing the efficacy of such a strategy is difficult in most human T-cell–mediated diseases.

Genetic Factors Genetic makeup plays a role in susceptibility to autoimmune diseases. In particular, an association between certain MHC haplotypes and disease has been noted. MS is linked to the HLA-DR2 allele, and the relative risk of having this allele in the Northern European population

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is 3.8. MG has been linked to HLA-DR3. However, the presence of the allele does not guarantee disease. In general, the relative risk of developing disease among individuals who carry the antigen may be calculated by the following formula: [number of patients carrying the HLA antigen] × [number of controls lacking the antigen] [number of patients lacking the HLA antigen] × [number of controls carrying the antigen] Association of a particular HLA haplotype with autoimmune disease may be due to the ability of a particular MHC molecule to bind and present autoantigen to the T cell, as in MS where the MHC class II allele, DRB1*1501, has been shown to be effective in presenting myelin basic protein (MBP peptide) to T-cell clones isolated from MS patients (Wucherpfennig et al., 1995). Conversely, if an MHC molecule does not bind a particular self-antigen in the thymus, the developing T cell will not recognize that antigen as self and will escape negative selection. Therefore certain MHC haplotypes have an association with disease, whereas others protect against disease. Disease linkage tends to be with class II genes of the MHC rather than class I, suggesting a key role for T-cell autoimmunity. Association of a particular HLA-haplotype with disease may be due to its linkage to another locus or disease susceptibility gene. Linkage disequilibrium refers to the increased chance of inheriting two alleles together because they are genetically linked, as opposed to inheriting them together as separate random events. Sex is one of the most important genetic determinants associated with autoimmune disease. Many autoimmune diseases are more frequent in females; systemic lupus erythematosus (SLE) is 10 times more common in women, and MS twice as common. Evidence from animal models has shown that females are more resistant to infections and reject foreign skin grafts sooner than their male counterparts. This is especially true during periods of high estrogen availability. Estrogen levels decrease after ovulation or during pregnancy, and this is associated with a progesterone surge. The lowering of estrogen ensures immunological tolerance toward the sperm and subsequently toward the fetus. Therefore estrogen’s effects on the immune system may predispose women toward autoimmune diseases. This is reflected in experimental disease models of autoimmunity. Only female (NZB × NZW)F1 mice develop the SLElike disease, and this is abrogated by androgen treatment. Similarly, in experimental autoimmune encephalomyelitis (EAE), an experimental model for MS, female SJL mice are more susceptible to disease induction and are protected with testosterone (Dalal et al., 1997). Preliminary studies testing the effectiveness of a testosterone gel in males with MS have shown encouraging results but require additional validation. Initial studies investigating estriol effects in women with MS have shown a potent effect on reduction of new lesion formation, evident on gadolinium-enhanced magnetic resonance imaging (MRI) (Sicotte et al., 2002). Independent of sex hormones, the XY sex chromosome complement induces increased severity of EAE, with an increased expression of TLR-7 on CNS neurons (Du et al., 2014).

Environmental Factors Environmental factors may play a role in the pathogenesis of autoimmune diseases. Molecular mimicry is one of the mechanisms implicated. In this situation, an environmental antigen resembling a self-antigen elicits an immune response to both itself and the self-antigen. The environmental antigen involved in molecular mimicry may

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be a superantigen. Superantigens have the property of stimulating all T cells that express a given TCR variable gene family, regardless of their exact specificity, because of direct TCR-superantigen interaction. They are usually of bacterial or viral origin and bind as intact molecules to MHC. In many cases of molecular mimicry, the environmental antigen is a pathogen, and autoimmune disease follows the pathogen-caused disease. The classic example of this is streptococcal-induced endocarditis. Neurological diseases caused by this mechanism include streptococcal-induced chorea, Gd1b axonal neuropathy, Semple rabies vaccine–induced encephalomyelitis, and the anti-Hu paraneoplastic syndrome. Several studies have demonstrated that both adult (Ascherio and Munger 2007) and pediatric (Alotaibi et al., 2004; Pohl et al., 2006; Banwell et al., 2007; Lunemann et al., 2008) MS patients more frequently demonstrate evidence of a remote infection with Epstein-Barr virus (EBV) than controls, implicating a role for this virus in disease pathogenesis. Interestingly, epitopes of EBV resemble MBP, supporting a role for molecular mimicry in disease pathogenesis (Lang et al., 2002). However, despite these associations, it is clear that the majority of persons are infected with EBV without autoimmune sequelae. Recent studies have integrated risk factors in the pathogenesis of MS and found that the relative risk of MS among DR15-positive women with elevated (>1 : 320) anti-EBNA-1 titers was ninefold higher than that of DR15negative women with low ( women). Almost 80% have recovery but are often left hyponatremia, and less often REM behavior Less than 10% have an underlying with residual memory or cognitive deficits disorder. About 30%–40% patients faciobratumor (usually thymoma) chial dystonic seizures that precede the limbic encephalitis. Morvan syndrome, limbic encephalitis, neuroFrequent coexisting autoimmunities About 70% have full or substantial recovery pathic pain, peripheral nerve hyperexcitability Rapidly progressive, severe encephalopathy with Extensive MRI FLAIR/T2 cortical-subcor- Half of patients have good response to refractory seizures tical abnormalities. Frequent coexisting immunotherapy, but patients may die from autoimmunities (TPO, GAD antibodies) medical complications during status Agitation, paranoia, hallucinations, tremor, Protracted course with relapses when Partial but meaningful improvement myoclonus, and/or seizures. Less often immunotherapy is reduced cerebellar signs, hyperekplexia, or PERM-like syndrome. Symptoms are usually preceded by severe diarrhea Encephalitis, no specific syndrome Hodgkin lymphoma or no tumor Full recovery Cerebellar ataxia No tumor or rarely lymphoma May respond to immunotherapy Infrequent cases of basal ganglia encephalitis, No tumor association Improvement or full recovery with early Sydenham chorea immunotherapy Encephalopathy with seizures No tumor association May partially respond to immunotherapy Encephalopathy with REM and non-REM Usually chronic and slowly progressive, Largely unresponsive to immunotherapy. parasomnias, obstructive sleep apnea, stridor less often rapidly progressive Patients usually have sudden death during preceded by or concurrent with gait dysfuncwakefulness tion, chorea, and cognitive decline

GABAB receptor

AMPA receptor

LGI1

CASPR2 GABAA receptor

DPPX

mGluR5 mGluR1 Dopamine receptor 2 Neurexin 3α IgLON5

Other Associations

Responses to Immunotherapies

AMPA, Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; CASPR2, contactin-associated protein-like 2; DPPX, dipeptidyl-peptidase-like protein 6; FLAIR, fluid attenuated inversion recovery; GABAA, Gamma-aminobutyric acid-A; GABAB, Gamma-aminobutyric acid-B; GAD, glutamic acid decarboxylase; IGLON5, immunoglobulin-like cell adhesion molecule 5; LGI1, leucine-rich glioma-inactivated protein-1; mGluR5, metabotropic glutamate receptor 5; mGluR1, metabotropic glutamate receptor 1; MRI, magnetic resonance imaging; NMDA, N-methyl-D-aspartate; PERM, progressive encephalomyelitis with rigidity and myoclonus; REM, rapid eye movement. SCLC, small-cell lung cancer; TPO, thyroid peroxidase.

SPECIFIC SYNDROMES Anti-NMDAR Encephalitis Anti-NMDAR encephalitis is the most frequent antibody-associated encephalitis and the second most common cause of immune-mediated encephalitis after acute disseminated encephalomyelitis (ADEM) (Granerod et al., 2010). It is most common in young women and children who represent about 80% of patients but can also affect men and older individuals. The syndrome is highly characteristic and usually occurs as a multistage process. Patients develop acute psychiatric symptoms, seizures, memory deficits, decreased level of consciousness, and dyskinesias (orofacial, limb, and trunk) (Dalmau et al., 2008; Titulaer et al., 2013). Autonomic instability is common, and, in some patients, it results in central hypoventilation, often requiring weeks of mechanical ventilation. Many adults are initially evaluated by psychiatry services. Patients or their families should be questioned about a

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viral-like prodrome that can elevate the suspicion for an autoimmune process. Children are often brought to medical attention due to mood and behavioral change at times with new-onset seizures, movement disorders, insomnia, or reduction of speech. Partial syndromes with predominant psychiatric symptoms or abnormal movements, and less severe phenotypes can occur, although almost all patients eventually develop several elements of the syndrome (Kayser et al., 2013;Titulaer et al., 2013). Atypical symptoms, such as cerebellar ataxia or hemiparesis, can occur and are more common in children than in adults. Approximately 40% of female patients over 18 years have uni- or bilateral ovarian teratomas compared to less than 9% of girls under 14 years of age. Younger children and men only rarely have tumors. Isolated cases with other tumor types—including teratoma of the mediastinum, small-cell lung cancer (SCLC), Hodgkin lymphoma, neuroblastoma, breast cancer, and germ-cell tumor of the testis—have been reported (Titulaer et al., 2013).

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Autoimmune Encephalitis with Antibodies to Cell Surface Antigens

Fig. 82.1 Antibodies to GluN1 subunit of the NMDA receptor in a patient with anti-NMDAR encephalitis. Live rat hippocampal neurons incubated with the patient’s CSF are immunolabeled with antibodies against cell surface antigens; subsequent characterization demonstrated that the antigen is the GluN1 subunit of the NMDA receptor. CSF, Cerebrospinal fluid; NMDA, N-methyl-D-aspartate; NMDAR, N-methyl-D-aspartate receptor.

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are almost always those of typical limbic encephalitis with memory loss, confusion, and prominent seizures (Hoftberger et al., 2013; Jeffery et al., 2013). Rare cases presenting with ataxia or opsoclonus-myoclonus have been reported, but in these cases the syndrome progresses to include limbic encephalitis (Hoftberger et al., 2013). Most seizures appear to have a temporal-lobe onset with secondary generalization, while some patients have status epilepticus or subclinical seizures demonstrated on EEG. The brain MRI is abnormal is almost two-thirds of the patients, showing unilateral or bilateral medial temporal lobe FLAIR/T2 signal, which is consistent with limbic encephalitis. As in other autoimmune encephalitis, the CSF can show lymphocytic pleocytosis. In addition to the presence of GABABR antibodies, these patients may have other autoantibodies (e.g., TPO, ANA, GAD65) reflecting a tendency to autoimmunity or the presence of an underlying cancer (e.g., Sox1, amphiphysin, and/or Ri antibodies). In contrast to NMDAR antibodies, patient GABABR antibodies act as selective GABABR antagonists without causing receptor internalization (Dalmau et al., 2017). Patients who receive immunotherapy together with tumor control often have full or substantial recoveries, including cases where treatment is delayed by several months. A previously healthy 3-year-old child developed GABABR and GABAAR antibodies with opsoclonus, limb and trunk ataxia, and seizures; he died as a result of sepsis while receiving intensive care support (Kruer et al., 2014; Petit-Pedrol et al., 2014).

Anti-AMPA Receptor Encephalitis In almost 80% of patients the CSF shows lymphocytic pleocytosis and, less commonly, increased proteins and/or oligoclonal bands. About 35% of the patients have increased signal on MRI FLAIR/T2 sequences and less often, faint or transient contrast enhancement of the cerebral cortex, overlaying meninges, basal ganglia, or brainstem. The electroencephalogram (EEG) is abnormal in 95% of cases and usually shows focal or generalized slow or disorganized activity without epileptic discharges that may overlap with electrographic seizures (Sonderen et al., 2018). About 10%–30% of patients have a unique EEG pattern called extreme delta brush due to its similarity to the delta brush pattern seen in neonatal EEG (Schmitt et al., 2012). This pattern may be associated with prolonged illness and the finding of extreme delta brush in a patient with an undiagnosed encephalopathy should raise consideration for anti-NMDAR encephalitis. Diagnosis of the disorder is confirmed by demonstration of NMDAR antibodies in CSF and serum (Fig. 82.1). As noted above, testing of CSF should be done for all initial evaluations (Gresa-Arribas et al., 2014). The antibodies are immunoglobulin G (IgG) subtype and target the GluN1 (previously called NR1) subunit of the NMDAR. These antibodies are highly specific for anti-NMDAR encephalitis and are different from other less nonspecific and unrelated immunoglobulin M (IgM) and immunoglobulin A (IgA) anti-NMDA antibodies, or IgG antibodies that target other NMDAR subunits such as the GluN2 (Hara et al., 2018). The pathogenicity of the antibodies has been shown in vitro and in vivo animal models. These studies show that the antibody binding to the NMDAR results in a reversible internalization of NMDARs that associates with a reduction of NMDAR-mediated currents (Hughes et al., 2010; Planaguma et al., 2015)

Anti-GABAB Receptor Encephalitis Anti-gamma-aminobutyric acid B receptor (GABABR) encephalitis similarly affects men and women and more than half have an associated tumor, almost always a SCLC (Boronat et al., 2011). When the disorder is cancer-related, the onset of the encephalitis usually precedes the cancer diagnosis. The median age of patients in one study was 62 years, with older patients more likely to have cancer. The presenting features

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Anti-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) encephalitis predominantly affects middle-aged women (median age 62 years). Just over half the patients present with subacute ( women) who develop memory loss, confusion, and temporal lobe seizures. About

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60% of patients also develop hyponatremia and less often rapid eye movement (REM) sleep behavior disorders, which can be additional clues in formulating the differential diagnoses (Lai et al., 2010). About 30%–40% of patients develop brief tonic or myoclonic-like seizures (also called faciobrachial dystonic seizures) (Irani et al., 2011). In a few cases patients develop additional symptoms of peripheral nerve hyperexcitability (PNH) (Morvan syndrome). The rapidly progressive memory disturbance along with myoclonic-like movements can lead to the suspicion of rapid onset dementia such as Creutzfeldt-Jakob disease. In one study, about 15% of patients presented with rapidly progressive cognitive deficits with no clear evidence of encephalitis (Arino et al., 2016). The disorder is usually not cancer associated, and less than 10% of patients have an underlying neoplasm, usually a thymoma. The MRI often shows findings typical of limbic encephalitis, although seizures can result in similar abnormalities, confounding interpretation. The CSF is usually normal, although mild inflammatory changes or oligoclonal bands may be present; despite normal routine CSF studies, the antibodies are almost always detectable in both serum and CSF. Patients’ antibodies target LGI1, a secreted neuronal protein that interacts with pre- and postsynaptic epilepsy-related proteins (Fukata et al., 2006). The antibodies cause a decrease of Kv1.1 and AMPAR altering pre- and postsynaptic signaling and resulting in neuronal hyperexcitability (Petit-Pedrol et al., 2018). Mutations in LGI1 are linked to the human disorder, autosomal dominant lateral temporal lobe epilepsy (also called autosomal dominant partial epilepsy with auditory features) (Gu et al., 2002; Kalachikov et al., 2002). About 80% of patients have substantial responses to immunotherapy although many are left with deficits that prevent them from returning to work. Relapses occur in about 27%–35% of the patients (Arino et al., 2016; van Sonderen et al., 2016b).

autoimmune encephalitis in which the brain MRI is either normal or shows predominant involvement of the limbic system, almost all patients have extensive MRI abnormalities on FLAIR/T2 imaging with multifocal cortical-subcortical involvement without contrast enhancement (Fig. 82.2). Almost one-third have an associated tumor (mostly thymoma). More than half of the patients have partial or complete response to immunotherapy despite the severity of the illness and the seizures. Deaths that have been reported were attributed to status epilepticus or complications such as sepsis. Most patients also have coexisting autoimmunity including antibodies to GAD or thyroid peroxidase (TPO), raising the question of whether some patients with severe seizures attributed to GAD65 antibodies may in fact have other more disease-relevant antibodies such as GABAAR. The findings may also provide an explanation for some encephalitis attributed to TPO antibodies (erroneously considered Hashimoto encephalitis). The disorder can be triggered by viral encephalitis (herpes simplex virus 1 or human herpesvirus 6), and these patients usually have coexisting anti-NMDAR antibodies. Patients’ have antibodies that target the gamma aminobutyric acid A receptor (GABAAR). These antibodies produce a relocation of the receptor from synaptic to extrasynaptic sites, leading to neuronal hyperexcitability and supporting a pathogenic role (Petit-Pedrol et al., 2014).

Anti-DPPX Encephalitis

Patients with contactin-associated protein-like 2 (CASPR2) antibodies often develop symptoms involving both the central nervous system (e.g., encephalopathy, cerebellar dysfunction, hallucinations, seizures, insomnia, autonomic dysfunction) and peripheral nervous system (PNH, neuropathy, allodynia) (Irani et al., 2012; Lancaster et al., 2011a; van Sonderen et al., 2016a). The combination of the indicated CNS symptoms and PNH is called Morvan syndrome. Rare cases of isolated limbic encephalitis or PNH have been reported. Patients may have other coexisting immune-mediated disorders such as myasthenia gravis with anti-acetylcholine (AChR) or muscle-specific kinase (MuSK) antibodies (Fleisher et al., 2013). Anti-CASPR2 associated encephalitis is usually not cancer related, and those patients with a tumor (most commonly thymoma) are more likely to have Morvan syndrome as opposed to isolated central or PNH symptoms. In contrast to most of the autoimmune encephalitis (LGI1, DPPX, and IgLON5 are other exceptions), antibodies to CASPR2 are primarily of the IgG4 isotype. Studies suggest that patient CASPR2 antibodies interfere with the normal clustering of VGKCs at juxtaparanodes, resulting in hyperexcitability of peripheral nerves (Patterson et al., 2018).

Patients with encephalitis associated with antibodies to dipeptidyl-peptidase-like protein6 (DPPX) develop severe prodromal weight loss or diarrhea followed by the development of prominent neuropsychiatric symptoms, CNS hyperexcitability (e.g., agitation, hallucinations, myoclonus, tremor, seizures, hyperekplexia), and/or cerebellar or brainstem dysfunction (Boronat et al., 2013; Hara et al., 2017; Tobin et al., 2014).The weight loss and severe diarrhea occur, on average, 4 months before the onset of neurological symptoms and can result in extensive evaluations for a primary gastrointestinal disorder. The triad of weight loss, cognitive dysfunction, and symptoms of CNS hyperexcitability should raise the suspicion for anti-DPPX encephalitis. The encephalitis is chronic and progresses over months (median 8 months to disease peak). The CSF can show pleocytosis or oligoclonal bands but can be normal. The MRI is usually nonspecific. Tumor associations are unusual but do occur (mostly B-cell neoplasms). Some patients develop a syndrome resembling progressive encephalomyelitis with rigidity and myoclonus (PERM) or present with hyperekplexia (Balint et al., 2014; Hara et al., 2017). The prodromal gastrointestinal symptoms, severe loss of weight, and/or prominent cognitive or mental alterations helps to distinguish DPPX encephalitis from PERM. Patients often respond to immunotherapy with relapses mainly occurring in the setting of reduced immunotherapy. All patients have a combination of IgG1 and IgGg4 anti-DPPX antibodies. These antibodies produce a reversible decrease of the density of DPPX receptor clusters as well as the associated Kv4.2 potassium channels (Hara et al., 2017). The myenteric plexus is enriched in DPPX receptors and this may explain the prominent gastrointestinal symptoms.

Anti-GABAA Receptor Encephalitis

Anti-mGluR5 Encephalitis

The median age of patients with this syndrome is 40 years, but it may occur in children and adolescents. Patients develop a progressive, severe encephalopathy that in 90% of cases includes refractory seizures with frequent status epilepticus. Other symptoms include cognitive impairment, altered behavior, decreased consciousness, and movement disorders (Petit-Pedrol et al., 2014; Spatola et al., 2017). Over half of the patients have CSF abnormalities, including pleocytosis, increased proteins, and/or oligoclonal bands. In contrast to other

Anti-mGluR5 antibodies were initially described in two patients with limbic encephalitis and Hodgkin lymphoma (Ophelia syndrome) (Lancaster et al., 2011b). An evaluation of additional patients showed that most have a viral-like prodrome followed by the development of a complex neuropsychiatric syndrome with prominent psychiatric and cognitive dysfunction, movement disorders, sleep dysfunction, and/or seizures (Spatola et al., 2018). There is CSF pleocytosis in almost all cases and, less commonly, oligoclonal bands. In approximately half of the

Anti-CASPR2 Associated Encephalitis

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A

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B Fig. 82.2 A, Brain MRI of a patient with limbic encephalitis and antibodies against LGI1, showing typical increased FLAIR signal involving the medial temporal lobes. Similar findings occur in greater than 50% of patients with AMPA or GABAB receptor antibodies, and less frequently in patients with CASPR2 antibodies. B, Brain MRI of a patient with GABAA receptor antibodies showing FLAIR abnormalities involving multiple cortical and subcortical regions. These abnormalities occur in 80% of patients with this disorder; diffusion weighted imaging rarely show restricted diffusion. These multifocal abnormalities appear and disappear in an asynchronous manner, are highly suggestive of GABAA receptor encephalitis, and do not occur in patients with other types of antibody-mediated encephalitis. AMPA, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; CASPR2, contactin-associated protein-like 2; FLAIR, fluid-attenuated inversion recovery; GABAA, gamma-aminobutyric acid A; GABAB, gamma-aminobutyric acid B; LGI1, leucine-rich glioma inactivated 1; MRI, magnetic resonance imaging. (Reprinted with permission from Lancaster et al., Neurology 2011;77(2):179–189 and Spatola et al., Neurology 2017;88(11):1012–1020.)

patients, the MRI showed FLAIR abnormalities in limbic or extralimbic regions. There was a tumor association in about half of the cases (most commonly Hodgkin lymphoma, and one patient reported with SCLC). Patients can respond to immunotherapy and tumor treatment when appropriate, but can have relapses.

Anti-mGluR1 Cerebellar Dysfunction Cerebellar ataxia in association with antibodies to the mGluR1 receptor was initially described in two patients with a history of Hodgkin disease (Sillevis et al., 2000). Since then a few additional patients have been reported but other than one patient with a T-cell lymphoma, the disorder was not cancer related (Lopez-Chiriboga et al., 2016). All patients developed cerebellar ataxia, and rarely cognitive changes, psychiatric symptoms, and/or seizures. Some patients responded to early administration of immunotherapy. Injection of patient antibodies to the subarachnoid space near the cerebellum resulted in progressive ataxia, suggesting a direct pathogenic role of the antibodies in the disorder (Sillevis et al., 2000).

Anti-Dopamine Receptor Encephalitis A very rare number of patients, mostly children with basal ganglia encephalitis, Sydenham chorea, or Tourette syndrome have been reported to have antibodies to the dopamine-2 receptor (Dale et al., 2012). There is preliminary evidence that the antibodies have pathogenic effects. These antibodies have also been found in some patients with autoimmune encephalitis, which developed after a herpes simplex viral infection. Most of these patients have concurrent antibodies to NMDAR. Patients can have full recovery with early immunotherapy (Dale et al., 2012). F ECF

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Anti-neurexin 3α Encephalitis This disorder was initially described in five patients (median age 44 years) who presented with prodromal fever, headache, or gastrointestinal symptoms followed by the onset of confusion, seizures, and a decreased level of consciousness (Gresa-Arribas et al., 2016). Two of the patients developed facial dyskinesias suggestive of anti-NMDAR encephalitis (anti-NMDAR antibodies were absent). The MRI was normal in four patients, and in one showed medial temporal lobe FLAIR abnormality. Three patients had partial recovery after immunotherapy; however, two patients died—one death was related to refractory seizures and brain edema and the other to sepsis. Studies in cultured neurons showed that the patient antibodies decrease receptor cluster density as well as the number of synapses (Gresa-Arribas et al., 2016).

Anti-IgLON5 Disease Patients with this disease develop a characteristic sleep disorder before or concurrently with the onset of bulbar symptoms, gait abnormalities, chorea, oculomotor problems and, less commonly, cognitive decline (Sabater et al., 2014). The sleep disorder includes REM and non-REM sleep disturbances characterized by abnormal movements and behaviors that predominate in the early hours of sleep. In some patients the disorder is progressive over years while in other patients the course is rapidly progressive and may result in death within months of symptom onset. The disorder is poorly responsive to treatment. Video polysomnography demonstrates undifferentiated non-REM sleep or poorly structured non-REM stage N2, along with REM parasomnias and sleep breathing dysfunction, including obstructive sleep

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apnea and stridor. The brain MRI, EEG, CSF studies, and electromyography are usually normal. In the patients who were studied, the CSF hypocretin levels were normal. Autopsy studies of six patients showed neuronal loss and gliosis associated with an atypical tauopathy mainly involving the tegmentum of the brainstem and the hypothalamus. There was no glial pathology, grains, or globular glial inclusions that would allow classification of these cases within any of the presently known tauopathies (Gelpi et al., 2016). All patients have antibodies targeting immunoglobulin-like cell adhesion molecule 5 (IgLON5), a member of the IgLON family, which is part of the immunoglobulin superfamily of cell adhesion molecules. The antibodies are predominantly of the IgG4 subclass, and there is a strong association with the HLA-DRB1*10.01 allele (Gaig et al., 2017). The IgLON proteins appear to play a role in neuronal pathfinding and synaptic formation although the exact function of IgLON5 is unknown.

GENERAL TREATMENT RECOMMENDATIONS The optimal management of these disorders is still being elucidated, and current recommendations are largely derived from the experience with anti-NMDAR encephalitis (Titulaer et al., 2013). Based on data that demonstrate a pathogenic role of the antibodies, treatments are focused

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on antibody depletion and immunosuppression. In tumor-associated cases, the first step in management should be its identification and treatment. Patients with anti-NMDAR or AMPAR encephalitis, whose tumors were not removed, had less frequent recoveries and an increased risk of relapses compared to those whose tumors were treated. While it is not known if this applies to other disorders it strongly supports early tumor treatment when appropriate (Titulaer et al., 2013). Despite the severity of many patients’ symptoms, the majority of patients respond to treatment. Recovery can be slow and some disorders have a tendency to relapse. Corticosteroids and/or intravenous immunoglobulin (IVIG) or plasma exchange are considered first-line therapies and should be considered in all patients. There are no data to support the use of IVIG over plasma exchange, although the poor medical condition and autonomic instability of some patients may favor the use of IVIG. For patients who do not show early improvement with these therapies or who are severely affected, rituximab and/or cyclophosphamide should be considered and are increasingly being used upfront (Nosadini et al., 2015). The use of rituximab appears to reduce the risk of relapses and there is evidence it is effective for IgG4 antibody-mediated diseases (Huijbers et al., 2015), supporting its early or upfront use. The complete reference list is available online at https://expertconsult. inkling.com/.

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83 Anoxic-Ischemic Encephalopathy Jennifer E. Fugate, Eelco F.M. Wijdicks

OUTLINE Pathophysiological Concepts, 1269 Clinical Examination, 1270 Management, 1271

Predicting Prognosis, 1272 Laboratory and Electrophysiological Testing, 1272 Neuroimaging, 1273

When the heart stops and cerebral blood flow is interrupted during a cardiac arrest, patients lose consciousness and may remain comatose after resumption of circulation. Such a global injury to the brain is understandably profound, and more than 70% of patients die or remain comatose 24 hours after cardiopulmonary resuscitation (CPR) (Rogove et al., 1995; Zandbergen et al., 2006). Anoxia describes the complete lack of oxygen delivery (e.g., complete cessation of blood flow during cardiac arrest), whereas hypoxia describes what may occur during times of decreased oxygen delivery, but with some degree of continued blood flow. Hypoxic-ischemic brain injury—albeit less well defined and less clearly understood than anoxic-ischemic injury—can occur in patients with respiratory arrest or severe hypoxemia (e.g., asphyxia). Approximately 100,000 patients a year in the United States are admitted to intensive care units with anoxic-ischemic brain injury after CPR (Peberdy et al., 2003). Although the pathophysiology of brain injury caused by cardiac arrest is reasonably well understood, less is known about neuroprotection. For nearly two decades, there was enthusiasm that induced hypothermia could not only improve survival rates but also improve neurological outcomes (Broccard, 2006), but these beliefs have been challenged (Nielsen et al., 2013). This chapter critically evaluates the current knowledge of anoxic-ischemic brain injury. Studies have reported tools for predicting outcomes, and guidelines for prediction of poor outcome have been developed by the American Academy of Neurology (Wijdicks et al., 2006). The accuracy of these predictors after the use of therapeutic hypothermia or targeted temperature management (TTM) is a subject of ongoing research.

better outcome than nonshockable rhythms such as asystole, pulseless electrical activity, and bradyarrhythmias, reflected by restoration of adequate cerebral blood flow when ejection fraction of the ventricle improves (Callans, 2004). Secondly, there might be a critical time period after which CPR may fail to restore neuronal function. This time interval is poorly defined, but we know that the neuronal oxygen stores are depleted within 20 seconds of cardiac arrest, and cerebral necrosis occurs as a result of ischemia. There is some uncertainty about whether hypoxemia alone could produce necrosis, and, although it can cause damage (preferentially in the striatum), necrosis is rarely seen even in patients with arterial Pao2 values less than 20 mm Hg. After 2–4 minutes of anoxia, several biochemical mechanisms that result in irreversible neuronal damage may become operative (Fig. 83.1). Selective neuronal vulnerability to this type of injury involves areas in the CA-1 sector of the hippocampus, the thalami, the neocortex, and the cerebellar Purkinje cells (Fig. 83.2). Necrosis of the cortex involves layers three, four, and five and is pathologically known as laminar necrosis. The vulnerability of these areas may be explained by the presence of receptors for excitatory neurotransmitters or the high metabolic demands of these neurons. An important question is whether necrosis or apoptosis occurs. The cell death cascade that involves several modulatory and degradation signals has been documented in global cerebral ischemia, but whether these processes can be effectively manipulated remains unclear (Ogawa et al., 2007). A caspase inhibitor did not affect neurological outcome after 6 minutes of cardiopulmonary arrest in rats (Teschendorf et al., 2001). Another mechanism of neuronal and glial damage is excitatory brain injury. Glutamate efflux due to ischemic injury increases intracellular calcium concentration, which results in neuronal injury. The excess release of calcium leads to other processes that include activation of catabolic enzymes and endonucleases. Glutamate excitotoxicity has remained the major hypothesis to explain this type of neuronal injury and was made more probable after the documentation of neuroprotection with N-methyl-d-aspartate (NMDA) or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists. In addition, research interest in anoxic brain injury has pointed toward a phenomenon called no reflow. This concept is based on the premise that after resumption of circulation, there are major microcirculatory reperfusion deficits. Coagulation may occur within these reperfusion zones, with intravascular fibrin formation and

PATHOPHYSIOLOGICAL CONCEPTS One of the more vital questions for scientists and clinicians is whether there is a specific period during resuscitation in which interventions can modify the degree of anoxic-ischemic brain injury and improve clinical outcomes. Is the damage to the brain permanent and present at ictus, or are there processes at work that could potentially be influenced and modulated? Several clinical facts are important. First, with cardiac arrest, whether due to asystole or ventricular fibrillation, there is no measurable flow to the brain. Moreover, even with standard CPR techniques, only one-third of the pre-arrest cerebral blood flow can be attained (Maramattom and Wijdicks, 2005). In addition, the shockable rhythms (ventricular tachycardia and ventricular fibrillation) have a

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CLINICAL EXAMINATION

Cardiac arrest

Cerebral blood flow—zero

Apoptosis

No reflow

Excitotoxicity

Fig. 83.1 Mechanisms of Brain Injury after Cardiac Arrest.

Fig. 83.2 Purkinje Cell Loss after Cardiac Arrest (Asterisks Point to a Few Surviving Cells).

microthrombosis. This concept has served as a basis for experimental studies using recombinant tissue-type plasminogen activator (tPA) (Echeverry et al., 2010; Haile et al., 2012). Despite our understanding of the pathophysiology of anoxic-ischemic injury based on careful animal experiments, the clinical reality of neuroprotection is discouraging. Clinical trials using barbiturates or calcium channel antagonists have been unsuccessful (Maramattom and Wijdicks, 2005). Induced hypothermia, which inhibits apoptosis and reduces free radical formation and excitatory neurotransmitters, was considered to be the only potentially beneficial intervention (Bernard et al., 2002; HACA Study Group, 2002), but even this has come into question and strict normothermia may be just as beneficial (Nielsen et al., 2013). Patients who are comatose after CPR unfortunately often have a devastating outcome. Improvement of outcome might come from very early intervention and administration of neuroprotective agents at the onset of resuscitation, rather than when a patient enters the hospital.

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Early awakening after CPR, clinical signs of localizing pain stimuli, and following commands are generally considered positive. However, the current literature provides no criteria on which a good long-term outcome can be reliably predicted. Most studies that have concentrated on the examination of the patient assume a poor outcome. Clinical neurological examination follows a standard procedure, with examination of brainstem reflexes, motor response to pain, specific attention to myoclonus, and spontaneous or elicited eye movements. Because the brainstem is far more resilient to anoxic-ischemic injury than the cortex, brainstem reflexes, including the pupillary reflex to light, are often normal. Absent pupil responses can be caused by a high dose of intravenous atropine used during resuscitation, although a pupil response might still be found when examined under the magnifying glass. Fixed, dilated pupils presenting 6 hours after resuscitation are a sign of poor prognosis, but this is rarely present in isolation and is usually an indication that the rest of the brainstem has also been involved in the anoxic-ischemic injury. The eye examination may provide useful supporting evidence of anoxic injury (Wijdicks, 2002). Sustained upward gaze is often indicative of a significant global bihemispheric injury that may include the thalamus. A proposed mechanism explaining this phenomenon is a complete disinhibition of the vestibulo-ocular reflexes from the cerebellar flocculus (Nakada et al., 1984). Although forced upgaze is usually associated with poor outcomes, it is still compatible with survival in approximately 12%– 15% of cases (Fugate et al., 2010). In some patients, downward gaze can be elicited using rapid head shaking or attempting to elicit a vestibular ocular response (Johkura et al., 2004). Other eye abnormalities, including ping-pong gaze or periodic lateral gaze deviations, have not been specifically examined for their prognostic value (Diesing and Wijdicks, 2004). Continuous blinking is often a common finding in comatose patients, although its anatomical substrate is unknown. An important clinical sign is myoclonus status epilepticus, defined as continuous and vigorous jerking movements involving facial muscles, limbs, and abdominal muscles (Thomke et al., 2005; Young et al., 2005). These jerks can often be elicited or aggravated by touch or hand clap and may also involve the diaphragm, which complicates ventilation. Myoclonus status epilepticus has classically been considered an agonal phenomenon indicating an almost invariably poor prognosis, although exceptional cases have been reported (Greer, 2013). This sustained, diffuse, vigorous myoclonus should not be confused with occasional myoclonic jerks. The majority of these patients have a malignant burst-suppression pattern on electroencephalogram (EEG) and do not survive. In others, EEG may show a continuous background with polyspikes concordant with myoclonic jerks, and, in these cases, favorable outcome is possible (Elmer et al., 2016). Myoclonus status epilepticus must be distinguished from myoclonus due to intoxication or hepatic encephalopathy and from generalized tonic-clonic seizures. Convulsive status epilepticus is uncommon, as is nonconvulsive status epilepticus (NCSE). The motor response to pain should be classified and described as absent to pain, extensor response, pathological flexion response, withdrawal to pain, or localization. Lack of motor response to nail-bed compression at the initial assessment does not necessarily predict poor outcome. It may represent the “man-in-the-barrel” syndrome that occurs after bilateral border-zone infarction in the anterior and middle cerebral watershed regions. Involvement in this territory will result in prolonged weakness of the arms, with normal findings in the lower limbs. The outcome in these patients is often better than that for other patients with ischemic-anoxic injury.

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TABLE 83.1 Clinical Syndromes after Post–Anoxic-Ischemic Encephalopathy

BOX 83.1

Clinical Syndrome Mechanism

Sedate patient prior if paralysis is initiated: Midazolam, initial dose 0.01–0.05 mg/kg intravenously (IV), then 0.02 mg/ kg/h IV, titrate up to 0.1 mg/kg/h IV or Propofol, 5 mcg/kg/min, titrated by 5 mcg/kg/min IV every 5 min to a goal of 30–50 mcg/kg/min as tolerated by the blood pressure or Fentanyl, 0.7–10 mcg/kg/h IV as tolerated by the blood pressure Paralysis: Atracurium, 0.2–0.5 mg/kg bolus, followed by an infusion of 11–13 mcg/kg/min or Vecuronium 0.1 mg/kg bolus, then 1 mcg/kg/min; titrate paralysis to a 1–2/4 train-of-four every hour to suppress shivering Lacri-Lube to eyes Target temperature control with cooling device Place bladder catheter to monitor temperature

“Man-in-the-barrel” syndrome Parkinsonism Action myoclonus

TABLE 83.2

Medications

Temperature Control Protocol for Out-of-Hospital Cardiopulmonary Arrest

Outcome

Bilateral water- Uncertain, may improve substanshed infarcts tially Infarcts in the Improvement possible striatum Cerebellar In awake patients, could improve infarcts with medication

Sedative and Analgesic

Agent

Elimination Half-Life (h)

Morphine Fentanyl Alfentanil Midazolam Lorazepam Propofol

1.5–4 2–5 1.5–3.5 1–4 10–20 2

The outcomes for patients in coma range from death, including brain death, to persistent vegetative state (see Chapters 5 and 6), to awakening with disabilities ranging from the minimally conscious state (see Chapter 6) to complete recovery (see Chapter 55). Awakening from coma can be protracted and prolonged, although the vast majority of patients who will awaken will do so within the first few days, provided they are not kept sedated. In our series of patients, 94 of 101 patients with post–anoxic-ischemic injury awoke within 3 days after cardiac arrest and induced hypothermia did not seem to directly influence this (Fugate et al., 2011). However, awakening can occur even 3 months after onset, although rarely without a severe deficit such as an amnesic syndrome or other neurological findings (Table 83.1). The neurological examination can be confounded by an additional systemic injury associated with CPR. Several patients may have an associated acute renal failure or liver injury. In addition, medications may have been administered to counter pain or to facilitate mechanical ventilation. Often patients have been treated with fentanyl and lorazepam, both of which have long elimination half-lives (Table 83.2). The use of therapeutic hypothermia (TH) or targeted temperature management (TTM) may further prolong medication effects, as hepatic metabolism and renal clearance are decreased, which may cause an enhanced and prolonged effect of medications (Polderman, 2009).

MANAGEMENT The optimal management of anoxic-ischemic injury is unclear, and little guidance is available from clinical trials. The initial management of a comatose patient requires intubation and mechanical ventilation. Optimal hemodynamic goals are not well established. A mean arterial pressure of 65–80 mm Hg is a common goal and often requires norepinephrine, with or without inotropes, in addition to fluid resuscitation (Hassager et al., 2018). Blood pressure, clearance of lactate, and adequate urine output are important measures of the initial resuscitative efforts. Patients with severe cardiogenic shock may require more advanced interventions such as intraaortic balloon pumps or extracorporeal membrane oxygenation. Prevention of hyperglycemia that may reduce regional cerebral blood flow is advised. This includes the avoidance of dextrose-containing solutions and use of insulin drips to

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↓ Insulin secretion ↑ Hyperglycemia

↓ Coronary perfusion ↓ Cardiac output ↑ Cardiac arrhythmias

↑ Pneumonia ↑ Atelectasis

↑ Cold diuresis ↑ Hypovolemia

↓ Clearance of benzodiazipines ↓ Opioids

Fig. 83.3 Potential Systemic Effects of Induced Hypothermia.

maintain a normoglycemic state. The practice of induced hypothermia in post–cardiac arrest management became widespread after the publication of two influential trials in 2002 (Bernard et al., 2002; HACA Study Group, 2002). These early trials found improved survival, but details on the neurological condition of the patients were insufficient (Maramattom and Wijdicks, 2005). The beneficial effect of cooling has been challenged by two more recent clinical trials. One showed that prehospital cooling did not improve outcomes, and the other—the TTM trial—found no benefit in targeting 33°C compared with 36°C (Kim et al., 2014; Nielsen et al., 2013). The results of the latter study raise the possibility that it is the avoidance of hyperthermia—and not the induction of moderate hypothermia—that may confer the neuroprotective effect. An ongoing clinical trial (TTM 2) aims to answer that hypothesis. A cooling protocol for out-of-hospital cardiopulmonary arrest is shown in Box 83.1. This requires reduction in core temperature with ice packs, rapid infusion of cold intravenous fluids, and the use of external cooling devices or endovascular cooling systems (Holzer et al., 2006). Temperature management is initiated within 2–3 hours to reduce core temperatures to 32°C–36°C and is maintained for 24 hours, followed by gradual rewarming. Sedation and neuromuscular blockade are needed to control shivering. Major potential systemic complications may include pneumonia, cardiac arrhythmias, pancreatitis, and hyperglycemia, particularly in those cooled to 32°C–34°C (Fig. 83.3). The benefit of

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Concerns When Evaluating Patients Treated with Cooling Protocols

BOX 83.2

Coma after CPR Confounders

Potentially confounded neurological examination because hypothermia necessitates sedatives, neuromuscular blockers, and analgesics: Motor response and corneal reflexes may not be reliable as early as day 3 Pupil examination maintains prognostic reliability Decreased metabolism and clearance of sedative and analgesic medications related to hypothermia effects and kidney/liver injury Metabolic abnormalities and systemic shock Nonconvulsive seizures are not uncommon and require electroencephalogram for detection

S, A, B, H, HT Exam if none

MRI: Cortical Injury SSEP: Absent N20 EEG: Burst suppression, low amplitude; no reactivity NSE: 3 fold increase

PREDICTING PROGNOSIS

Poor outcome

In the prehypothermia era, the assessment of prognosis was summarized in practice guidelines commissioned by the Quality Standard Subcommittee of the American Academy of Neurology (Wijdicks et al., 2006). This extensive literature review found that the circumstances surrounding CPR were not predictive of outcome. Several clinical features were highly predictive. The presence of myoclonus status epilepticus within the first 24 hours in patients with circulatory arrest, absence of pupillary responses within day 1–3 after cardiopulmonary arrest, absence of corneal reflexes within day 1–3, and absent or extensor motor responses after day 3 were all associated with invariably poor neurological outcome. Eye movement abnormalities were insufficiently predictive, but clinical studies in these patients have not focused on the prediction of specific eye motor abnormalities. These guidelines were based on studies done prior to the routine use of TTM, and the reliability of predictors in this setting has been an area of great interest and investigation. Neurologists need to consider key factors when prognosticating for patients treated with cooling protocols (Box 83.2). A suggested algorithm for estimating neurological prognosis is shown in Fig. 83.4. Brainstem reflexes are crucial in the clinical evaluation of comatose patients after cardiac arrest. Because the brainstem is relatively resistant to anoxic-ischemic injury, the absence of pupil or corneal reflexes indicates a severe and often widespread injury that also involves much of the cortex. In a meta-analysis of 10 studies of prognostication after mild therapeutic hypothermia (TH), the pupil response was tested in 566 patients at 72 hours. The absence of pupillary light reactivity remained a reliable predictor of poor outcome with a false-positive rate (FPR) of 0.004 (confidence interval [CI] 0.001–0.03) (Kamps et al., 2013). In contrast, after TH, the absence of corneal reflexes at 72 hours did not remain as reliable in outcome prediction with an FPR of 0.02 (CI 0.002–0.13). The reliability of the motor response at 72 hours after TH protocol has also been questioned (Al Thenayan et al., 2008; Rossetti et al., 2010). Although it is still associated with outcome, an absent or extensor motor response at 72 hours after cardiac arrest after TH appears less reliable than in studies done in the pre-TH era (Rossetti et al., 2010). In a meta-analysis, the motor response at 72 hours in 811 patients treated with TH had an unacceptably high FPR of 0.21 (CI 0.08–0.43) (Kamps et al., 2013). Patients treated with TH are more likely to receive sedation than those not treated with TH, and in studies with a “normothermia” comparison group, the motor response in patients sedated in that group also can be unreliable (Fugate et al., 2010; Samaniego et al.,

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Myoclonus Status; loss of >1 BSR

hypothermia has not been established in patients after in-hospital CPR or in those with initial cardiac rhythms other than ventricular fibrillation.

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BSR = brainstem reflexes, MRI = magnetic resonance imaging, SSEP = somatosensory evoked potentials, EEG = electroencephalography NSE = neurospecific enolase, S = sedatives, A = analgesics, B = neuromuscular junction blockers, H = hypothermia

Fig. 83.4

2011). Thus it is crucial to ensure that there are no residual effects of sedative or analgesic medications used when assessing motor responses in patients who remain comatose after cardiac arrest.

LABORATORY AND ELECTROPHYSIOLOGICAL TESTING As a complement to the clinical examination, several widely used tests are EEG, neuroimaging (computed tomography [CT] or magnetic resonance imaging [MRI]), evoked potentials, and serum biomarkers. However, an evidence-based review of all laboratory tests found that many have insufficient prognosticating value (Wijdicks et al., 2006). These tests can be useful adjuncts in the estimation of neurological prognosis but should not be interpreted or used for decision making in isolation. The approach to estimating neurological prognosis in comatose survivors of cardiac arrest should be multifaceted: a combination of the neurological examination, results of tests, and the overall clinical context. EEG has been used since the 1950s to aid in prognostication. “Highly malignant” patterns defined by the American Neurophysiological Society include suppressed background, suppressed background with continuous periodic discharges, and burst suppression These predict a poor outcome with 50% sensitivity and 100% specificity. A continuous background with preserved background reactivity is considered “benign” and has a positive predictive value of about 80% for good outcomes (Rossetti et al., 2017). Continuous electroencephalography (cEEG) monitoring after cardiac arrest has become more widely applied as it has become recognized that nonconvulsive seizures and NCSE can occur (Abend et al., 2009; Al Thenayan et al., 2010; Legriel et al., 2009; Rundgren et al., 2006). Electrographic seizures have been found in 9%–33% of patients (Cloostermans et al., 2012; Crepeau et al., 2013; Knight et al., 2013; Mani et al., 2012; Rittenberger et al., 2012; Sadaka et al., 2014) and NCSE in 2%–12% (Crepeau et al., 2013; Legriel et al., 2009; Rittenberger et al., 2012) who are monitored during cooling protocols. Although continuous EEG (cEEG) monitoring increases the detection of epileptiform activity, it has not been shown that

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CHAPTER 83 Anoxic-Ischemic Encephalopathy earlier detection and treatment of seizures in this setting changes outcomes. The labor and resources needed for cEEG are substantial, and the added value and yield of cEEG compared with “spot” EEGs in this population are not clear (Alvarez et al., 2013; Crepeau et al., 2014; Fatuzzo et al., 2018). Also of interest are somatosensory evoked potentials (SSEPs) (Madl and Holzer, 2004). SSEPs are not influenced by drugs, temperature, or acute metabolic derangements and thus are a useful adjunct for prognostication (Chen et al., 1996). SSEP requires stimulation of the median nerve that then results in a potential at the brachial plexus, cervical spinal cord, and finally bilateral cortex potentials (N20). For SSEPs to be reliable, the cervical spine potential must be recognized, and this could be of potential concern in patients with injury involving the cervical spinal cord. The bilateral absence of cortical potentials (N20 component) is nearly 100% specific in predicting unfavorable outcomes when performed between 1 and 3 days after cardiac arrest (Wijdicks et al., 2006). However, the presence of N20 cortical responses—the much more common finding—is less useful because they have very low sensitivity to predict outcomes. Evidence indicates that absent N20 responses during mild hypothermia after resuscitation maintains accuracy in predicting a poor neurological outcome (Bouwes et al., 2009; Rossetti et al., 2010). In a meta-analysis including 492 TH-treated postarrest patients with bilaterally absent cortical responses on SSEPs, the FPR was 0.007 (CI 0.001–0.047), which is comparable with that in patients not treated with TH (Kamps et al., 2013). Serum biomarkers have also been used in prognostication. Most studies of biomarkers in comatose survivors of cardiac arrest have examined serum neuron-specific enolase (NSE) and S100. NSE is a gamma isomer of enolase that is located in neurons, and S100 (Bottiger et al., 2001; Tiainen et al., 2003; Wang et al., 2004) is a calcium-binding astroglial protein. The usefulness of these biomarkers in prognostication may be more limited than the electrophysiological testing because none of these studies are automated, long lab turn-around times may be impractical, and standardization may not be optimal. In studies done prior to the routine use of hypothermia, only NSE predicted outcomes well, with a level greater than 33 µg/L at days 1–3 being associated with poor outcome. However, TH may have an effect on the metabolism and clearance of these biomarkers, clouding their prognostic value. Results of studies on the predictive value of NSE during or after cooling protocols are conflicting, with some finding that NSE levels maintain prognostic accuracy (Oksanen et al., 2009; Rundgren et al., 2009) and others finding the prognostic value to be reduced (Fugate et al., 2010; Steffen et al., 2010). With a cutoff value of 33 µg/L, FPRs have been reported as high as 22%–29% after TH protocols (Fugate et al., 2010; Samaniego et al., 2011) and one study found an NSE level as high as 79 µg/L is needed to achieve an FPR of 0% for predicting unfavorable outcomes (Steffen et al., 2010). In a large study of 686 TTM-treated patients (1823 NSE samples), NSE values of 61, 46, and 35, at 24, 28, and 72 hours, respectively, corresponded to an FPR less than 5% (Stammet et al., 2015). Differences in laboratory assays have made comparisons difficult, and there is not a strict threshold level of NSE that can be recommended for use in prognostication after cardiac arrest after hypothermia until there is further research and standardization of laboratory assays. Tau protein, an indicator of axonal injury, is another promising serum biomarker. In patients from the TTM trial, a tau protein threshold of 11.2 ng/L at 72 hours after arrest had a 98% specificity and 66% sensitivity to predict poor neurological outcomes (Mattsson et al., 2017). It may be more accurate than NSE (area under the ROC curve 0.91 vs. 0.86), but it is not currently widely available.

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NEUROIMAGING The use of neuroimaging is growing as an adjunct to estimating neurological prognosis in comatose survivors of cardiac arrest, despite a lack of high-quality evidence (Hahn et al., 2014). CT imaging performed early is often normal and cannot determine the severity of anoxic-ischemic injury. After 3–5 days in severe cases, global brain edema may be visualized. Several studies have found that the disappearance of the gray/white junction on noncontrast head CT has been associated with poor outcomes and failure to awaken (Inamasu et al., 2010; Torbey et al., 2000). Findings should be interpreted cautiously because much of the literature is limited to retrospective case series and the timing of CT has ranged from minutes to nearly 3 weeks after the insult. Still, a more recent study based on the TTM trial cohort showed that edema on brain CT detected qualitatively predicts poor neurological outcome with 97.4% specificity and 14.4% sensitivity within 24 hours of cardiac arrest (Moseby-Knappe et al., 2017). Imaging with MRI holds promise as an adjunct to prognosis in comatose patients after cardiopulmonary arrest (Wijman et al., 2009), but there are currently insufficient data to systematically guide prognostication with MRI. Diffusion-weighted imaging (DWI) is particularly sensitive to ischemia, and apparent diffusion coefficient (ADC) values can provide a quantitative measure of injury. Current literature is limited by heterogeneity of MRI timing and patient selection bias. MRI parameters associated with poor outcome include widespread and persistent cortical DWI abnormalities (Barrett et al., 2007; Wijdicks et al., 2001), the combination of cortical and deep gray matter DWI/ fluid-attenuated inversion recovery (FLAIR) abnormalities (Greer et al., 2011; Mlynash et al., 2010), and severe global ADC reduction (Wijman et al., 2009; Wu et al., 2009). Still, 20%–50% of patients with good outcomes have DWI abnormalities on MRI (Choi et al., 2010; Greer et al, 2012; Roine et al., 1993), and some patients have poor outcomes despite a normal MRI (Fig. 83.5). Thus decisions on continuing medical care or withdrawal of life-sustaining treatments should not be made on the basis of MRI findings alone, and larger prospective studies with standardized imaging are needed. Some practical limitations that could impact the widespread use of MRI in this population include the difficult nature of transporting patients who may be too hemodynamically unstable to move to the MR suite. The assessment of prognosis in comatose survivors of CPR is important in clinical practice. It allows discussion about the level of care, whether the patient would have wanted another resuscitative effort, or whether medical care should be escalated. In many cases the family will decide to withdraw support. However, with all of these prognosticating studies, there continues to be a concern about prognostication error. Prognostication is difficult in patients who have received sedative drugs, despite examination beyond drug elimination half-life, and in patients who have had a cardiorespiratory arrest in the setting of drug overdose. In these patients, one should be prudent in making a definitive assessment. In conclusion, anoxic-ischemic injury to the brain is damaging at ictus and often leads to prolonged coma, and in many patients a persistent unconsciousness can be anticipated if care is not withdrawn. The continuous care of comatose patients after cardiopulmonary arrest results in a major burden to the healthcare system, and family members should be adequately informed about the chances of recovery. There is some indication that treatments are on the horizon, but for now, early resumption of circulation is the best guarantee for awakening. The complete reference list is available online at https://expertconsult. inkling.com/.

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B A

C

D Fig. 83.5 Diffusion-weighted magnetic resonance imaging (MRI) in anoxic-ischemic injury show diffuse cortical hyperintensities indicative of cortical injury, likely laminar necrosis (A, B). In a different patient, T1 post-gadolinium MRI shows contrast enhancement in the basal ganglia (C) and T2 hyperintensity involving the cortex (D), indicative of some anoxic injury despite clinical awakening. Noncontrast head computed tomography shows diffuse cerebral edema, loss of gray-white differentiation

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E

F Fig. 83.5 cont’d (E), and “pseudosubarachnoid hemorrhage” (F) in a patient who did not survive.

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84 Toxic and Metabolic Encephalopathies Karin Weissenborn, Alan H. Lockwood

OUTLINE Clinical Manifestations, 1276 Toxic Encephalopathies, 1277 Hepatic Encephalopathy, 1277 Acute Liver Failure, 1283 Uremic Encephalopathy, 1283 Twitch-Convulsive Syndrome, 1284 Restless Leg Syndrome, 1284 Wernicke Encephalopathy, 1284

Mild Cognitive Impairment/Dementia in Chronic Renal Disease, 1284 Central Nervous System Symptoms Associated with Dialysis Therapy, 1284 Dialysis Encephalopathy, 1284 Metabolic Disturbances, 1285 Disorders of Glucose Metabolism, 1285 Disorders of Water and Electrolyte Metabolism, 1287

Toxic and metabolic encephalopathies are a group of neurological disorders characterized by an altered mental status—that is, a delirium, defined as a disturbance of consciousness characterized by a reduced ability to focus, sustain, or shift attention that cannot be accounted for by preexisting or evolving dementia and that is caused by the direct physiological consequences of a general medical condition (see Chapter 4). Fluctuation of the signs and symptoms of the delirium over relatively short time periods is typical. Although the brain is isolated from the rest of the body by the blood-brain barrier, the nervous system is often affected severely by organ failure that may lead to the build-up of toxic substances normally removed from the body. This is encountered in patients with hepatic and renal failure. Damage to homeostatic mechanisms affecting the internal milieu of the brain, such as the abnormalities of electrolyte and water metabolism also affects brain function. In some cases, a deficiency of a critical substrate such as glucose is the precipitating factor. Frequently, the history and physical examination provide information that defines the affected organ system. In other cases, the cause is evident only after laboratory data are examined.

on a specific task. Evidence from studies of patients with cirrhosis suggests that metabolic encephalopathies are the result of a multifocal subcortical and cortical disorder rather than uniform involvement of all brain regions. Abnormalities of psychomotor function may also be present. Among patients with coma of unknown cause, nearly twothirds ultimately are found to have a metabolic cause. A complete discussion of coma is found in Chapter 5. The neuro-ophthalmological examination is extremely important in differentiating patients with metabolic disorders from those with structural lesions. The pupillary light reflex and vestibular responses are almost always present, even in patients in deep coma. However, it is common for these reflexes to be blunted. Exceptions include severe hypoxia, ingestion of large amounts of atropine or scopolamine, and deep barbiturate coma, which is usually associated with circulatory collapse and an isoelectric electroencephalogram (EEG). The pupils are usually slightly smaller than normal and may be somewhat irregular. The eyes may be aligned normally in patients with mild encephalopathy. With more severe encephalopathy, dysconjugate roving movements are common. Other cranial nerve abnormalities may be present but are less useful in formulating a differential diagnosis. Motor system abnormalities, particularly slight increases in tone, are common. Other signs and symptoms of metabolic disorders may include spasticity with extensor plantar signs and extrapyramidal as well as cerebellar signs (in patients with liver disease), multifocal myoclonus (in patients with uremia), cramps (in patients with electrolyte disorders), Trousseau sign (in patients with hypocalcemia), tremors, and weakness. Asterixis, a sudden loss of postural tone, is common. To elicit this sign, the patient should extend the arms and elbows while dorsiflexing the wrists and spreading the fingers. Small lateral movements of the fingers may be the earliest manifestation. More characteristically, there is a sudden flexion of the wrist with rapid resumption of the extended position, the so-called flapping tremor. Asterixis also may be evident during forced extrusion of the tongue, forced eye closure, or at the knee in prone patients asked to sustain flexion of the knee. Electrophysiological studies have shown that the onset of the lapse of posture is associated with complete electrical silence in the tested

CLINICAL MANIFESTATIONS Encephalopathy that develops insidiously may be difficult to detect. The slowness with which abnormalities evolve and replace normal cerebral functions makes it difficult for patients and families to recognize deficits. When examining patients with diseases of organs that are commonly associated with encephalopathy, neurologists should include encephalopathy in the differential diagnosis. Mental status abnormalities are always present and may range from subtle abnormalities, detected by neuropsychological testing, to deep coma. The level and content of consciousness reflect involvement of the reticular activating system and the cerebral cortex. Deficits in selective attention and the ability to process information underlie many metabolic encephalopathies and affect performance on many tasks. These deficits are manifested as disorders of orientation, cognition, memory, affect, perception, judgment, and the ability to concentrate

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CHAPTER 84 Toxic and Metabolic Encephalopathies muscle. This sign, once thought to be pathognomonic of hepatic encephalopathy (HE), occurs in a variety of conditions including uremia, other metabolic encephalopathies, and drug intoxication. Asterixis may also be present in patients with structural brain lesions, especially thalamic lesions. Generalized seizures occur in patients with water intoxication, hypoxia, uremia, and hypoglycemia, but only rarely as a manifestation of chronic liver failure. Seizures in patients with liver failure are generally due to alcohol or other drug withdrawal, or cerebral edema associated with acute liver failure (ALF). Focal seizures, including epilepsia partialis continua, may be seen in patients with hyperglycemia, and multifocal myoclonic seizures may occur in patients with uremia. Myoclonic status epilepticus may complicate hypoxic brain injury (see Chapter 83).

TOXIC ENCEPHALOPATHIES Hepatic Encephalopathy Cirrhosis of the liver affects an estimated 5.5 million adults in the United States. In 2011, over 33,000 Americans died as the result of chronic liver disease (Tsochatzis et al., 2014). Among the poor, the incidence of cirrhosis may be as much as 10 times higher than the national average and accounts for almost 20% of their excess mortality. As patients with chronic liver disease enter the terminal phases of their illness, HE becomes an increasingly important cause of morbidity and mortality. In this portion of the chapter, the term hepatic encephalopathy will be used to differentiate this condition from disorders associated with ALF, discussed in the next section. About 20,000 patients per year were hospitalized in the United States between 2005 and 2009 after developing HE (Stepanova et al., 2012). It is important to stress that minimal HE—the mildest form of HE, which interferes with the patients’ daily living ability but usually does not result in seeking medical care—is far more common, affecting about half of all patients with cirrhosis. Minimal HE can be diagnosed using neuropsychological tests, EEG, or critical flicker frequency (CFF), for example, but is commonly overlooked. A World Gastroenterological Association consensus statement seeks to minimize the substantial confusion in the literature and in clinical practice concerning the diagnosis of HE by using a multiaxial approach (Ferenci et al., 2002). The initial categorization addresses the presence of hepatocellular disease and portacaval shunting. Patients with acute liver disease or fulminating hepatic failure, a disorder occurring in patients with previously normal livers who exhibit neurological signs within 8 weeks of developing liver disease, form the first group (type A HE). A second group consists of a small number of patients who are free of hepatocellular disease but have portacaval shunting of blood (type B HE). The largest number of patients have hepatocellular disease with shunts (type C HE). Further subdivisions address temporal aspects—whether HE is episodic, chronic progressive, or persistent. Causal considerations are then applied to separate patients with precipitated HE from those with recurrent and idiopathic encephalopathy, and to identify the severity of the syndrome. The features that differentiate patients with ALF from those with the much more common portal systemic encephalopathy are shown in Table 84.1. Rating the severity of HE is complex but essential for evaluating the results of the treatment of individual patients and for evaluating potential treatments in the research setting. The so-called West Haven criteria supplemented by an evaluation of asterixis was used in the large multicenter trial that led to the approval of rifaximin for the treatment of HE. Both scales are ordinal. The West Haven Scale is scored as the following: 0, no personality or behavioral abnormality detected; 1, trivial lack of awareness, euphoria, or anxiety, shortened

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TABLE 84.1 Features Distinguishing Acute Liver Failure from Chronic Hepatic Encephalopathy or Portal Systemic Encephalopathy Feature

Acute Liver Failure

History Onset

Usually acute

Portal Systemic Encephalopathy

History of liver disease

Varies; may be insidious or subacute Mania may evolve to Blunted consciousness deep coma Viral infection or Gastrointestinal hemorhepatotoxin rhage, exogenous protein, drugs, uremia, infection No Usually yes

Symptoms Nausea, vomiting Abdominal pain

Common Common

Unusual Unusual

Signs Liver Nutritional state Collateral circulation Ascites

Small, soft, tender Normal Absent Absent

Usually large, firm, no pain Cachectic May be present May be present

Laboratory Test Transaminases Coagulopathy

Very high Present

Normal or slightly high Often present

Mental state Precipitating factor

attention span, or impairment of the ability to add or subtract; 2, lethargy, disorientation with respect to time, obvious personality change or inappropriate behavior; 3, somnolence or semistupor, responsiveness to verbal stimuli with confusion or gross disorientation; 4, coma. Asterixis is graded as follows: 0, no tremors; 1, few flapping tremors; 2, occasional flapping tremors; 3, frequent flapping tremors; 4, almost continuous flapping tremors. Recently, a subdivision into “covert” and “overt” HE has been recommended (Vilstrup et al., 2014). Patients with grade 2–4 according to the West Haven Scale thereby are included in the “overt HE” group, while those with grade 1 according to the West Haven Scale and those with only psychometric or neurophysiological but no clinical signs of HE are included in the “covert HE” group. The decision to combine grade 1 HE and minimal HE to “covert HE” originates from the observation of a significant inter-rater variability in diagnosing grade 1 HE but is still controversial. An episode of HE may be precipitated by one or more factors, some of which are iatrogenic. In one series, the use of sedatives accounted for almost 25% of all cases. A gastrointestinal (GI) hemorrhage was the next most common event (18%), followed by drug-induced azotemia and other causes of azotemia (15% each). Excessive dietary protein accounted for 10% of episodes; hypokalemia, constipation, infections, and other causes accounted for the remaining cases. As liver disease progresses, patients appear to become more susceptible to the effects of precipitants. This phenomenon has been referred to as toxin hypersensitivity. A transjugular intrahepatic portosystemic shunt (TIPSS), an endovascular procedure developed to treat intractable severe ascites, predisposes a patient to the development of encephalopathy, particularly among the elderly. TIPSS is more effective than large-volume paracentesis but does not prolong survival. TIPSS-related

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encephalopathy often responds to conventional treatment. Refractory cases may require endovascular treatment with coils to block a portion of the shunted blood.

Laboratory Evaluations The diagnosis of HE is based on the signs and symptoms of cerebral dysfunction in a setting of hepatic failure. Usually, standard laboratory test results, including serum bilirubin and hepatic enzymes, are abnormal. Products of normal hepatic function, including serum albumin and clotting factors, often are low, leading to elevation of the international normalized ratio (INR). Measurements of the arterial ammonia level may be helpful in diagnosing HE, but an ammonia level within the normal range does not exclude HE. Several consensus conferences sponsored by the International Society for Hepatic Encephalopathy and Nitrogen Metabolism have made recommendations concerning the use of electrophysiological and neuropsychological tests to evaluate patients with HE (Guerit et al., 2009; Randolph et al., 2009). The favored electrophysiological tests are those that are responsive to cortical function and include event-related potentials (ERPs) such as P300 tests and the EEG. Bursts of moderate- to high-amplitude (100–300 µV), low-frequency (1.5–2.5 Hz) waves with predominance in the frontal derivations are the most characteristic EEG abnormality in patients with severe HE. But even patients without clinical signs of HE may show a reduction of the mean dominant frequency. Recently EEG was used to investigate functional cortical connectivity in patients with liver cirrhosis and an alteration was shown as well in patients with normal cognitive function compared to controls (Olesen et al., 2019). Abnormal ERPs may also be found in patients with minimal encephalopathy. Auditory P300 potential recordings, in which the subject is asked to discriminate between a rare and a common tone, showed prolonged latencies in patients with overt encephalopathy (including HE grade 1) and in some of the patients without clinical evidence of HE, indicating minimal encephalopathy. The need of more sophisticated equipment for the P300 assessment than for the EEG assessment has precluded broad use of this method for clinical purposes. Neuropsychological tests are useful for diagnosing minimal HE and for follow-up of patients with low-grade HE (grades mHE–grade II HE). Domains to be evaluated include attention, visuoconstructional ability, and motor speed and accuracy. Up to 60% of all patients with cirrhosis with no overt evidence of encephalopathy exhibit significant abnormalities when given a battery of neuropsychological tests. Tests of attention, concentration, visuospatial perception, and motor speed and accuracy are the most likely to be abnormal (Schomerus and Hamster, 1998). The Portosystematic Encephalopathy (PSE) Syndrome Test—a test battery consisting of the Number Connection Tests A and B, serial dotting, line tracing, and the Digit Symbol Test—has been recommended for evaluating patients who may have HE (Randolph et al., 2009; Weissenborn et al., 2001). This battery is sensitive and relatively specific for the disorder, compared with other metabolic encephalopathies. Besides EEG and neuropsychological tests, occasionally the analysis of the CFF is used for diagnosing HE and follow-up (Vilstrup et al., 2014). Subclinical cognitive impairment of patients with cirrhosis, particularly attention deficits and impairment in the visuospatial sphere, may be severe enough to interfere with the safe operation of an automobile or other dangerous equipment. A study comparing patients with minimal encephalopathy with nonencephalopathic patients with cirrhosis and a third group with GI disease found that those with minimal encephalopathy performed the worst during an on-the-road driving test. Specific problems centered on handling, adaptation to road

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Fig. 84.1 T1-weighted magnetic resonance images from a patient with cirrhosis of the liver. Note high signal in basal ganglia, cerebral peduncles, and substantia nigra.

conditions, and accident avoidance. Language functions are usually normal. These data, combined with other studies showing that the quality of life is affected by these abnormalities, suggest that neuropsychological tests should be used more extensively for routine evaluation of all patients with cirrhosis, particularly those without overt evidence of HE. Although the diagnosis of HE is typically made on the basis of clinical criteria, neuroimaging techniques are commonly employed to exclude structural lesions. Magnetic resonance imaging (MRI) and spectroscopic (MRS) studies have revealed new insights into the pathophysiology of HE (Lockwood et al., 1997). On T1-weighted images, it is common to find abnormally high signals arising in the pallidum. These are seen as whiter-than-normal areas in this portion of the brain, as shown in Fig. 84.1. In addition to these more obvious abnormalities, a systematic analysis of MR images shows that the T1 signal abnormality is widespread and found in the limbic and extrapyramidal systems, and generally throughout the white matter. A generalized shortening of the T2 signal also occurs. These abnormalities have been linked to an increase in the cerebral manganese content. The abnormalities become more prominent with time and regress after successful liver transplantation. The unexpected finding of high T1 signals in the pallidum should suggest the possibility of liver cirrhosis. Proton MRS techniques also have been applied to the study of patients with cirrhosis and are available in many centers. In the absence of absolute measures that are referable to concentrations, the signal of specific compounds has often been referenced to creatine and expressed as a compound-to-creatine ratio in the past. Irrespective of the use of a quantitative or semi-quantitative approach, there is general agreement among studies that an increase in the intensity of the signal occurs at approximately 2.5 ppm; this is attributed to glutamine plus glutamate (Glx). With high-field-strength magnets, this peak can be

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The pathophysiological basis for the development of HE is still not completely known. However, treatment strategies for the disorder are all founded on theoretical pathophysiological mechanisms. A number of hypotheses have been advanced to explain the development of the disorder. Suspected factors include hyperammonemia, altered amino acids and neurotransmitters—especially those related to the γ-aminobutyric acid (GABA)–benzodiazepine complex—mercaptans, short-chain fatty acids, and manganese deposition in the brain. An interaction between hyperammonemia and a systemic pro-inflammatory status is now considered a major cause of HE (Cabrera-Pastor et al., 2019).

by the hepatic portal vein, where detoxification reactions take place. Portal systemic shunts cause ammonia to bypass the liver and enter the system circulation, where it is transported to the various organs as determined by their blood flow. The liver is the most important organ for the detoxification of ammonia. However, in patients with portacaval shunting of blood, because of the formation of varices, TIPS, or other surgically created shunts, skeletal muscle becomes more important as the fraction of blood bypassing the liver increases. Under the most extreme conditions, muscle becomes the most important organ for ammonia detoxification. It is partly for this reason that nutritional therapy for patients should be designed to prevent development of a catabolic state and muscle wasting. Ammonia is always extracted by the brain as arterial blood passes through the cerebral capillaries. When ammonia enters the brain, metabolic trapping reactions convert free ammonia into metabolites (Fig. 84.3). The adenosine triphosphate (ATP)–catalyzed glutamine synthetase reaction is the most important of these reactions. The bloodbrain barrier is approximately 200 times more permeable to uncharged ammonia gas (NH3) than it is to the ammonium ion (NH4+); however, because the ionic form is much more abundant than the gas at physiological pH values, substantial amounts of both species appear to cross the blood-brain barrier. Because of this permeability difference and because ammonia is a weak base, relatively small changes in the pH of blood relative to the brain have a significant effect on brain ammonia extraction. As blood becomes more alkalotic, more ammonia is present as the gas and cerebral ammonia extraction increases; however, the role this has in the production of HE is not known. The permeability surface-area (PS) product of the blood-brain barrier may be affected by prolonged liver disease. However, the experimental data about this change are in conflict: one study reported an increase in the PS product, others reported no change (Ahl et al., 2004; Dam et al., 2013; Goldbecker et al., 2010; Keiding et al., 2006; Lockwood et al., 1991).

Cerebral Blood Flow and Glucose Metabolism

Other Pathophysiological Mechanisms

resolved into its components; the increase is attributed to glutamine, as expected on the basis of animal investigations. Glx increase is accompanied by a decrease in my-oinositol and choline signals, whereas N-acetylaspartate resonances (a neuronal marker) are consistently normal. Correlations between the glutamine concentration, generally considered to be a reflection of exposure of the brain to ammonia, and the severity of the encephalopathy, have led some to propose that MR spectroscopy may be useful in the diagnosis of HE. However, the data currently available are controversial. Neuroimaging is useful in the diagnosis of coexisting structural lesions of the brain, such as subdural hematomas or other evidence of cerebral trauma, or complications of alcohol abuse or thiamine deficiency, or both, such as midline cerebellar atrophy, third ventricle dilatation, mamillary body atrophy, or high-signal-strength lesions in the periventricular area on T2 fluid-attenuated inversion recovery (FLAIR) images. It must be emphasized that none of the methods described in this section delivers findings that are specific for HE. Thus, a diagnosis of HE can be made only after exclusion of other possible causes of cerebral dysfunction.

Pathophysiology

Whole-brain measurements of cerebral blood flow (CBF) and metabolism are normal in patients with grade 0–1 HE. Reductions occur in more severely affected patients. Sophisticated statistical techniques designed to analyze images have made it possible to identify specific brain regions in which glucose metabolism is abnormal in patients with low-grade encephalopathy and abnormal neuropsychological test scores (Lockwood et al., 2002). These positron emission tomography (PET) data show clearly that minimal forms of HE are caused by the selective impairment of specific neural systems rather than by global cerebral dysfunction. Reductions occur in the cingulate gyrus, an important element in the attentional system of the brain, and in frontal and parietal association cortices. These PET data are in accord with cortical localizations based on the results of neuropsychological tests. Fig. 84.2 shows the results of correlation analyses between scores on selected neuropsychological tests and sites of reduced cerebral glucose metabolism.

Role of Ammonia HE is linked to hyperammonemia. Patients with encephalopathy have elevated blood ammonia levels that correlate to a degree with the severity of the encephalopathy. Metabolic products formed from ammonia—most notably glutamine and its transamination product, α-ketoglutaramic acid—also are present in excess in cerebrospinal fluid (CSF) in patients with liver disease. Treatment strategies that lower blood ammonia levels are the cornerstone of therapy. Tracer studies performed with [13N]-ammonia have helped clarify the role of this toxin in the pathophysiology of HE. Ammonia and other toxins are formed in the GI tract and carried to the liver

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Astrocyte swelling and the role of concomitant disorders. Although there is a strong correlation between the plasma ammonia level and the grade of HE, there is also substantial overlap in ammonia levels by grade of HE, indicating that other factors besides hyperammonemia must play a role in the development of HE. An increase in ammonia detoxification in the brain is associated with an increase of glutamine concentrations within astrocytes and cell swelling. Initially, glutamine is counterbalanced by the release of cellular osmolytes such as myo-inositol to avert cell swelling. If the cells are depleted of myo-inositol, cell swelling can be induced with small amounts of ammonia. Astrocyte swelling may be induced also by inflammatory cytokines, hyponatremia, or benzodiazepines. This is of special interest since HE episodes are frequently precipitated by infection, electrolyte dysbalance, or the application of sedative drugs. Overall, the vulnerability of the brain against these precipitating factors increases with decreasing concentration of intracellular myo-inositol. Astrocyte swelling is considered a key factor in the pathogenesis of HE (Häussinger and Sies, 2013). It has been shown to trigger multiple alterations of astrocyte function and gene expression. Astrocyte swelling induces the formation of reactive oxygen species and nitrogen oxide. Ammonia has been shown to induce the mitochondrial permeability transition (mPT) probably mediated by oxidative stress. Induction of the mPT leads to a collapse of the mitochondrial inner membrane potential, swelling of the mitochondrial matrix, defective oxidative phosphorylation, cessation of ATP synthesis, and finally the generation of reactive oxygen species. Thus, induction of the mPT is part of the vicious circle of oxidative/nitrosative stress and astrocytic dysfunction (Norenberg et al., 2009). Oxidative stress is closely related

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Negative line drawing time

Negative dotting

Negative line drawing error

Negative Trail Making B

Positive Symbol Digit

Negative Trail Making A

Fig. 84.2 Correlations between performance in the various subtests of the PSE Syndrome Test, as measured by age-corrected z scores, and cerebral glucose metabolism, as measured by fluorodeoxyglucose-positron emission tomography metabolism. Only those subjects able to complete the test are included in the analyses. The statistical parametric mapping Z image projections show significant correlations with bilateral parietal associative cortex, with increasing correlations with frontal regions. (Used with permission from Lockwood, A.H., Weissenborn, K., Bokemeyer, M., et al., 2002. Correlations between cerebral glucose metabolism and neuropsychological test performance in nonalcoholic cirrhotics. Metab Brain Dis 17, 29–40.)

to astrocytic senescence; it has recently been suggested that this plays an important role in the pathophysiology of HE (Görg et al., 2018). Abnormalities of neurotransmission. Since the early 1970s, a variety of hypotheses have suggested that HE is caused by disordered neurotransmission. Although early hypotheses related to putative false neurotransmitters were disproved, there is still effort in this direction. F ECF

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As a result of the false neurotransmitter hypothesis, it was shown that the ratio of plasma amino acids (valine + leucine + isoleucine) to (phenylalanine + tyrosine) was abnormal in encephalopathic patients, leading to the development of branched chain amino acid (BCAA) solutions designed to normalize this ratio, which are now commercially available. A meta-analysis of studies analyzing the effects of 02 .4.(1( 4 (

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Brain Glutamine synthetase

Liver

Skeletal muscle

Glutamine Glutamine synthetase

Urea

Urea cycle

Glutamine

NH3

Urea

NH3

NH3

Glutamine (NH3)

NH3

Glutamine (NH3)

Ammonia glutamine urea

Portacaval NH3

shunt Hepatic portal vein

Systemic vascular pool

(NH3) Kidney Urea Nitrogen excretion

GI tract Nitrogen source

>

Urease amino acid oxidase

>

NH3

Fig. 84.3 Human Ammonia Metabolism. The brain becomes more sensitive to ammonia as time progresses. The reasons for this are largely unknown. In addition, ammonia may cause anorexia by stimulating hypothalamic centers, leading to reductions in muscle mass and an impaired ability of muscle to detoxify ammonia. GI, Gastrointestinal. (Adapted from Lockwood, A.H., McDonald, J.M., Reiman, R.E., et al., 1979. The dynamics of ammonia metabolism in man: effects of liver disease and hyperammonemia. J Clin Invest 63, 449–460.)

oral or intravenous application of BCAA came to the conclusion that BCAAs have a beneficial effect upon HE, but not upon mortality in patients with liver cirrhosis (Gluud et al., 2017). Substantial effort has been focused on potential abnormalities of the GABA–benzodiazepine complex. Initial attention was directed at GABA itself. However, early reports that GABA concentrations were elevated in patients with encephalopathy have been disproved. Still, a number of anecdotal reports have described dramatic improvements in patients after they were given flumazenil—a benzodiazepine antagonist; very low concentrations of benzodiazepines and their metabolites may be found in blood and CSF of patients with encephalopathy. In controlled studies, patients given flumazenil are more likely to improve than those given placebo. It is unclear whether benzodiazepine displacement is the mechanism because these patients do not usually have clinically significant blood levels of benzodiazepines. More recent theories have linked the presence of increased expression of peripheral types of benzodiazepine receptors (currently called translocator protein [TSPO]) to HE. These receptors are found on mitochondrial membranes and are implicated in intermediary metabolism and neurosteroid synthesis. Hyperammonemia causes an increase in TSPO and thereby stimulates the production of neurosteroids such as allopregnanolone, which activates GABA and benzodiazepine receptor sites of the GABA-A receptor, resulting in an increase in GABA-ergic tone in the brain. In addition, there are significant alterations in cerebral serotonin and dopamine metabolism and a reduction in postsynaptic glutamate receptors of the N-methyl-d-aspartate type. Thus, there is a substantial interest in the potential role of neurotransmitters in the pathogenesis of HE. As of yet, there is no unifying hypothesis and no rational therapeutic approach based on altering neurotransmission.

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Manganese. Blood manganese levels are increased in patients with liver cirrhosis due to an impairment of biliary manganese excretion. Manganese deposition within the brain increases, with predominance in the basal ganglia. These manganese deposits are considered to cause the brain MRI signal alterations in patients with liver cirrhosis. Manganese potentiates the toxic effects of ammonia. Moreover, manganese deposition per se results in neuronal loss, Alzheimer type II astrocytosis, alteration of dopaminergic neurotransmission, and expression of the “peripheral-type” benzodiazepine receptor (TSPO) mentioned earlier (Butterworth, 2010).

Neuropathology The Alzheimer type II astrocyte is the neuropathological hallmark of hepatic coma. An account of the original descriptions of this change was provided in translation by Adams and Foley in 1953. In this report, they presented their own findings concerning this astrocyte change in the cerebral cortex and the lenticular, lateral thalamic, dentate, and red nuclei, offering the tentative proposal that the severity of these changes might be correlated with the length of coma. The cause of the astrocyte change was established by studies that reproduced the clinical and pathological characteristics of HE in primates by continuous infusions of ammonia. In studies of rats with portacaval shunts, astrocyte changes become evident after the fifth week. Before coma develops, astrocytic protoplasm increases and endoplasmic reticulum and mitochondria proliferate, suggesting that these are metabolically activated cells. After the production of coma, the more typical signs of the Alzheimer type II change became evident as mitochondrial and nuclear degeneration appeared. Norenberg (1987) suggested that HE is an astrocytic disease, although oligodendroglial cells are affected as well. More recent evidence from his laboratory

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has shown that ammonia affects a wide variety of astrocytic functions and aquaporin-4. The neuropathological–neurochemical link between astrocytes and the production of hyperammonemic coma is strengthened by immunohistochemical studies that localized glutamine synthetase to astrocytes and their end-feet. Similar findings for glutamate dehydrogenase have been described. Long-standing or recurrent HE may lead to the degenerative changes in the brain characteristic of non-Wilson hepatocerebral degeneration. Brains of these patients have polymicrocavitary degenerative changes in layers five and six of the cortex, underlying white matter, basal ganglia, and cerebellum. Intranuclear inclusions that test positive by periodic acid–Schiff are also seen, as are abnormalities in tracts of the spinal cord. More recent histopathological studies showed lymphocyte infiltration in the meninges, microglia activation in the molecular layer, and loss of Purkinje and granular neurons of the cerebellum, already in patients with steatohepatitis grade 1, and increasing glial activation and neuronal loss with progression of the liver disease to cirrhosis (Balzano et al., 2018).

Treatment Ideally, the management of cirrhosis should involve a cooperative effort between hepatologists, surgeons, neurologists, and psychologists, with additional input from nurses and dieticians. Practice guidelines published by the European and the American Association for the Study of the Liver (EASL/AASL) recommend a four-pronged approach to management of HE: (1) provision of supportive care, (2) identification and treatment of precipitating factors, (3) search for and treatment of concomitant causes of encephalopathy, and (4) commencement of empirical HE treatment (Vilstrup et al., 2014). Initial diagnostic and therapeutic efforts should be directed at the identification and mitigation of precipitating factors, and at reducing the nitrogenous load arising from the GI tract. This is accomplished by a brief withdrawal of protein from the diet and the administration of cleansing enemas, followed by the use of lactulose. Antibiotics such as rifaximin, metronidazole, or neomycin may be used as an alternative or add-on to lactulose. Rifaximin has the advantage of showing no systemic side effects (Bass et al., 2010). Oral BCAAs were shown to improve both overt and minimal HE, and thus are a possible add-on therapy if a patient does not respond to conventional therapy. After the acute phase of HE, patients should receive the maximum amount of protein that is tolerated. Prolonged periods of protein restriction should be avoided. Protein is required for the regeneration of hepatocytes and prevention of a catabolic state and muscle wasting. In patients without overt encephalopathy, diagnostic efforts should be directed toward identifying patients with minimal encephalopathy and monitoring the effects of treatment. Patients with minimal encephalopathy have a diminished quality of life and benefit from therapy, typically lactulose. Follow-up testing is needed to monitor treatment. Lactulose. Lactulose is a mainstay for the treatment of both acute and chronic forms of HE. It has been used for the treatment of overt HE for decades despite sparse data from randomized placebo-controlled trials. According to a recent Cochrane review, lactulose has a beneficial effect on minimal and overt HE and also may prevent recurrence of HE (Gluud et al., 2016). Lactulose is a synthetic disaccharide metabolized by colonic bacteria to produce acid, and causes an osmotic diarrhea. The effect of lactulose is attributable to its role as a substrate in bacterial metabolism, leading to an assimilation of ammonia by bacteria or reducing deamination of nitrogenous compounds. It is probably the single most important agent in the treatment of acute and chronic encephalopathy. The usual dose of lactulose is 20–30 g, 3 or 4 times a

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day, or an amount sufficient to produce 2 or 3 stools per day. Lactulose also can be given as an enema. Amino acids. BCAAs improve skeletal muscular protein synthesis and thereby ammonia detoxification. A meta-analysis of 16 randomized controlled trials of BCAA versus placebo, diet, lactulose or neomycin showed a significant effect of BCAA upon minimal and overt HE (Gluud et al., 2017). Antibiotics. Nonabsorbable antibiotics such as neomycin were among the initial treatments for HE but have been abandoned because of their nephrotoxicity and ototoxicity. In 2010, the US Food and Drug Administration (FDA) approved the use of oral rifaximin, 550 mg, twice daily “to reduce risk for recurrence of overt HE in patients with advanced liver disease.” This nonabsorbable antibiotic had a relatively long history of use for the treatment of traveler’s diarrhea. Its efficacy was shown in a multicenter randomized, placebo-controlled, doubleblind clinical trial involving 299 patients who were in remission after sustaining at least two episodes of HE (Bass et al., 2010). A breakthrough episode of HE occurred in 22.1% of the patients in the rifaximin group and in 45.9% of the patients in the placebo group, yielding a hazard ratio of 0.42 (95% confidence interval [CI] 0.28–0.64; P < .001). There was also a significant reduction in a secondary endpoint, the probability of rehospitalization. It is important to note that more than 90% of the patients in this trial were already receiving and continued to receive lactulose. Thus, rifaximin should be considered as a valuable add-on therapy.

Complications and Prognosis Although studies done over 2 decades ago demonstrated that patients with hepatic coma were more likely to survive with minimal residua, this disorder still carries a substantial risk of death. Transplant-free survival at 1 year is less than 50% after an initial episode and less than 25% at 3 years. To aid in the selection of patients for transplantation, a simple rating system or MELD (Model for End-stage Liver Disease) score has been developed and validated to predict mortality. HE has no effect in the selection of patients for transplantation. The MELD score is based on bilirubin, serum creatinine, and the INR. The higher the MELD score, the worse the prognosis. Currently the use of the MELD score is controversial. While the mortality on the waiting list for liver transplantation decreased since introduction of the MELD score as a means for organ allocation, the mortality after transplantation continuously increased. The incidence of HE is probably underestimated, mainly because neurologists are not usually the primary physicians of these patients, and early subtle signs of cerebral dysfunction may be missed. It is important to establish the diagnosis of HE promptly and proceed with vigorous treatment. HE was considered completely reversible in the past. There is, however, increasing evidence that the recovery may remain incomplete (Bolzano et al., 2018; Campagna et al., 2014). Prolonged or repeated episodes risk transforming this reversible condition into non-Wilson hepatocerebral degeneration, a severe disease with fixed or progressive neurological deficits including dementia, dysarthria, gait ataxia with intention tremor, choreoathetosis, and— most frequently—parkinsonism (Tryc et al., 2013). Other patients may develop evidence of spinal cord damage, usually manifested by a spastic paraplegia. This complication may be a part of the spectrum of hepatocerebral degeneration. Differentiating correctly between early myelopathy or hepatocerebral degeneration and the motor abnormalities that characterize reversible encephalopathy may not always be possible in a first visit but can be done with follow-up examinations. Patients with HE may develop toxin hypersensitivity, wherein previously innocuous levels of toxins cause symptoms. This concept implies that there may be a steadily increasing risk for developing permanent neurological damage as toxin hypersensitivity evolves.

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Acute Liver Failure ALF is usually the result of massive necrosis of hepatocytes and is defined as a syndrome in which the signs of encephalopathy develop within up to 3 months after the onset of the symptoms of liver disease in a patient with a previously normal liver. Modern classifications differentiate between hyperacute (HE within 1 week), acute (HE within 4 weeks), and subacute courses (HE develops between 1 and 3 months after the onset of the liver disease). Hyperacute, acute, and subacute ALF differ in regard to etiology and prognosis (Bernal, 2017; Bernal and Wendon, 2013). HE in patients with ALF and HE in patients with cirrhosis share many symptoms. However, due to the different time course and extent of the metabolic alterations, there are some significant differences. In contrast to patients with cirrhosis, patients with ALF frequently develop irritability, agitation, seizures, and brain edema, whereas extrapyramidal and cerebellar symptoms, which are frequent in patients with cirrhosis, are lacking in ALF. In patients with ALF, blood ammonia levels may rise extremely, and have been shown to correlate with intracranial pressure (ICP), severity of clinical presentation, and death by brain herniation (Bernal et al., 2007; Bernal and Wendon, 2013). Recently, it was shown that persistent hyperammonemia above 122 µmol/L for 3 days is accompanied with increased risk of developing brain edema, seizures, and death. Brain edema is present in 25%–35% of patients with grade 3 HE and in 65%–75% of those with grade 4 HE in ALF. According to a retrospective analysis from King’s College, London, the percentage of patients with intracranial hypertension significantly decreased between 1973 and 2008 from 76% to 20% (Bernal et al., 2013). Nevertheless, brain edema is one of the leading causes of mortality in ALF, while both diagnosis and treatment are difficult. The diagnosis is impeded by the fact that the patients are intubated and mechanically ventilated, and thus a clinical neurological assessment is impossible. Repeated brain imaging is not feasible. In addition, there is no strong correlation between ICP and CCT results. Therefore, occasionally continuous monitoring of ICP is recommended, but is not without controversy, since these patients with altered hemostasis may develop intracranial hemorrhages. In a series of 324 patients with acute hepatic failure, 28% underwent ICP monitoring. In a subset of these, 10.3% had radiographic evidence of an intracranial hemorrhage, half of which were incidental findings (Vaquero et al., 2005). Basic treatment of patients with ALF aims to reduce plasma ammonia levels and systemic cytokine levels, and to hold plasma sodium levels within the normal range. Therefore, patients are treated prophylactically with antibiotics as well as early renal support. Of note, lactulose has not shown a significant effect in ALF, neither with regard to plasma ammonia levels nor with survival. Brain edema is treated with mannitol infusion given either every 6 hours (1 g mannitol/kg body weight) or in patients with ICP monitoring as a response to ICP increases above 20–25 mm Hg. A precondition is that serum osmolality is less than 320 mOsm/L and patients have not yet developed acute renal dysfunction. Based on clinical observations, moderate hypothermia (32°C–34°C) has been recommended to reduce ICP in patients with uncontrolled intracranial hypertension who are awaiting emergency liver transplantation. However, a randomized, controlled, multicenter study has not confirmed these observations (Bernal et al., 2016). Besides supportive care, the quick identification of those patients who will need liver transplantation is important. Risk factors considered for this decision are the grade of encephalopathy and coagulopathy, age, bilirubin and creatinine plasma levels, and pH. Substantial research efforts have been devoted to the development of artificial livers or cellbased perfusion systems designed to remove toxins from circulating blood. But none of the systems has shown significant effect on survival (Bernal and Wendon, 2013; Lee, 2012; Shawcross and Wendon, 2012).

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In contrast, a recent multicenter study showed a significant effect of therapeutic plasma exchange upon liver transplant–free survival (Larsen et al., 2016). ALF has been described as “metabolic chaos” because of coexisting acid-base, renal, electrolyte, cardiac, and hematological abnormalities, usually culminating in GI bleeding, ascites, sepsis, and often death. Due to continuous improvement in intensive care management and emergency liver transplantation, mortality of ALF decreased from about 80% in the 1970s to currently about 30%–40%.

Uremic Encephalopathy Neurological disorders in patients with renal failure may present more problems for the neurologist than are found in patients with failure of other organ systems. This is primarily because of the complexity of the clinical status of many of these patients. Many of the disorders that lead to the development of renal failure (e.g., hypertension, systemic lupus erythematosus, diabetes mellitus) are frequently associated with disorders of the nervous system that are independent of a patient’s renal function. Thus it may be difficult to determine whether new neurological problems are caused by the primary disease or by the secondary effects of uremia. Similarly, it is frequently difficult to determine whether neurological problems are the consequence of the progression of renal disease and progressive azotemia, the treatment of renal failure by measures such as dialysis and its associated dysequilibrium and dementia syndromes, or a complication of transplantation and immunosuppression. With increasing numbers of renal transplants and improved treatment designed to prevent rejection, it is likely that the complexity of these issues will continue to increase. For these reasons, good cooperation and communication between neurologists and the nephrologists and transplant teams who care for these patients are important. Uremic encephalopathy is considered to be caused by uremic toxins, in particular guanidino compounds, that accumulate due to renal dysfunction. These compounds interfere with both glutamatergic and GABA-ergic neurotransmission, finally leading to an enhanced excitability. In addition, disturbance of the dopaminergic neurotransmission has been observed in experimental animals (uremic rats) and was related to impairment of motor activity. Secondary hyperparathyroidism is suggested as leading to increased neuronal calcium levels and neuroexcitation. Experimental studies have shown a doubling of the brain calcium content and serum parathyroid hormone levels within days of the onset of acute renal failure. EEG slowing correlates with elevations in the plasma content of the N-terminal fragment of parathyroid hormone. Treatment with 1,25-dihydroxyvitamin D leads to improvements in the EEG and reductions in N-terminal fragment parathyroid hormone concentrations. Alteration of the blood-brain barrier due to uremia as well as systemic inflammation that accompanies renal failure facilitates access of toxins to the brain (Jabbari and Vaziri, 2018). Clinical symptoms range from emotional alterations, especially depression, and slight attention and memory deficits to severe alterations of consciousness and cognition, including (mostly agitated) confusion, psychosis, seizures, and coma. Slight neuropsychiatric symptoms are present in about 30% of patients on dialysis therapy. The advanced grades of uremic encephalopathy with confusion or coma are currently predominantly observed in patients in whom a decision has been made not to start dialysis. Action tremor, asterixis, and myoclonus, as well as hyperreflexia, are characteristic features of uremic encephalopathy. Occasionally, choreatic movements have been described. Both asterixis and myoclonus may be provoked by several drugs such as opioids, antiepileptic drugs, phenothiazines, or metoclopramide in patients with impaired renal function due to increased plasma levels.

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The diagnosis of uremic encephalopathy is made in the presence of the characteristic symptoms in a patient with severe renal dysfunction after exclusion of other possible causes. The diagnosis is proven if symptoms disappear with successful renal replacement therapy. EEG, CSF, and brain imaging produce unspecific results. The EEG shows a generalized slowing with excess theta and delta activity. Sometimes bilateral spike-wave complexes are found. EEG correlates with clinical findings: with progression of encephalopathy, EEG becomes slower, but normalizes with successful therapy. CSF is often abnormal, and shows increased protein levels (2+) is seen at presentation or if plasma glucose is falling at a rate of less than 5 mmol/h (90 mg/dL) despite adequate fluid replacement (Gouveia and Chowdhury, 2013). The patients may require intensive monitoring with arterial and central venous catheters to monitor the circulatory system status and avoid inducing a volume overload. The exact mechanisms leading to the development of the syndrome, particularly the absence of ketosis, are not fully explained.

Complications of Treatment Although treatment of DKA has improved, the mortality rate is still appreciable. Among adults, the mortality rate of DKA is estimated as about 1%. However, DKA remains a leading cause of mortality in children and young adults with type 1 diabetes. The majority of patients who succumb do so because of cardiovascular collapse or from complications of the precipitating factor. A small number of patients die unexpectedly when laboratory and clinical indicators all show initial improvement. Clinically, patients with DKA who die experience rapid neurological then cardiovascular deterioration. Postmortem examinations of the brain show lesions similar to those seen in acute asphyxia, including capillary dilation with perivascular and pericellular edema. Death is heralded by a rapid evolution of signs and symptoms indicating an increase in ICP. About half of patients die during the initial episode of DKA. The rate and degree to which the plasma glucose level is lowered is not a major risk factor for death. Some degree of cerebral edema attends the treatment of most patients with DKA, occasionally to the high level of 600 mm H2O CSF pressure, as shown in Fig. 84.4. The data suggest that at least mild clinically silent cerebral swelling may be much more common than is realized in cases of DKA. Rare unknown factors appear to trigger a malignant increase in ICP in a small number of patients. Published experience suggests that if this diagnosis is made, prompt aggressive treatment of cerebral edema is indicated, preferably using ICP monitoring as a guide to therapy. Nevertheless, the associated mortality rate is high. The estimated mortality rate in patients with nonketotic hyperosmolar coma, ranging between 5% and 20%, is much higher than that of DKA. This difference is partially due to affected patients being older and with comorbid conditions that contribute to volume depletion more often than those with DKA. Available evidence suggests that hyperglycemic emergencies are associated with an inflammatory and procoagulant state, which both contribute to an increased risk of thrombotic complications. Thus, heparin should be administered subcutaneously for prophylaxis of thrombosis.

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Case 1 CSF pressure

600 Glucose

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Fig. 84.4 Blood Glucose and Intracranial Pressure During Treatment of Diabetic Ketoacidosis. The untreated hyperosmolar state leads to the intracerebral accumulation of idiogenic osmoles. As blood glucose and osmolality levels decrease during treatment, free water enters the brain more rapidly than idiogenic osmoles are shed, leading to an increase in intracranial pressure from the swollen brain. This mechanism presumably operates in all cases in which hyperosmolality is corrected rapidly. CSF, Cerebrospinal fluid. (Reprinted with permission from Clements, R.S. Jr., Blumenthal, S.A., Morrison, A.D., et al., 1971. Increased cerebrospinal fluid pressure during treatment of diabetic ketoses. Lancet 2, 671–675.)

Disorders of Water and Electrolyte Metabolism Patients with abnormalities of water and electrolyte metabolism frequently exhibit signs and symptoms of cerebral dysfunction. Typically these patients have altered states of consciousness or epileptic seizures that herald the onset of the abnormality. The vulnerability of the nervous system to abnormalities of water and electrolyte balance arises from changes in brain volume, especially the brain swelling that may be associated with water intoxication. The role played by electrolytes is also important in maintaining transmembrane potentials, neurotransmission, and a variety of metabolic reactions. Although most clinicians are aware of the importance of water and electrolyte disturbances as a cause of brain dysfunction, the importance of the brain in the control of water and electrolytes is less well appreciated. Excellent reviews of these disorders have been written by Adrogué and Madias (2000a, 2000b, 2012, 2014).

Disordered Osmolality Osmotic homeostasis. Serum osmolality, and hence wholebody osmolality, are regulated by complex neuroendocrine and renal interactions that control thirst and water and electrolyte balance. When serum osmolality increases, the brain loses volume; when osmolality falls, the brain swells. Events related to water loss are illustrated in Fig. 84.5. The brain has little protection in terms of volume changes when osmotic stress is acute. Examples of acute osmotic stress may be found in patients with heatstroke, inadvertent solute ingestion (particularly in infants), massive ingestion of water (which may be psychogenic), hemodialysis, and diabetics with nonketotic coma. Recent reports also suggest that excessive water consumption occurs in some marathon runners, leading to acute water intoxication. When osmotic stress is applied more slowly over a longer period, the predicted volume changes are smaller than would be expected. The mechanisms that underlie these protective adaptations are not known completely but involve the gain of amino acids in the case of the hyperosmolar state and the loss of potassium in the hypo-osmolar state. Experimental studies have failed to identify all of the osmotically active particles that must exist in the brain after a given osmotic stress is applied. These unidentified molecules are called idiogenic osmoles. Hypo-osmolality and hyponatremia. Hypo-osmolality is almost always associated with hyponatremia. The diagnosis usually is made by

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BOX 84.2

Water loss

Increased osmolality

ADH release

Thirst

Water retention

Water intake

Combined Water and Sodium Depletion (Hypovolemia) Renal Loss Primary renal disease Osmotic diuresis (glucose, mannitol) Adrenal insufficiency

Brain adapts

Nonrenal Loss Gastrointestinal (diarrhea, suction, vomiting) Transcutaneous (sweating, burns) Sequestration (ascites, peritonitis)

Decreased osmolality

ADH inhibition

Hyponatremia without Water Loss Edema with water and sodium retention Dilutional (iatrogenic, psychogenic) Sick cell syndrome Hyperosmotic (hyperglycemia or mannitol administration) Syndrome of inappropriate antidiuretic hormone secretion Artifact (laboratory error, hyperlipidemia)

Brain adapts

Thirst inhibition

Fig. 84.5 Water Balance and the Brain. A reduction in water (or an increase in water loss or solute gain) stimulates thirst and vasopressin release, leading to increased water conservation and intake, which in turn reduces vasopressin levels and ends thirst. Excessive water intake or excessive water loss leads to hypo-osmolality or hyperosmolality and the loss or gain of osmotically active particles in the brain, respectively. Excessively rapid treatment of these conditions may lead to the development of neurological symptoms. ADH, Antidiuretic hormone.

laboratory testing. Conditions associated with hyponatremia are shown in Box 84.2. When hyponatremia is encountered, a measurement of serum osmolality should be performed to differentiate true from pseudo hypo-osmolality, which may be encountered in patients with lipidemic serum or in neurological patients treated with mannitol. Elevated osmolality may be encountered in patients with hyponatremia due to elevated urea or ethanol concentrations who are subject to the same risks as patients with hyponatremia associated with reduced osmolality. A large and diverse group of neurological conditions is associated with hyponatremia as a result of syndrome of inappropriate antidiuretic hormone secretion (SIADH), as shown in Box 84.3. SIADH is characterized by hyponatremia in the face of normal or increased blood volume, normal renal function, and the absence of factors that normally operate to produce antidiuretic hormone (ADH) release. The syndrome may be relatively asymptomatic, in which case water restriction is the treatment of choice. In more severe cases, hypertonic saline combined with a diuretic may be required. Overly zealous treatment may produce central pontine myelinolysis (see the upcoming section, Therapy). Chronic syndromes have been treated successfully with a variety of drugs including the tetracycline demeclocycline, which interferes with the action of ADH on the renal tubules. Great care must be taken when considering the diagnosis of SIADH in patients with subarachnoid hemorrhage. Patients with subarachnoid hemorrhage, hyponatremia, and reduced blood volume may not have true SIADH. In these patients, fluid restriction may lead to further volume reduction and cerebral infarcts during the period of the highest risk for vasospasm. The mechanisms underlying this phenomenon are unclear but may be related to the complexity of the peptidergic neurotransmitter systems in the vicinity of the third ventricle and to the possibility that they are damaged by the ruptured aneurysm. Damage is especially likely with an aneurysm on the anterior communicating artery. Hyponatremia occurs in approximately 1% of patients with recent surgical procedures. Because the symptoms are frequently mild or

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attributed to the surgery itself, this diagnosis may be missed. Typically, these patients seem to do well in the immediate postoperative period and then develop symptoms and signs of encephalopathy. Men and postmenopausal women are less likely to develop postoperative hyponatremia than women who are still menstruating. Complications such as respiratory arrest are particularly likely to occur more frequently in menstruating women than in men or menopausal women. Thus, it is important to be particularly vigilant when evaluating younger women with postoperative encephalopathy. Clinical features. The signs and symptoms of deranged osmolality depend on the severity of the disturbance and the length of time elapsed between onset and clinical presentation. Often these syndromes are of insidious onset. Typical complaints are nonspecific and include malaise, nausea, and lethargy, leading to obtundation and coma. Headache due to brain swelling, and epileptic seizures may be encountered in patients with hyponatremia, especially in patients with an acute alteration of serum sodium levels, as for example in patients with psychosis, Ecstasy use, or in patients with postoperative intravenous fluid application. Although serum sodium levels below 120 mmol/L are considered serious, patients who develop this level of hyponatremia as a side effect of diuretics or antiepileptic treatment over a long period of time may present with only minor, if any, symptoms. Minor symptoms include dizziness, cognitive dysfunction, gait disturbances, and falls. Since, in these chronic states of hyponatremia, the brain can counteract cell swelling by release of endogenous osmolytes, severe symptoms often occur only after serum sodium levels have decreased below 110 mmol/L. However, patients in whom serum sodium levels decrease within a short time interval due to an acute overload of total body water are prone to develop brain edema, alterations of consciousness, and seizures. Children and young women are particularly vulnerable to hyponatremic brain damage. Of note, brain adaptation to low serum sodium levels increases the risk of osmotic demyelination after rapid resolution of hyponatremia. Symptoms of the osmotic demyelination syndrome (ODS) occur several days after successful treatment of hyponatremic encephalopathy. Characteristic are seizures, behavioral disturbances, swallowing dysfunction, dysarthria, paralysis, or movement disorders. Cerebral MRI may show demyelination in the pons or symmetrically extra-pontine in the white matter. The extent of MRI lesions, however, does not correlate with the severity of clinical symptoms.

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CHAPTER 84 Toxic and Metabolic Encephalopathies

Causes of the Syndrome of Inappropriate Antidiuretic Hormone Secretion BOX 84.3

Malignant Neoplasms Small cell carcinoma of lung Pancreatic tumors Thymoma Mesothelioma Lymphoma (lymphosarcoma, reticulum cell sarcoma, Hodgkin disease) Bladder, ureter, prostate tumors Duodenal tumors Ewing sarcoma Central Nervous System Disorders Infections (meningitis, encephalitis, abscess, Rocky Mountain spotted fever) Trauma Subarachnoid hemorrhage Infarction Guillain-Barré syndrome Acute intermittent porphyria Hydrocephalus Neonatal hypoxia Shy-Drager syndrome Delirium tremens Systemic lupus erythematosus Drugs Vasopressin Oxytocin Vinca alkaloids Thiazides Chlorpropamide Phenothiazines Carbamazepine Clofibrate Nicotine Monoamine oxidase inhibitors Tricyclic antidepressants Cyclophosphamide Narcotics Pulmonary Diseases Tuberculosis Other pneumonias Abscess or cavity Empyema Cystic fibrosis Obstructive airway disease Pneumothorax Asthma Positive pressure ventilation Miscellaneous Causes Hypothyroidism Acute psychosis Postoperative state Idiopathic

Of note, rapid correction of hyponatremia is not the only known cause of pontine myelinolysis (ODS). Other possible causes include hypernatremia, severe hyperglycemia, malignancy, hyperammonemia, or alterations of serum potassium levels. Patients after liver transplant seem especially at risk to develop ODS. F ECF

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Therapy. Current European and US guidelines recommend slow correction of hyponatremia in patients who developed the electrolyte imbalance in an interval of more than 48 hours, but a more rapid correction in case of acute water intoxication. In acute hyponatremia a rapid correction by about 4–6 mmol/L is considered both effective in regard to counteracting osmotic brain swelling and safe in regard to the risk of osmotic demyelination. Fortunately, both death from cerebral edema as well as osmotic demyelination are rare complications of hyponatremia. However, the risk increases with extremely low serum sodium levels. Fifty percent of rapidly corrected patients develop osmotic demyelination if their serum sodium levels at baseline were lower than 105 mmol/L. The preferred therapy for hyponatremia might be water restriction and discontinuing diuretics if patients show only slight if any symptoms. The recommendations for treatment of symptomatic hyponatremia differ slightly between the European and the US guidelines. The former differentiate between severely and moderately symptomatic cases and recommend infusion of two 150-mL boluses of 3% saline, measuring serum sodium levels in between for severely symptomatic hyponatremia, and repeating this treatment until the serum sodium level has increased by 5 mmol/L. In case of moderately severe symptoms a single 150-mL infusion of 3% saline is recommended. The US experts recommend an infusion of 100 mL of 3% saline up to 3 times if needed in case of severe symptoms such as seizures and coma and in case of acute water intoxication. In patients with mild to moderate symptoms, 3% saline at 0.5–2 mL/kg per hour to correct by 4–6 mmol/L is recommended. Caution is recommended in patients with hypovolemic hyponatremia. Correction of hypovolemia may induce brisk water diuresis and then lead to rapid sodium correction. The limits for sodium level correction are 10 mmol/L within the first 24 hours, and 8 mmol/L/day thereafter in the European guidelines while the American guidelines set a daily 4–6 mmol/L goal and a limit of 8 mmol/L per day for patients with high risk to develop ODS, and a daily correction goal of 4–8 mmol/L for those with low risk In patients with euvolemic or hypervolemic hyponatremia, vaptans, which antagonize the effect of vasopressin, thereby promoting aquaresis, can be administered. Sodium replacement cannot be done without considering potassium levels. Replacement of 1 mmol/L potassium affects serum sodium levels as much as 1 mEq of retained sodium. The effect of a given infusate on the serum sodium concentration can be estimated from the formula ∆Na+ in serum = [Na+ + K+] in infusion—[Na+] in serum/total body water +1, where total body water is calculated as fraction of body weight. This fraction is 0.6 in children, 0.55 in men, and 0.5 in women. In case of substantial ongoing fluid loss, it is recommended to combine this formula with the so-called fluid loss formula (see Adrogué and Madias, 2012). In case of severe symptomatic hyponatremia, continuous monitoring of vital signs and repeated measurement (every 2 hours) of the electrolyte levels are mandatory. Overcorrection of the serum sodium level should be treated by prompt administration of 5% glucose solution. Hyperosmolality. Hyperosmolality is less common than hypoosmolality but may manifest with similar symptoms or evidence of intracranial bleeding caused by the tearing of veins that bridge the space between the brain and dural sinuses. Usually, hyperosmolality is diagnosed by laboratory findings of an elevated serum sodium level or, perhaps more commonly, hyperglycemia in diabetics. The syndrome frequently is caused by dehydration (especially in hot climates), by uncontrolled diabetes with or without ketosis, and (less frequently) by central lesions that reset the osmotically sensitive regions of the brain. As with hypo-osmolality, cautious correction of the defect is important. Replacement should be given orally if possible. Treatment is based on the answers to two questions: What is the water deficit?

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How rapidly should it be corrected? The deficit can be computed for adults from the equation deficit = current body water (Na+/140 − 1). Current body water can be estimated as ranging from 50% to 60% of the lean body weight. A safety factor of 10% has been suggested; therefore, current body water should be taken as about 45% of the lean body weight. Thus, a 70-kg person with a sodium concentration of 160 mEq/L would require about 4.5 L of free water. Chronic hyperosmolality is associated with relative brain volume preservation as a result of the production of idiogenic osmoles, as described earlier. Administering free water at a rate that exceeds the rate at which the brain is able to rid itself of idiogenic osmoles is associated with the development of paradoxical brain edema that occurs at a time when serum glucose and electrolyte concentrations are normalized. This is illustrated by the data in Fig. 84.4, in which the CSF pressure was measured continuously as hyperglycemia due to diabetes mellitus was corrected. The increase in ICP is undoubtedly caused by adapted brain cells imbibing free water as serum osmolality decreases in response to therapy. If patients undergoing treatment for hyperosmolar states develop new neurological signs, including altered consciousness and seizures, the diagnosis of brain swelling should be considered. Mannitol treatment to restore osmolality to the prior elevated level may be required to prevent death due to brain swelling. To avoid the production of brain edema, seizures, and other complications, the rate of correction should not exceed 0.5 mmol/L in any given hour, and no more than 10 mmol/L/day.

Disorders of Calcium Metabolism Hypercalcemia and hypocalcemia both have diverse causes associated with disordered parathyroid gland function and a variety of other conditions. In normal circumstances, approximately half of the total serum calcium is bound to proteins, mainly albumin, and half is in the ionized form, the only form in which it is active. When there is doubt about the Ca2+ concentration, as in patients with hypoalbuminemia, direct measurement of Ca2+ with ion-sensitive electrodes may be required. Hypercalcemia is associated with hyperparathyroidism, granulomatous diseases (especially sarcoidosis), treatment with drugs including thiazide diuretics, vitamin D, calcium itself, tumors that have metastasized to bone, and thyroid disease. Many cases are idiopathic. The symptoms and signs of hypercalcemia may be protean. Severe hypercalcemia affects the brain directly, causing coma in extreme cases. In this group of patients, metastatic tumors are common, especially multiple myeloma and tumors of the breast and lung. Cancer patients seem to be particularly vulnerable to developing hypercalcemia after a change in therapy. Less severe hypercalcemia may cause altered consciousness, with a pseudodementia syndrome and weakness. GI, renal, and cardiovascular abnormalities also may be present. Severe hypercalcemia is life threatening. Initial treatment consists of a forced diuresis using saline and diuretics. Because the volumes of saline that are required may be large, a central venous or Swan-Ganz catheter may be needed to monitor therapy. Once the initial phase of treatment is accomplished, further management is determined by the cause of the hypercalcemia. Hypocalcemia usually is associated with hypoparathyroidism. The neurological symptoms are attributable to the enhanced excitability of the nervous system. Symptoms include paresthesias around the mouth and fingers, cramps caused by tetanic muscle contraction, and in more extreme cases, epileptic seizures. In more chronic hypocalcemia, headache secondary to increased ICP may occur, and extrapyramidal signs

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and symptoms such as chorea or parkinsonism may be encountered. These patients may have calcification of the basal ganglia, evident on computed tomography of the brain. The physical examination should include attempts to elicit Chvostek and Trousseau signs. Cataracts and papilledema may be seen. Severe hypocalcemia should be treated with infusions of calcium to treat or prevent epileptic seizures or laryngeal spasms, both of which are life-threatening but unusual complications. Chronic therapy usually involves administration of calcium and vitamin D. Care must be taken to avoid hypercalcemia and hypercalciuria. Consultation with an endocrinologist is prudent, but continued neurological care may be necessary, especially in patients with extrapyramidal syndromes, who may require specific treatment.

Disorders of Magnesium Metabolism Hypermagnesemia is an unusual condition because of the ease with which normal kidneys act to preserve magnesium homeostasis. Hypermagnesemia is most commonly due to infusions given to treat blood pressure and nervous system dysfunction in patients with eclampsia. Care must be observed in administering magnesium to patients with renal failure. This group of patients is the most vulnerable and the most likely to develop hypermagnesemia because the kidneys’ homeostatic function is impaired. Hypocalcemia potentiates the effects of excess magnesium. Severe hypermagnesemia is life threatening, and concentrations in excess of 10 mEq/L must be treated. Discontinuation of magnesium preparations usually suffices. When cardiac arrhythmias are present or circulatory collapse is possible, calcium must be infused, especially when hypocalcemia is present. Isolated hypomagnesemia is unusual. Magnesium deficiency usually occurs in patients with deficiencies of other electrolytes. Hypomagnesemia may result from a diet deficient in magnesium, including prolonged parenteral alimentation with insufficient or no magnesium replacement, malabsorption, and alcoholism. Excess magnesium loss from the GI tract or the kidneys may also lead to calcium deficiency. Magnesium deficiency is usually part of a complex electrolyte imbalance, and accurate diagnosis and management of all aspects of the state are necessary to ensure recovery. Pure magnesium deficiency has been produced experimentally and is expressed primarily through secondary reductions in serum calcium levels despite adequate dietary calcium intake. Ultimately, anorexia, nausea, a positive Trousseau sign, weakness, lethargy, and tremor develop but are rapidly abolished by magnesium repletion. Balance studies indicate that magnesium deficiency causes a positive sodium and calcium balance and a negative potassium balance. Magnesium is necessary for proper mobilization and homeostasis of calcium and the intracellular retention of potassium. Some of the effects of magnesium depletion are secondary to abnormalities of potassium and calcium metabolism.

Disorders of Manganese Metabolism Manganese poisoning occurs primarily in manganese ore miners and causes parkinsonism. As presented in the Hepatic Encephalopathy section, there is increasing evidence that accumulation of this metal in the brain causes hyperintensities on T1-weighted MRI and may be associated with disorders of dopaminergic neurotransmission. The complete reference list is available online at https://expertconsult. inkling.com/.

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85 Deficiency Diseases of the Nervous System Yuen T. So

OUTLINE Cobalamin (Vitamin B12), 1291 Causes of Deficiency, 1291 Clinical Features, 1292 Laboratory Studies, 1292 Pathology, 1293 Treatment, 1293 Folate Deficiency and Homocysteine, 1293 Causes of Deficiency, 1293 Clinical Features, 1294 Laboratory Studies, 1294 Treatment, 1294 Vitamin E, 1294 Clinical Features, 1295 Laboratory Studies, 1295 Treatment, 1295 Pellagra (Nicotinic Acid Deficiency), 1295 Vitamin B6 (Pyridoxine), 1295 Thiamine, 1296 Thiamine Deficiency Neuropathy (Beriberi), 1296

Infantile Beriberi, 1296 Wernicke-Korsakoff Syndrome, 1296 Laboratory Studies, 1297 Pathology, 1297 Treatment, 1297 Other Diseases Associated With Alcoholism, 1298 Alcohol-Withdrawal Syndromes, 1298 Alcoholic Neuropathy, 1299 Tobacco–Alcohol or Nutritional Amblyopia, 1299 Marchiafava-Bignami Disease, 1299 Alcoholic Cerebellar Degeneration, 1299 Vitamin A, 1300 Vitamin D, 1300 Miscellaneous Deficiency Diseases, 1300 Complications after Bariatric Surgery, 1300 Acute Nutritional Neuropathy, 1301 Copper Deficiency, 1301 Protein-Calorie Malnutrition, 1301

Malnutrition causes a wide spectrum of neurological disorders (Table 85.1). Despite socioeconomic advances, nutritional deficiency diseases such as kwashiorkor and marasmus are still endemic in many underdeveloped countries. The problem in Western countries is usually the result of dietary insufficiency from chronic alcoholism or malabsorption due to gastrointestinal (GI) diseases. Bariatric surgery has become an important risk factor of malabsorption due to its increased use in the treatment of obesity. Individual vitamin requirements are influenced by many factors. The daily need for thiamine and nicotinic acid, important compounds in energy metabolism, increases proportionally with increasing caloric intake and energy need. For example, symptoms of thiamine deficiency may occur in at-risk patients during periods of vigorous exercise and high carbohydrate intake. Other factors such as growth, infection, and pregnancy may also worsen deficiency states.

parietal cells. Cobalamin binds to intrinsic factor, and the complex is transported to the ileum where it is absorbed into the circulation. A small amount of free cobalamin, about 1%–5%, is also absorbed through the entire intestine without intrinsic factor. Once absorbed, cobalamin binds to a transport protein, transcobalamin, for delivery to tissues. As much as 90% of total body cobalamin is stored in the liver. Even when vitamin absorption is severely impaired, many years are needed to deplete the body store. A clinical relapse in pernicious anemia after interrupting cobalamin therapy takes an average of 5 years to be recognized. Two biochemical reactions depend on cobalamin. One involves methylmalonic acid as precursor in the conversion of methylmalonyl coenzyme A (methylmalonyl-CoA) to succinyl-CoA. The importance of this to the nervous system is unclear. The other is a folate-dependent reaction in which the methyl group of methyltetrahydrofolate is transferred to homocysteine to yield methionine and tetrahydrofolate. The reaction depends on the enzyme methionine synthase, which uses cobalamin as a cofactor. Methionine is converted to S-adenosylmethionine (SAM), which is used for methylation reactions in the nervous system.

COBALAMIN (VITAMIN B12) The terms vitamin B12 and cobalamin are used interchangeably in the literature. Cobalamins are abundant in meat, fish, dairy, and other animal byproducts. Vegetables generally contain only trace amounts of cobalamin (Watanabe, 2014). Although only 1 µg/day of cobalamin is needed, strict vegetarians are at risk and may rarely develop clinically significant deficiency. Intestinal absorption of cobalamin requires the presence of intrinsic factor, a binding protein secreted by gastric

Causes of Deficiency The classic disease pernicious anemia is caused by defective intrinsic factor production by parietal cells, leading to malabsorption. These patients may have demonstrable circulating antibodies to parietal cells or lymphocytic infiltrations of the gastric mucosa, suggesting an

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TABLE 85.1 Neurological Manifestations in Deficiency Diseases

BOX 85.1

Neurological Manifestations

Associated Nutritional Deficiencies

Dementia, encephalopathy Seizures Myelopathy Myopathy Peripheral neuropathy Optic neuropathy

Vitamin B12, nicotinic acid, thiamine, folate Pyridoxine Vitamin B12, vitamin E, folate, copper Vitamin D, vitamin E Thiamine, vitamin B12, vitamin E, and many others Thiamine, vitamin B12, and many others

Elevated Methylmalonic Acid Cobalamin deficiency Renal insufficiency Inherited metabolic disorders Hypovolemia

underlying autoimmune disorder. A more common cause of malabsorption is food-cobalamin malabsorption (Dali-Youcef and Andres, 2009). Under some clinical settings, the normal digestive process fails to release cobalamin from food or intestinal transport protein. Cobalamin remains bound and cannot be absorbed even in the presence of available intrinsic factors. Predisposing factors include atrophic gastritis and hypochlorhydria, and malabsorption may be seen with Helicobacter pylori infection, gastrectomy or other gastric surgeries, intestinal bacterial overgrowth, and prolonged use of H2 antagonists, proton pump inhibitors, or biguanides (e.g., metformin). Patients with human immunodeficiency virus (HIV) are often observed to have a low serum cobalamin level, usually with normal homocysteine and methylmalonic acid. The significance of this association is unknown. Nitrous oxide, a commonly used anesthetic gas, may cause a clinical syndrome of myeloneuropathy indistinguishable from that of cobalamin deficiency. It interferes with the cobalamin-dependent conversion of homocysteine to methionine. Prolonged exposure is necessary to produce neurological symptoms in normal individuals and is primarily seen in individuals who abuse the gas for its euphoric properties (Keddie et al., 2018). By contrast, patients who are already deficient in cobalamin may experience neurological deficits after only brief exposures during routine general anesthesia with nitrous oxide. Symptoms appear subacutely after surgery and resolve quickly with cobalamin treatment (Singer et al., 2008).

Clinical Features The onset of symptoms is insidious, with paresthesias in the hands or feet experienced by most patients. Weakness and unsteadiness of gait are the next most frequent complaints. Lhermitte sign may be present. Mental slowing, depression, confusion, delusions, and hallucinations are common, and occasionally patients present with only cognitive or psychiatric symptoms. On examination, signs of both peripheral nerve and spinal cord involvement may be present, although either can be affected first or disproportionately. Loss of vibration or joint position sense in the legs is common. If impaired position sense is severe, a Romberg sign may be present. Motor impairment, if present, results from pyramidal tract dysfunction and is most severe in the legs, ranging from mild clumsiness and hyperreflexia to spastic paraplegia and extensor plantar responses. Tendon reflexes are variably affected depending on the degree of pyramidal and peripheral nerve involvement. Visual impairment is occasionally present and may antedate other manifestations of vitamin deficiency. Ophthalmological examination may reveal bilateral visual loss, optic atrophy, and centrocecal scotomata. Brainstem or cerebellar signs, chorea, autonomic insufficiency, or even reversible coma may rarely occur.

Laboratory Studies Serum assays of vitamin B12 and cobalamin-dependent metabolites provide direct measures of cobalamin homeostasis, although there are important limitations. Blood cobalamins are bound to two transport

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Causes of Elevated Serum Levels of Homocysteine and Methylmalonic Acid

Elevated Homocysteine Cobalamin deficiency Folate deficiency Pyridoxine deficiency Renal insufficiency Hypothyroidism Psoriasis Inherited metabolic disorders Hypovolemia

proteins, transcobalamin and haptocorrin. The cobalamin bound to transcobalamin, known as holotranscobalamin, is the fraction that is available to tissues, although it accounts for only 10%–30% of the serum level measured by standard laboratory methods. Serum levels are influenced by conditions that affect the concentrations of these transport proteins. Myeloproliferative and hepatic disorders may raise the concentration of haptocorrin and cause a falsely normal serum level. A misleadingly high serum level also may result from the presence of an abnormal cobalamin-binding protein. In contrast, pregnancy and contraceptives may give falsely low measurements in the absence of deficiency. Folate deficiency also causes a falsely low cobalamin serum level that corrects after folate replacement. These confounding factors diminish the sensitivity and specificity of the commonly used assay of total serum cobalamin in the diagnosis of deficiency state. Although measurement of holotranscobalamin is better in theory, available data suggest that its diagnostic sensitivity is approximately equivalent or only modestly better than that of total serum cobalamin, and its specificity is uncertain (Oberley and Yang, 2013). Homocysteine and methylmalonic acid are precursors of cobalamin-dependent biochemical reactions. The concentrations of these metabolites increase during cobalamin deficiency. Measurement of these metabolites is especially useful when the serum cobalamin concentration is in the low range of normal, between 200 and 350 pg/mL, and in patients with suspected nitrous oxide abuse who may have normal serum cobalamin levels. Homocysteine level should be measured either at fasting or after an oral methionine load. The blood sample should be refrigerated immediately after collection because the level increases if whole blood is left at room temperature for several hours. Elevated levels of homocysteine and methylmalonic acid are not specific for cobalamin deficiency, as there are many other causes of increase in these metabolites (Box 85.1). In patients with autoimmune gastritis and intrinsic factor deficiency, antibodies against parietal cell and intrinsic factor may be elevated. Anti-parietal cell antibodies are nonspecific and are present in other autoimmune endocrinopathies as well as occasional normal individuals. Anti-intrinsic factor antibodies are less sensitive (50%–70%) but are specific for pernicious anemia. Elevated serum gastrin level is a marker of atrophic gastritis and hypochlorhydria and is a sensitive (up to 90%) but nonspecific indicator of pernicious anemia. The classic hematological manifestation of pernicious anemia is a macrocytic anemia. Erythrocyte or bone marrow macrocytosis or hypersegmentation of polymorphonuclear cells may be present

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Fig. 85.2 Subacute Combined Degeneration of the Spinal Cord in Vitamin B12 Deficiency. Demyelination and loss of axons are more widespread in posterior than in lateral columns (Weigert stain). (Courtesy Dr. Michael F. Gonzales.)

85.2). Pathological changes also are seen commonly in the lateral columns, whereas the anterior columns are involved in only a small number of the advanced cases. The pathological findings of the peripheral nervous system are those of axonal degeneration, but in some cases there is evidence of demyelination. Involvement of the optic nerve and cerebral white matter also occurs.

Treatment Fig. 85.1 Vitamin B12 Deficiency Myelopathy. Gadolinium-enhanced, T1-weighted cervical and upper thoracic magnetic resonance image showing marked enhancement of posterior cord of a 30-year-old African American woman wheelchair-bound due to an 18-month history of progressive myelopathy; vitamin B12 level, 60 pg/mL. (Courtesy Dr. R. Laureno.)

without anemia. Hematological abnormalities may be absent at the time of neurological presentation and are thus insufficiently sensitive for use in diagnosis. Because most patients present with clinical features suggesting a myelopathy or encephalopathy, imaging studies are necessary to exclude structural causes. Results of magnetic resonance imaging (MRI) may be normal, or T2-signal abnormalities may be seen in the lateral or posterior columns in patients with subacute combined degeneration (Kumar and Singh, 2009) (Fig. 85.1). Both gadolinium enhancement and spinal cord swelling have been described. Patients with encephalopathy or dementia often have multiple foci of T2 signal abnormalities in the deep white matter that may become confluent with disease progression. Diffusion tensor imaging (DTI) may be more sensitive in revealing brain changes that correlate with cognitive dysfunction (Gupta et al., 2014). Nonspecific abnormalities of electroencephalography, as well as visual and somatosensory evoked responses, are present in many patients with neurological abnormalities. Nerve conduction studies show small or absent rural nerve sensory potentials in approximately half of patients, providing evidence for an axonal polyneuropathy.

Pathology The term subacute combined degeneration of the spinal cord describes the pathological process seen in this disorder. Microscopically, spongiform changes and foci of myelin and axon destruction are seen in the white matter of the spinal cord. The most severely affected regions are the posterior columns at the cervical and upper thoracic levels (Fig.

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Recommendations for treatment of cobalamin deficiency vary widely. A typical regimen uses intramuscular daily injections of 1000 µg for the first week, followed by weekly 1000 µg injections for 1 month, and monthly injections thereafter. These parenteral doses provide quantities considerably higher than the body requirement. There is no evidence that overdosing can speed neurological recovery, but high doses of cobalamin appear to be safe. Oral supplementation at 1000 µg daily has also been used with some success, even in patients with suspected malabsorption, although close monitoring is necessary to ensure adequacy of treatment. With proper treatment, serum levels of homocysteine and methylmalonic acid return to normal in about 2 weeks. Neurological improvement is more delayed and may be incomplete. Most of the symptomatic improvement occurs during the first 6–12 months of therapy. The need for early diagnosis and treatment is underscored by the observation that remission correlates inversely with the time lapse between onset of symptoms and initiation of therapy.

FOLATE DEFICIENCY AND HOMOCYSTEINE Folate deficiency may produce the same neurological deficits as those seen in cobalamin deficiency because of its central role in the biosynthesis of methionine, SAM, and tetrahydrofolate (see the previous section Cobalamin [Vitamin B12]). Overt neurological manifestations are rare in folate deficiency, probably owing to alternative cellular mechanisms that are available to preserve SAM levels in times of folate scarcity.

Causes of Deficiency Absorption of folate occurs in the jejunum and to a lesser extent the ileum. Chronic alcoholism is an important cause of folate deficiency. Folate deficiency also may complicate small-bowel disease (e.g., sprue, Crohn disease, ulcerative colitis). Other populations at risk are pregnant women and patients receiving anticonvulsant drugs that interfere with folate metabolism. Sulfasalazine, methotrexate, triamterene, and

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oral contraceptives also can cause folate deficiency. Intrathecal methotrexate, in particular, causes a leukoencephalopathy associated with marked elevation of homocysteine levels in the cerebrospinal fluid (CSF).

Clinical Features The majority of patients with laboratory evidence of folate deficiency do not have overt neurological findings. The classic syndrome of folate deficiency is similar to subacute combined degeneration seen in cobalamin deficiency. Presenting symptoms are limb paresthesias, weakness, and gait unsteadiness. These patients have megaloblastic anemia, impaired position and vibration sense, pyramidal signs, and possibly dementia. Chronic folate deficiency may result in mild cognitive impairment or increased stroke risk in adults. Although low folate level is present in many elderly asymptomatic people, the prevalence seems to be higher in the psychiatric and Alzheimer disease populations. Moreover, a low folate level appears to correlate with depression and cognitive impairment. Even in healthy older adults, a low folate level is associated with subtle deficits in neuropsychological test performance. Chronic folate deficiency during pregnancy leads to an increased frequency of neural tube defects in babies. Serum homocysteine is an important surrogate marker for folate metabolism, although there are other causes of elevated homocysteine levels (see Box 85.1). Hyperhomocysteinemia is a risk factor for vascular diseases and venous thrombosis. For cerebrovascular disease, the association is strongest for multi-infarct dementia and white-matter microangiopathy. Even a modestly increased serum level in the range of 15–20 mmol/L engenders a recognizable increase in vascular risk. A meta-analysis of randomized control trials suggests a modest 10% reduction in stroke and 4% reduction in cardiovascular risk with long-term folate supplementation (0.5–15 mg/day, mean duration 3.2 years) (Li et al., 2016). Clinical observations in two inborn errors of metabolism reinforce our understanding of the role of homocysteine in neurological diseases. Hereditary deficiency of cystathionine β-synthase leads to hyperhomocysteinemia and hyperhomocysteinuria. The homozygous form presents with markedly elevated homocysteine levels, mental retardation, premature atherosclerosis, and seizures. Heterozygous individuals have milder elevations of homocysteine and also have increased risk of vascular disease. A much more common condition is a C-to-T substitution at codon 677 in the gene coding for N5, N10-methylenetetrahydrofolate reductase (MTHFR). Some 5%–10% of the White population are homozygotes for this C677T mutation. These individuals have mildly elevated homocysteine levels and increased risk of vascular disease.

Laboratory Studies Plasma and erythrocyte folate levels may be measured directly. Erythrocyte level is generally more reliable than plasma level because it is less affected by short-term fluctuation in intake. Serum homocysteine is increased in folate deficiency. Its measurement is discussed in Laboratory Studies under the previous section, Cobalamin (Vitamin B12).

Treatment In patients with documented folate deficiency, the initial dose is usually 1 mg of folate several times per day, followed by a maintenance dose of 1 mg/day. For acutely ill patients, parenteral doses of 1–5 mg may be given. Even with oral doses as high as 15 mg/day, there is no report of toxicity. In women of childbearing potential with epilepsy, daily folate supplementation of 0.4 mg or more is recommended as prophylaxis against neural tube defects. Since 1998, in an attempt to

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BOX 85.2

Causes of Vitamin E Deficiency

Gastrointestinal diseases Biliary atresia, chronic cholestasis Intestinal resection Crohn disease Pancreatic insufficiency (e.g., cystic fibrosis) Blind loop syndrome and bacterial overgrowth Bowel irradiation Celiac disease Other causes of steatorrhea Hereditary diseases: abetalipoproteinemia, hypobetalipoproteinemia, Anderson disease, α-tocopherol transfer protein mutation

lower the incidence of neural tube defects, the US Food and Drug Administration (FDA) has mandated fortification of grain products with folate. The fortification translates to an increased daily intake of 0.1–0.2 mg in a typical adult.

VITAMIN E Vitamin E refers to a group of tocopherols and tocotrienols, of which α-tocopherol is the most important. It is a free-radical scavenger and an antioxidant and has attracted attention for its potential in the prevention and treatment of a wide range of diseases. Unfortunately, the value of vitamin E for these indications has yet to be proven. We limit discussion here to the neurological manifestations of vitamin E deficiency. Like other fat-soluble compounds, vitamin E depends on the presence of pancreatic esterases and bile salts for its solubilization and absorption in the intestinal lumen. Neurological symptoms of deficiency occur most commonly in patients with fat malabsorption (Box 85.2). A reduced bile salt pool may be caused either by reduced hepatic excretion, as in congenital cholestasis, or by interruption of the enterohepatic reabsorption of bile, as in patients with extensive small-bowel resection. Pancreatic insufficiency contributes to malabsorption. Another setting is cystic fibrosis. A number of rare familial disorders lead to chronic diarrhea, abnormal blood lipid profile, and malabsorption of fat and fat-soluble vitamins. In addition to vitamin E deficiency, these patients also have deficiency of vitamins A and D. Abetalipoproteinemia or BassenKornzweig syndrome is an autosomal recessive disorder due to mutation in the microsomal triglyceride transfer protein (MTP) gene. This results in impaired absorption of fat and fat-soluble vitamins (Zamel et al., 2008). In addition to a neurological syndrome similar to that seen in other vitamin E-deficient states, spiky red blood cells (acanthocytes) and retinal pigment changes are characteristic. Two other disorders are also characterized by chronic fat malabsorption and vitamin E deficiency. SAR1B gene mutation leads to chylomicron retention disease or Anderson disease. Familial hypobetalipoproteinemia presents with variable degrees of malabsorption and symptoms, and about 50% are due to mutation in the APOB gene (Peretti et al., 2010). Another rare syndrome of ataxia with isolated vitamin E deficiency (AVED) occurs in patients without GI disease or generalized fat malabsorption. Mutations in the α-tocopherol transfer protein gene (TTPA) on chromosome 8q are responsible (El Euch-Fayache et al., 2014; Mariotti et al., 2004). This condition is inherited in an autosomal recessive manner. The defect appears to be impaired incorporation of the vitamin into hepatic lipoproteins that are necessary for delivery to tissues.

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Clinical Features Clinical symptoms typically do not begin until many years of malabsorption deplete the vitamin reserves. This takes 15–20 years in adults, but clinical onset as early as age 1–2 years may occur in children because of their small vitamin reserves. The usual presenting symptoms are weakness or gait unsteadiness. Neurological examination reveals a syndrome of spinocerebellar degeneration accompanied by peripheral nerve involvement. Some patients are diagnosed erroneously with Friedreich ataxia. The most consistent abnormalities are limb ataxia, areflexia, and loss of vibration and position sense. Cutaneous sensation usually is spared or affected to a lesser degree. About half of patients have nystagmus, ptosis, or partial external ophthalmoplegia. Mild to moderate proximal weakness is common, and some patients may have a myopathy. The pattern of weakness may also be diffuse or predominantly distal. Babinski sign may be present.

Laboratory Studies The diagnosis is not difficult when the appropriate neurological syndrome and a low serum vitamin E level are both present. Serum level should be interpreted in light of the clinical findings. Some patients with low levels do not have demonstrable neurological deficits. Moreover, plasma vitamin E is largely incorporated into chylomicrons and is highly dependent on the concentrations of total plasma lipids, cholesterol, and very low-density lipoproteins. Other laboratory abnormalities, despite their nonspecific nature, help clarify the diagnosis. Stool fat is increased in many patients, and serum carotene concentration is often abnormally low, both reflecting a generalized state of fat malabsorption. CSF should be normal. Nerve conduction studies usually reveal a sensory polyneuropathy, although motor conduction abnormality and features of a demyelinating neuropathy have been reported rarely (Puri et al., 2005). Somatosensory and visual evoked responses are frequently abnormal, and there may be high signal lesions in the posterior columns on T2-weighted MRI.

Treatment The recommended daily requirement of vitamin E in normal adults is 10 mg (equivalent to 10 IU) of dl-α-tocopherol acetate, a commonly available form of the vitamin. A wide range of doses has been used, from 200 mg/day to 100 mg/kg/day. Improvement, or at least stabilization, of neurological status is possible, even in those patients with hereditary diseases (El Euch-Fayache et al., 2014; Peretti et al., 2010), although there is no consensus on the optimal therapeutic dosage. A reasonable approach is to begin therapy with an oral preparation of water-miscible tocopherol at a dose of 200–600 mg/day. The clinical picture and serum level should be followed; if no improvement occurs, higher oral dosages or even parenteral administration should be tried. Supplementation of bile salts may be of value in those patients with intestinal malabsorption.

PELLAGRA (NICOTINIC ACID DEFICIENCY) Nicotinic acid or vitamin B3 is converted in the body to two important coenzymes in carbohydrate metabolism: nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). Niacin, another term for nicotinic acid, was introduced to avoid confusion with the alkaloid nicotine. Dietary deficiency of nicotinic acid produces pellagra (from the Italian pelle agra, meaning “rough skin”). Pellagra classically occurs in populations who consume primarily corn. Corn lacks nicotinic acid as well as tryptophan, a precursor that can be converted in the body to nicotinic acid. In underdeveloped countries, pellagra is still a common health problem. Even in the United States, pellagra was endemic until around 1940 in the South

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and in alcoholic populations. The disease is now rare due to the widespread consumption of bread enriched with niacin. In addition to cases still encountered in alcoholics, there are case reports of individuals with malabsorption from GI diseases or concurrent use of medications that interfere with the production of niacin from tryptophan, such as isoniazid, azathioprine, and some chemotherapy agents (Li et al., 2016). Pellagra affects three organ systems in the body: the GI tract, skin, and nervous system (hence the mnemonic of “three Ds”: diarrhea, dermatitis, and dementia). The chief GI symptoms are anorexia, diarrhea, stomatitis, and abdominal discomfort. Skin changes range from erythema to a reddish-brown hyperkeratotic rash distributed over much of the body, with the face, chest, and dorsal surfaces of the hands and feet being most involved. The neurological syndrome of pellagra is not well defined. Reported cases, especially of patients with alcoholic pellagra, frequently are confounded by other coexisting central nervous system disorders such as Wernicke encephalopathy. The primary early symptoms are neuropsychiatric (e.g., irritability, apathy, depressed mood, inattentiveness, memory loss) and may progress to stupor or coma. In addition to the confusional state, spasticity, Babinski sign, gegenhalten, and startle myoclonus may be prominent on neurological examination. Nonendemic pellagra occurs rarely in patients with alcoholism or malabsorption secondary to GI disease. The diagnosis of nonendemic pellagra can be made only on clinical grounds because there is no available method to make a blood niacin level determination, and this diagnosis may be difficult because diarrhea and dermatological changes are often absent. The condition is likely under-recognized and mistaken for other causes of encephalopathy. A postmortem study found pathological features suggestive of pellagra encephalopathy in 5 of 59 patients with suspected Creutzfeldt-Jakob disease (Kapas et al., 2012). The recommended daily allowance for nicotinic acid is 6.6 mg/1000 kcal dietary intake. Oral nicotinic acid in doses of 50 mg several times a day is usually sufficient to treat symptomatic patients. Alternatively, parenteral doses of 25 mg can be given 2–3 times a day. Nicotinamide has similar therapeutic efficacy in pellagra, but it does not have the vasodilatory and cholesterol-lowering activities of niacin.

VITAMIN B6 (PYRIDOXINE) Although the term pyridoxine often is used synonymously with vitamin B6, two other naturally occurring compounds—pyridoxal and pyridoxamine—possess similar biological activities. All three compounds are converted to pyridoxal-5'-phosphate (PLP), an important cofactor for glucose, lipids, and amino acid metabolism as well as neurotransmitter synthesis. In the early 1950s, physicians in the United States encountered cases of an unusual seizure disorder in infants at the age of several weeks to a few months. These seizures were difficult to control with the usual anticonvulsants. In contrast, the response was dramatic when vitamin B6 was given. It eventually became clear that the symptomatic infants were fed a commercial formula that contained approximately one-third the vitamin B6 found in other infant formulas. The cause was then traced to a manufacturing process that reduced the pyridoxine content. Even with better awareness of the problem, sporadic cases of infantile seizures from dietary vitamin B6 deficiency still occur, most commonly as a result of breastfeeding by malnourished mothers from poor socioeconomic backgrounds or in underdeveloped countries. The typical patients have a normal birth history and are entirely healthy until the development of hyperirritability and an exaggerated auditory startle. Recurrent convulsions often occur abruptly, as may status epilepticus. Once the dietary insufficiency is corrected, patients become free of seizures and develop normally.

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Another rare form of pyridoxine-responsive seizure occurs in infants with inborn errors in PLP metabolism. Mutations in several genes have been implicated. The current list includes ALDH7A1, ALDH4A1, PNPO, TNSALP, PLPBP, and PLPHP, and will likely continue to expand with advances in our understanding of this group of diseases (Johnstone et al., 2019; Pearl and Gospe, 2014; Wilson et al., 2019). In these children, seizures appear during the neonatal period. The seizures typically respond poorly to anticonvulsants. Long-term administration of large amounts of pyridoxine or PLP is needed to control seizures and to minimize adverse effects on cognitive development. Although adults are more tolerant of vitamin B6 deficiency, a high prevalence of low serum level is present in women and elderly populations (Morris et al., 2008), people with malabsorptive predisposition such as bariatric surgery, and renal failure patients with high loss of vitamins through dialysis. Medications such as isoniazid, hydralazine, penicillamine, and l-dopa/carbidopa intestinal gel have also been linked to pyridoxine deficiency (Loens et al., 2017). Chronic vitamin B6 deficiency probably causes a subacute sensory or sensorimotor neuropathy (Ghavanini, 2014). This is best described in patients receiving isoniazid. Sensory symptoms appear first in the distal feet. Burning pain may be disabling. Examination may show impaired sensation, distal weakness, and depressed tendon reflexes. In patients taking isoniazid, pyridoxine supplementation of 50 mg/ day prevents the development of neuropathy, although a lower dose likely suffices. Acute overdose of isoniazid may rarely lead to coma, metabolic acidosis, and seizures, and pyridoxine provides a specific antidote. Indiscriminate use of pyridoxine supplements may be harmful. The recommended daily allowance of vitamin B6 is approximately 2 mg. High doses of pyridoxine (1000 mg/day or more) can reliably cause a sensory neuropathy within a few months (Berger et al., 1992). Patients ingesting a high dose for a prolonged period have been described as developing sensory ataxia with impaired sensation, areflexia, and Romberg sign. Many years of taking doses as low as 200 mg/day of pyridoxine have been associated with a mild predominantly sensory polyneuropathy, although a safety threshold for chronic lower-dose usage has not been established. In general, it is prudent to limit the daily dosage to 50 mg or less for the therapeutic use of pyridoxine.

THIAMINE Thiamine is synonymous with vitamin B1. It is a water-soluble vitamin that plays a crucial role in the metabolism of carbohydrates, amino acids, and lipids. It is absorbed in the jejunum and ileum by active transport as well as passive diffusion. Thiamine is mostly stored in the liver. A continuous dietary supply is necessary as only a small amount is stored. Demand for thiamine increases with high glucose intake and during periods of high metabolic demands such as pregnancy and many systemic illnesses. The minimum daily requirement of thiamine is 0.3 mg/1000 kcal dietary intake in normal subjects, but the requirement is higher during pregnancy and old age. For therapeutic purposes, a target of 50–100 mg/day is often used. Diagnosis of thiamine deficiency is based on the appearance of appropriate clinical features in the setting of either nutritional deficiency or high metabolic demands. Thiamine levels in serum and urine may be decreased, although the levels do not reliably reflect tissue concentrations. Erythrocyte transketolase activity level is dependent on thiamine and provides an assay of functional status. Pyruvate accumulates during thiamine deficiency, and elevated serum level provides additional confirmation. A blood sample should be drawn before initiation of treatment because these laboratory abnormalities normalize quickly.

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Thiamine Deficiency Neuropathy (Beriberi) Beriberi literally means extreme weakness. It is caused by thiamine deficiency and affects the heart and peripheral nerves, producing congestive cardiomyopathy, sensorimotor polyneuropathy, or both. The classical wet and dry forms refer to the presence or absence of edema. The neuropathy generally develops over weeks or months. Affected patients complain of paresthesias or pain in the feet. Walking becomes difficult. The most common neurological finding is distal sensory loss. Weakness appears first in the finger and wrist extensors and the ankle dorsiflexors. Ankle stretch reflexes are lost in most patients. When cardiac dysfunction is present, patients also experience tachycardia, palpitations, dyspnea, fatigue, and ankle edema. Electrodiagnostic studies show an axonal neuropathy with reduced amplitude of sensory or motor responses, normal or mildly reduced conduction velocity, and neuropathic changes on electromyography. Lumbar puncture sometimes shows a mildly elevated opening pressure, a finding probably related to the presence of congestive heart failure. Findings of CSF examination are otherwise unremarkable. If cardiac impairment is present, electrocardiographic or other cardiac abnormalities may be seen. Thiamine, 100 mg, may be given intravenously (IV) in the acute stage, especially if there is doubt about adequate GI absorption. Long-term treatment consists of a balanced diet with oral supplements of thiamine and other vitamins. Gradual return of sensory and motor function can be expected after thiamine replenishment. In severe cases, improvement may take many months and may be incomplete.

Infantile Beriberi An acute syndrome of thiamine deficiency in infants occurs in the rice-eating populations of Asia, most frequently in breastfed infants younger than 1 year of age. Thiamine is often deficient in breast milk from mothers who eat primarily polished rice. Although the disorder is called infantile beriberi, it bears little resemblance to the adult form. Acute cardiac symptoms are common, often preceded by a prodrome of anorexia, vomiting, deficient weight gain, and restlessness. Dyspnea, cyanosis, and signs of heart failure follow and can lead rapidly to death. Arytenoid edema and recurrent laryngeal neuropathy may give rise to hoarseness, dysphonia, and eventually aphonia. Early signs of coughing and choking may be mistaken for respiratory tract infections. Central nervous system manifestations include drowsiness, ophthalmoplegia, and convulsions. These symptoms often begin abruptly and carry a grave prognosis. If given promptly, parenteral administration of 5–20 mg of thiamine can be lifesaving.

WERNICKE-KORSAKOFF SYNDROME In 1881, Carl Wernicke described a syndrome of mental confusion, ophthalmoplegia, and gait ataxia in three patients, two of whom were alcoholics. At autopsy, multiple small hemorrhages were seen in the periventricular gray matter, primarily around the aqueduct and the third and fourth ventricles. Shortly after Wernicke’s original treatise, Korsakoff, a Russian psychiatrist, described an amnesia syndrome in 20 alcoholic men. At the time, neither Wernicke nor Korsakoff recognized the relationship between the encephalopathy and impaired memory. The clinical connection and the pathological similarity between the two conditions were not appreciated until 10 years later by other investigators. Korsakoff syndrome and Wernicke encephalopathy do not represent separate diseases but are different stages of one disease process (Wernicke-Korsakoff syndrome). Korsakoff syndrome typically follows Wernicke encephalopathy, emerging as ocular symptoms and encephalopathy subside.

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Associated Conditions in Nonalcoholic Patients with Wernicke Encephalopathy

BOX 85.3

Hyperemesis of pregnancy Systemic malignancy Gastrointestinal surgery (e.g., bariatric surgery) Hemodialysis or peritoneal dialysis Prolonged intravenous feeding Refeeding after prolonged fasting or starvation Anorexia nervosa Dieting Acquired immunodeficiency syndrome

Fig. 85.3 Acute Wernicke Disease. Hemorrhagic areas are seen adjacent to the fourth ventricle and aqueduct in the (from right to left) medulla, pons, and midbrain. (Courtesy Dr. Michael F. Gonzales.)

Wernicke encephalopathy is due to thiamine deficiency. The most common clinical setting for this disorder is chronic alcoholism. However, a large number of cases occur in other conditions, with the only prerequisite being a poor nutritional state, from inadequate intake, malabsorption, or increased metabolic requirement (Box 85.3). Wernicke encephalopathy may be precipitated acutely in at-risk patients by IV glucose administration or carbohydrate loading. The classic triad in Wernicke encephalopathy is the combination of confusion, ophthalmoplegia, and gait ataxia, although all three elements are seen in fewer than half of all patients. In a retrospective study of 468 patients in Spain, the triad was present in only 39% of alcoholic and 29% of nonalcoholic patients (Chamorro et al., 2017). The Caine criteria was often used for its higher sensitivity in diagnosis of Wernicke encephalopathy (Caine et al., 1997). It requires only two of the following four features: dietary deficiency, oculomotor abnormalities, cerebellar ataxia, and confusion. Eighty-five percent of autopsy-confirmed cases of Wernicke encephalopathy met the Caine criteria, although the specificity is likely low. Confusion is the most common symptom and develops over days or weeks. This is characterized by inattention, apathy, disorientation, and memory loss. Stupor or coma is rare. Gait ataxia is likely a result of cerebellar abnormality, neuropathy, and vestibular dysfunction. On examination, truncal ataxia is common, but limb ataxia is not—findings similar to those seen in alcoholic cerebellar degeneration. Ophthalmoplegia, when present, commonly involves both lateral recti, either in isolation or together with palsies of other extraocular muscles. Patients may have horizontal nystagmus on lateral gaze, and many also have vertical nystagmus on upgaze. Sluggish reaction to light, light-near dissociation, and other pupillary abnormalities are sometimes seen. The clinical findings reflect the localization of pathological abnormalities in this disease—namely, the prominent symmetrical involvement of periventricular structures at the level of the third and fourth ventricles. Lesions of the nuclei of cranial nerves III, VI, and VIII are responsible for the eye findings. Other frequent findings include hypothermia and postural hypotension, reflecting involvement of hypothalamic and brainstem autonomic pathways. The Korsakoff syndrome follows repeated bouts of encephalopathy or an inadequately treated acute encephalopathy. As the acute encephalopathy subsides, it becomes obvious that the patient has an amnestic disorder. The memory impairment is out of proportion to other cognitive dysfunction and consists of both anterograde and retrograde amnesia. Affected patients have severe difficulty establishing new memories, always coupled with a limited ability to recall events that antedate the onset of illness by several years. Most patients are disoriented as to place and time. Alertness, attention, social behavior, and most other aspects of cognitive functioning are relatively preserved. Confabulation can be a prominent feature, especially in the early stages, although it

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may be absent in some patients. The memory disorder reflects the predilection of the lesions for the diencephalon and temporal lobes. Injury to these regions, regardless of cause (e.g., infarction, trauma, tumors, herpes encephalitis), can produce a syndrome indistinguishable from the amnesia syndrome seen in alcoholic patients.

Laboratory Studies Brain MRI is helpful in acute Wernicke encephalopathy. MRI typically shows signal abnormalities on T2-weighted fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted images, symmetrically distributed around the periaqueductal regions, tectal plates, medial thalami, and bilateral mammillary bodies. Other regions such as the cerebellar vermis, pons, medulla, dentate nuclei, cranial nerve nuclei, and basal ganglia are at times affected. Some lesions may show contrast enhancement. Petechial hemorrhages may be seen on T2-weighted images using susceptibility-weighted imaging (SWI) (Hattingen et al., 2016). There are differences in the distribution of lesions between alcoholic and nonalcoholic patients, but there is a considerable overlap between the two groups (Zuccoli et al., 2009). Brain computed tomography (CT) may be used when MRI is unavailable but is much less sensitive in demonstrating abnormalities. MRI signal abnormalities typically resolve completely with prompt treatment, but shrunken mammillary bodies may be seen as a late residual finding. The CSF is either normal or shows a mild elevation in protein. Serum thiamine level and erythrocyte transketolase activity may be depressed, and there may be an elevation of serum pyruvate.

Pathology The pathological process depends on the age of the lesions. Macroscopically, varying degrees of congestion, petechial hemorrhages, shrinkage, and discoloration are present (Fig. 85.3). Glial proliferation and myelin pallor characterize the more chronic lesions. The regions affected are the same as those observed to be involved on MRI. The frequency of Wernicke encephalopathy as estimated from autopsy studies is approximately 0.8%–2.8%, a figure far greater than that expected from clinical studies. Only 20% of the autopsy cases in one series were diagnosed during life. This is unfortunate because Wernicke encephalopathy is preventable and treatable. The under-recognition may result from an overemphasis on alcoholism as a cause (see Box 85.4) or a misconception that all three elements of the clinical triad are needed for a diagnosis. Wernicke encephalopathy occurring under other settings may be mistaken for encephalopathy of uremia, dialysis, sepsis, or other systemic diseases.

Treatment Wernicke encephalopathy should be suspected in all patients with encephalopathy and at risk for nutritional deficiency (see Box 85.3) (Galvin et al., 2010). Treatment should not be delayed while waiting

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for laboratory confirmation of thiamine deficiency. Intravenous thiamine is safe, inexpensive, and effective in the treatment of Wernicke encephalopathy. Patients suspected of having the disorder should receive thiamine before administration of glucose to avoid precipitation of symptom worsening. A dose of 500 mg should be given IV in the acute stage, followed by 100 mg 3 times daily during the first week. Parenteral administration is preferable over oral supplements because intestinal absorption is unreliable in debilitated and alcoholic patients. If left untreated, Wernicke encephalopathy is progressive. The mortality, even with thiamine treatment, was 10%–20% in the early studies. With treatment, the majority of ocular signs resolve within hours, although a fine horizontal nystagmus persists in approximately 60% of patients. The gait disturbance resolves slowly, and in over onethird of the cases, gait may be abnormal even months after treatment. As the global confusional state recedes, some patients are left with the Korsakoff syndrome. The treatment of Korsakoff syndrome is usually limited to social support. Many patients require at least some form of supervision, either at home or in a chronic care facility. There are anecdotal reports of success treating the memory loss with acetylcholinesterase inhibitors or memantine, but controlled studies in small numbers of patients did not show a consistent benefit (Luykx et al., 2008).

OTHER DISEASES ASSOCIATED WITH ALCOHOLISM The diverse neurological consequences of alcohol abuse have been recognized for centuries. Alcohol is a potent central nervous system depressant. It facilitates the inhibitory neurotransmitter γ-aminobutyric acid (GABA) and inhibits the excitation induced by N-methyld-aspartate (NMDA). It also has effects on the opioid, dopamine, and serotonin systems in the brain. Sustained heavy consumption of alcohol leads to dependency and increased tolerance, along with reduced sensitivity to GABA and increased sensitivity to NMDA. These alcohol abusers are also at risk for the development of withdrawal symptoms after cessation of alcohol consumption. In addition to the increased susceptibility to withdrawal symptoms, dietary deficiency is common in alcohol abusers. Alcohol contains so-called empty calories because it does not provide significant amounts of protein and vitamins. A gram of pure ethanol contains 7 calories. A person who drinks a pint of 86-proof liquor daily consumes well over 1000 calories a day, approximately half of the daily caloric requirement. The alcohol consumption inevitably results in reduced intake of other foods. The problem is compounded further by malabsorption and abnormal metabolism of vitamins, both of which are common in alcoholics. Despite the increased risk of malnutrition, only WernickeKorsakoff syndrome and rare cases of pellagra in alcoholics are clearly linked to nutritional deficiency. The pathogenesis of other neurological disorders is less clear (Box 85.4), though many have postulated a direct toxic effect of alcohol on both the central and peripheral nervous systems. For instance, neuropathy sometimes develops in alcohol abusers with normal nutritional status. The pattern of nerve fiber loss in these patients appears to be different from that in beriberi neuropathy from thiamine deficiency, thus suggesting a different pathological mechanism (Koike et al., 2003).

Alcohol-Withdrawal Syndromes Alcohol-withdrawal syndrome typically occurs in patients with a long history of sustained alcohol use. Symptoms appear 4–12 hours after the last consumption of alcohol. The initial symptoms are insomnia, anxiety, tremulousness, palpitations, and diaphoresis. It is not uncommon for symptoms to appear even when there is a significant alcohol level in the blood. Mild cases of alcohol withdrawal are self-limiting, with

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BOX 85.4

Nutritional Deficiency Wernicke encephalopathy Korsakoff syndrome Pellagra Direct Effects of Alcohol Acute intoxication Fetal alcohol syndrome Abnormalities of Serum Electrolytes and Osmolality Central pontine myelinolysis Alcohol Withdrawal Withdrawal seizures Alcoholic hallucinosis Delirium tremens Diseases of Uncertain Pathogenesis Alcoholic neuropathy Alcoholic myopathy Amblyopia Cerebellar degeneration Marchiafava-Bignami disease

symptoms peaking and resolving within 72 hours. Moderate to severe cases require urgent medical attention, as they are often complicated by withdrawal seizures, alcoholic hallucinosis, and delirium tremens. Alcohol-withdrawal seizures are generalized clonic-tonic convulsions that usually occur between 12 and 48 hours from the last drink, though shorter or longer time intervals are possible. Most patients have either a single seizure or seizures occurring in a brief flurry. Status epilepticus is rare in isolated alcohol withdrawal, though alcohol withdrawal frequently complicates seizure disorders from other causes. The occurrence of status epilepticus or the presence of ominous features such as focal seizures or focal deficits in the postictal state should prompt an investigation into other structural, metabolic, or infectious causes. Although most alcohol-withdrawal seizures are self-limiting, recurrent or prolonged seizures require treatment. Benzodiazepines or phenobarbital are preferred over phenytoin, which is ineffective in withdrawal seizures. With or without seizures, the initial symptoms of alcohol withdrawal may further progress to altered mentation. Visual and sometimes auditory and tactile hallucinations (alcoholic hallucinosis) often occur in the first 2 days after the last drink. They are then followed by delirium and agitation, accompanied by tachycardia, hypertension, fever, or diaphoresis (delirium tremens). Fluid and electrolyte disturbances often accompany delirium tremens. Hypovolemia, hypokalemia, hypomagnesemia, and hypophosphatemia are common and should be promptly treated if present. Other secondary complications may include cardiac failure, dysrhythmia, rhabdomyolysis, alcoholic pancreatitis, hepatitis, and pneumonia. Benzodiazepines and supportive care are the mainstays in the treatment of a severe alcohol-withdrawal state. A fast-acting benzodiazepine such as diazepam, lorazepam, or oxazepam should be given via the IV route. They are effective in controlling the agitation and sympathetic hyperactivity as well as any withdrawal seizures. This should be accompanied by aggressive support with IV fluids, nutritional supplementation (see the earlier section Wernicke-Korsakoff Syndrome), treatment of coexisting complications, and close monitoring of vital

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CHAPTER 85 Deficiency Diseases of the Nervous System signs, fluid status, and electrolytes. Less-proven agents such as β-adrenergic antagonists, clonidine, and carbamazepine may also be used as adjunctive measures in controlling alcohol-withdrawal symptoms. The improvement of treatment has reduced the mortality rate of delirium tremens from over 30% at the beginning of the 20th century to the current rate of no more than 5%.

Alcoholic Neuropathy Neuropathy is the most frequent neurological complication of alcoholism. Depending on the method of ascertainment, it may be diagnosed in 10%–75% of alcoholic patients. Most affected patients are between age 40 and 60, and, in essentially all cases, there is a history of chronic and heavy alcohol intake for many years.

Clinical Features Alcoholic neuropathy is a mixed sensory and motor disorder that affects large- and small-diameter nerve fibers to varying degrees (Zambelis et al., 2005). Symptom onset is insidious, beginning in the feet and progressing proximally and symmetrically. Paresthesia is the most common presenting complaint. Many patients also complain of pain, either an aching discomfort in the calves or a burning sensation over the soles. Dysesthesia may be so severe that a light touch or gentle rubbing over the skin is intensely unpleasant. Interestingly, pain is more often a problem in those with milder neuropathy. On examination, both deep and superficial sensations are affected. Ankle tendon reflexes and sometimes knee reflexes are lost. Weakness and wasting are limited to the distal feet in mild cases but can involve the distal upper extremities in more severe cases. Rarely there may be vagus or recurrent laryngeal nerve involvement, with prominent hoarseness and weakness of voice. Both alcohol neurotoxicity and thiamine deficiency likely play important roles in alcoholic neuropathy. One study (Koike et al., 2003) suggests that pure alcoholic neuropathy without thiamine deficiency is more likely to be painful and has less motor involvement than that associated with concomitant thiamine deficiency. Other manifestations of chronic alcoholism are often evident. Liver cirrhosis, hepatic encephalopathy, Wernicke-Korsakoff syndrome, alcoholic cerebellar degeneration, and alcohol-withdrawal symptoms all occur frequently at the time of evaluation. Trophic skin changes in the form of hyperpigmentation, edema, ulcers, and cellulitis in the distal part of the feet are sometimes encountered. There may be radiological suggestions of a distal neuropathic arthropathy (Charcot forefeet, acrodystrophic neuropathy), with phalangeal atrophy, bony resorption, and subluxation of small joints in the feet. Repeated trauma and infections to insensitive parts of the feet are probably responsible. This syndrome is prevalent in the south of France and Spain, where the term Thevenard syndrome is applied.

Laboratory Studies and Pathology The pathology of alcoholic neuropathy is predominantly axonal loss. Nerve conduction studies show reduced amplitude of sensory nerve responses, with normal or mildly reduced conduction velocities. Electromyography may reveal signs of denervation and reinnervation in distal muscles of the lower extremities. Axonal degeneration of both myelinated and unmyelinated fibers is present on sural nerve biopsy. In some patients, autonomic dysfunction may be demonstrated by abnormalities in heart rate variation to deep breathing, Valsalva maneuver, and postural change.

Treatment It is prudent to treat most affected patients with abstinence from alcohol, supplemental multivitamins, and a balanced diet. Even under ideal conditions, recovery is slow and incomplete.

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Tobacco–Alcohol or Nutritional Amblyopia Tobacco–alcohol amblyopia is a syndrome of vision loss caused by a selective lesion of the optic nerves. In Western countries, most affected patients are chronic and severe alcoholics, often with a history of poor dietary intake or marked weight loss. Vision loss occurs insidiously and painlessly, progressing in both eyes over a period of several weeks. The most common deficits are impaired visual acuity and the presence of central or centrocecal scotomata. Even in severely affected subjects, the optic discs may show only mild pallor. The commonly used term tobacco–alcohol amblyopia is likely incorrect, as neither agent has been proven to be directly responsible. The disease is probably identical to the nutritional amblyopia seen in prisoners of war and malnourished individuals who have no access to either alcohol or tobacco. Moreover, treatment with a combination of an adequate diet and B vitamins, despite the continuation of drinking and smoking, results in visual recovery. Dietary deficiencies of vitamin B12, thiamine, folate, and riboflavin, all of which have been linked to optic neuropathy, may individually or together be responsible.

Marchiafava-Bignami Disease In 1903, Marchiafava and Bignami, two Italian pathologists, described a syndrome of selective demyelination of the corpus callosum in alcoholic Italians who indulged in large quantities of red wine. The disease seems to affect primarily severe and chronic alcoholics in their middle or late adult life, with a peak incidence between ages 40 and 60. It is not restricted to any one ethnic group, and consumption of red wine is not an invariable feature. With the widespread use of MRI, there has been an increase in recognition of this previously rare disorder. A few cases have also been reported in nonalcoholics. The neurological presentation is variable. The most common are an acute confusional state or a dementing syndrome. Patients may present with a variable combination of psychomotor slowing, behavioral changes, incontinence, dysarthria, and spasticity. Seizures, hemiparesis, and coma are sometimes seen. Pathologically, there is selective involvement of the central portion of the corpus callosum; the dorsal and ventral regions are spared or affected to a lesser degree. There also may be symmetrical involvement of other white-matter tracts. MRI is valuable and shows increased T2 and FLAIR signals along with restricted diffusion in the body of the corpus callosum, sometimes with extension into the genu or the splenium (Menegon et al., 2005). Abnormalities may also be seen in the subcortical white matter and cerebellar peduncles. Thinning of the corpus callosum is seen commonly in alcoholics without symptoms of Marchiafava-Bignami disease. It is unclear what causes the overt disease in susceptible individuals. Treatment of Marchiafava-Bignami disease should be directed at supportive care, nutritional supplements, and rehabilitation from alcoholism. In those patients who recovered, it is not clear whether improvement was a result of nutritional supplementation or merely a reflection of the disease’s natural history.

Alcoholic Cerebellar Degeneration Alcoholic cerebellar degeneration is likely the most common of the acquired degenerations of the cerebellum. Men are affected more frequently than women, and the incidence peaks in the middle decades of life. Alcohol abuse is long-standing in all patients, and alcoholic polyneuropathy accompanies most of them. The clinical syndrome is usually quite stereotyped. The presentation is a progressive unsteadiness in walking that evolves over weeks or months. Less commonly, a mild gait difficulty may be present for some time, only to worsen suddenly during binge drinking or an intercurrent illness. On examination, the most prominent finding is a truncal ataxia, demonstrated by a widebased gait and difficulty with tandem walking. Limb ataxia, if present,

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is much milder than the truncal ataxia and more severe in the legs than in the arms. In contrast to Wernicke encephalopathy, nystagmus and ocular dysmetria are uncommon. Dysarthria, tremor, and hypotonia are rare findings. The pathogenesis of cerebellar degeneration is unknown, though both nutritional deficiency and direct toxicity of alcohol may play a role. The pathological changes consist of selective atrophy of the anterior and superior parts of the cerebellar vermis, with the cerebellar hemispheres involved to a lesser extent. Cell loss involves all neuronal types in the cerebellum, although Purkinje cells are the most severely affected. A mild secondary loss of neurons is common in the deep cerebellar nuclei and the inferior olivary nuclei. In some patients, concomitant pathological changes of Wernicke encephalopathy may be present. Abstinence is the main treatment and can lead to a partial but incomplete improvement. With abstinence from alcohol and nutritional supplements, improvement in cerebellar symptoms occurs slowly but is often incomplete.

VITAMIN A Dietary deficiency of vitamin A is uncommon in Europe and the United States. Deficiency may occur rarely in fat malabsorption syndromes such as sprue, biliary atresia, and cystic fibrosis. A few cases have occurred in infants put on nondairy formula free of vitamin A. The earliest sign of deficiency is reduced ability to see in dim light. Retinol, an aldehyde form of vitamin A, binds with the protein, opsin, to form rhodopsin, which is responsible for vision at low light level. Xerosis, or keratinization, of the conjunctiva and cornea often accompanies night blindness. Some patients have the characteristic Bitot spots, which are white foam-like spots appearing at the side of the cornea. These eye findings are caused by metaplasia of epithelial cells and, if severe, can lead to permanent blindness. Rarely, infants may manifest a syndrome of raised intracranial pressure, bulging fontanelles, and lethargy. Patients with signs of vitamin A toxicity or overdose are also likely to see a neurologist. The classic syndrome of toxicity is that of pseudotumor cerebri with headache, papilledema, nausea, and vomiting. The skin is often dry and pruritic, and patients may complain of generalized joint or bone pain. Especially in children, joint swelling and hyperostoses are often evident on roentgenography. Chronic daily consumption of more than 25,000 IU may produce toxicity, although most reported patients consumed much higher doses over a shorter period of time. Unusual foods, such as polar bear liver and halibut liver, contain high concentrations of vitamin A and have caused acute toxicity. Serum retinol level is useful in the diagnosis. The generally accepted lower limit of normal is 20 mg/dL, whereas concentrations in excess of 100 mg/dL are suggestive of toxicity.

VITAMIN D Vitamin D is important for bone and calcium metabolism. Deficiency may be caused by a diversity of systemic conditions including dietary insufficiency, malabsorption, inadequate sunlight exposure, immobility, anticonvulsant use, hypophosphatemia, and hyperparathyroidism. The recommended laboratory assay is the serum level of 25-hydroxyvitamin D (25[OH]D). The optimal 25(OH)D level is unsettled, although most favor a serum level between 20 and 40 ng/ mL for ideal bone health. A recent surge in interest in the role of vitamin D in neurological disorders arose from three lines of observation. First, a large portion of the elderly population may be deficient in vitamin D, most likely from a combination of inadequate dietary intake, decreased exposure to sunlight, and decreased vitamin D skin production with aging. Second, vitamin D has potentially diverse effects in the

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nervous system through its action on inflammatory cytokines, neurotrophins, and calcium-binding proteins. Third, low levels of 25(OH) D have been associated with a number of neurological diseases including multiple sclerosis, Parkinson disease, stroke, and cognitive decline (Miller, 2010). On the other hand, an observed association does not prove causation. Whether vitamin D supplementation has any beneficial impact in central nervous system diseases remains to be seen (McLaughlin et al., 2018). The best-documented neurological syndrome attributable to overt vitamin D deficiency is a myopathy characterized by proximal weakness (Al-Said et al., 2009). Progressive weakness develops over many months. Weakness leads to difficulty in going up stairs and rising from a chair. When severe, some patients are wheelchair dependent. Diffuse bone pain, muscle pain, or back pain is common. Stretch reflexes and sensation are normal. Some patients may already have a diagnosis of osteomalacia. Serum creatine kinase level is usually normal or only mildly elevated. Serum alkaline phosphatase is abnormally high, and calcium and phosphorus may be normal or mildly decreased. Electromyography typically shows short-duration low-amplitude and polyphasic motor unit potentials without spontaneous activities; these features are similar to those of other metabolic myopathies. Nonspecific type II muscle fiber atrophy is seen on biopsy. Oral supplementation of vitamin D is recommended in patients with low serum 25(OH)D levels. There are various effective regimens. Cholecalciferol, vitamin D3, appears slightly more effective than ergocalciferol, vitamin D2, although both are suitable. One approach in severely depleted patients (100 µg over 24 hours). The most common cause is impaired absorption of dietary copper after gastric surgeries, including bariatric surgery. GI disorders predisposing to malabsorption, such as sprue, celiac disease, and bacterial overgrowth, are also risk factors. Excessive dietary consumption of zinc and iron may impair the absorption of copper. Some cases have been reported in the setting of parenteral zinc overload from renal dialysis. Menkes disease is a form of congenital copper deficiency and is due to an inherited disorder of intestinal copper absorption. Clioquinol, an antibiotic with the property of being a copper-zinc chelator, may rarely be responsible. Even in cases of malabsorption, dietary supplementation of 2–6 mg of copper salt per day is usually sufficient to reverse a deficiency state. Intravenous infusion may be used if needed. Replenishment appears to halt progression of disease but with little neurological improvement (Jaiser and Winston, 2010; Kelkar et al., 2008).

Protein-Calorie Malnutrition Millions of infants and children in underdeveloped countries suffer from varying degrees of protein and calorie deficiencies and manifest two interrelated syndromes: marasmus and kwashiorkor. Marasmus is primarily a result of caloric insufficiency and is characterized by extreme emaciation and growth failure in early infancy. These infants usually have never been breastfed or were weaned before 1 year of age. Kwashiorkor is seen most commonly in children weaned between 2 and 3 years of age, and its primary underlying cause is protein deficiency. The signs of kwashiorkor are edema, ascites, hepatomegaly, sparse hair, and skin depigmentation. The earliest and most consistent neurological signs in these children are apathy to the environment and extreme irritability. Weakness, generalized muscle wasting, hypotonia, and hyporeflexia occur frequently. Cognitive deficits may be permanent despite improvement in nutrition. It is difficult to separate the effects of malnutrition from those of socioeconomic deprivation, but comparison studies in siblings show persistent impairment of intelligence attributable to malnutrition. Autopsy and imaging studies show the brain to be slightly atrophic, and neuronal development is less mature. A mild encephalopathy, usually no more than transient drowsiness, sometimes occurs during the first week of dietary treatment. Occasionally, children develop asterixis or coma or even die as a result of their treatment. Other children manifest a transient syndrome of rigidity, coarse tremors, myoclonus, and exaggerated tendon reflexes during the first few weeks of recovery from malnutrition. The complete reference list is available online at https://expertconsult. inkling.com/.

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86 Effects of Toxins and Physical Agents on the Nervous System Michael J. Aminoff, Yuen T. So

OUTLINE Occupational Exposure to Organic Chemicals, 1303 Acrylamide, 1303 Allyl Chloride, 1303 Carbon Disulfide, 1303 Carbon Monoxide, 1304 Ethylene Oxide, 1304 Hexacarbon Solvents, 1304 Methyl Bromide, 1304 Organochlorine Pesticides, 1305 Organophosphates, 1305 Pyrethroids, 1306 Pyriminil, 1306 Solvent Mixtures, 1306 Styrene, 1306 Toluene, 1306 Trichloroethylene, 1306 Occupational Exposure to Metals, 1307 Aluminum, 1307 Arsenic, 1307 Lead, 1308 Manganese, 1308 Mercury, 1309 Tellurium, 1309 Thallium, 1309 Tin, 1309 Effects of Ionizing Radiation, 1309 Encephalopathy, 1310

Myelopathy, 1310 Plexopathy, 1310 Effects of Nonionizing Radiation, 1310 Electric Current and Lightning, 1311 Vibration, 1311 Hyperthermia, 1311 Hypothermia, 1312 Burns, 1312 Neurotoxins of Animals and Insects, 1312 Snakes, 1313 Spiders, 1313 Scorpions, 1313 Tick Paralysis, 1314 Neurotoxins of Plants and Fungi, 1314 Jimson Weed, 1314 Poison Hemlock, 1314 Water Hemlock, 1314 Peyote, 1315 Morning Glory, 1315 Medicinal Herbs, 1315 Excitatory Amino Acids, 1315 Mushroom Poisoning, 1315 Marine Neurotoxins, 1315 Ciguatera Fish Poisoning, 1316 Puffer Fish Poisoning, 1317 Shellfish Poisoning, 1317

Neurotoxic disorders are occurring increasingly as a result of occupational or environmental exposure and often go unrecognized. Exposure to neurotoxins may lead to dysfunction of any part of the central, peripheral, or autonomic nervous system and the neuromuscular apparatus. Neurotoxic disorders are recognized readily if a close temporal relationship exists between clinical onset and prior exposure to an agent, especially one known to be neurotoxic. Known neurotoxins produce stereotypical neurological disturbances that generally cease to progress soon after exposure is discontinued and ultimately improve to a variable extent. Recognition of a neurotoxic disorder may be difficult, however, when exposure is chronic or symptoms are nonspecific. The problem is compounded when the exposure history is unclear. Diagnosis may also be clouded by concerns about other confounding factors, such as other drugs, illnesses, and possible litigation. Patients often attribute symptoms of an idiopathic disorder to an exposure when no other cause can be found.

Single case reports that an agent is neurotoxic are unreliable, especially when the neurological symptoms are frequent in the general population. Epidemiological studies may be helpful in establishing a neurotoxic basis for symptoms. However, many of the published studies are inadequate because of methodological problems such as the selection of appropriate control subjects. Recognition of a neurotoxic basis for neurobehavioral disorders, for example, requires matching of exposed subjects and unexposed controls for many factors including age; gender; race; premorbid cognitive ability; educational, social, and cultural background; and alcohol, recreational drug, and medication use. Laboratory test results are often unhelpful in confirming that the neurological syndrome is caused by a specific agent, either because the putative neurotoxin cannot be measured in body tissues or because the interval since exposure makes such measurements meaningless. The part of the central, peripheral, or autonomic nervous system and the neuromuscular apparatus damaged by exposure to

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neurotoxins depends on the responsible agent. The pathophysiological basis of neurotoxicity is often unknown. In considering the possibility of a neurotoxic disorder, it is important to obtain a detailed account of the exposure, including details of the duration and severity, and any protective measures taken, if applicable. Then it must be determined whether any of these agents are known to be neurotoxic and whether symptoms are compatible with the known toxicity of the suspected compound. Many neurotoxins can produce clinical disorders that resemble other known metabolic, nutritional, or degenerative neurological disorders, and it is therefore important to consider these and any other relevant disease processes in the differential diagnosis. In recognizing new neurotoxic disorders, a clustering of cases is often important, but this may not be evident until patients are referred for specialist evaluation. Neurotoxins cause diffuse rather than focal or lateralized neurological dysfunction. The neurological disorder is typically monophasic. Depending on the neurotoxin, and on the duration and level of exposure, it most commonly takes the form of an acute or chronic encephalopathy or a peripheral neuropathy. Although progression may occur for several weeks after exposure has been discontinued (“coasting”), it is eventually arrested, and improvement may then follow, depending on the severity of the original disorder. Prolonged or progressive deterioration long after exposure has been discontinued, or the development of neurological symptoms months to years after exposure, suggests that a neurotoxic disorder is not responsible. Any discussion of developmental neurotoxicity (i.e., the adverse effects of industrial chemicals on the development of the brain and behavior) is beyond the scope of the present chapter.

tendon reflexes rather than simply the Achilles reflex, which is usually affected first in most length-dependent neuropathies. Autonomic abnormalities other than hyperhidrosis are uncommon. Gait and limb ataxia are usually greater than can be accounted for by the sensory loss. With discontinuation of exposure, the neuropathy “coasts,” arrests, and may then slowly reverse, but residual neurological deficits are common. These consist particularly of spasticity and cerebellar ataxia; the peripheral neuropathy usually remits because regeneration occurs in the peripheral nervous system. No specific treatment exists but recovery may occur if further exposure is prevented. Studies in rats have shown that administration of FK506 to increase Hsp-70 expression may exert a neuroprotective effect and have therefore suggested that compounds eliciting a heat shock response may be useful for treating the neuropathy in humans (Gold et al., 2004). Electrodiagnostic studies provide evidence of an axonal sensorimotor polyneuropathy. Workers exposed to acrylamide may be monitored electrophysiologically by recording sensory nerve action potentials, which are attenuated early in the course of the disorder, or by measuring the vibration threshold. Histopathological studies show accumulation of neurofilaments in axons, especially distally, and distal degeneration of peripheral and central axons. The large myelinated axons are involved first. The affected central pathways include the ascending sensory fibers in the posterior columns, the spinocerebellar tracts, and the descending corticospinal pathways. Involvement of postganglionic sympathetic efferent nerve fibers accounts for the sudomotor dysfunction. Measurement of hemoglobin–acrylamide adducts may be useful in predicting the development of peripheral neuropathy.

OCCUPATIONAL EXPOSURE TO ORGANIC CHEMICALS

Allyl chloride is used for manufacturing epoxy resins, certain insecticides, and polyacrylonitrile. Exposure leads to a mixed sensorimotor distal axonopathy. Cessation of exposure is followed by recovery of variable degree. Intra-axonal accumulation of neurofilaments occurs multifocally before axonal degeneration in animals exposed to this compound. Similar changes may also occur in the posterolateral columns of the spinal cord.

Acrylamide Acrylamide polymers are used as flocculators and are constituents of certain adhesives and products such as cardboard or molded parts. They also are used as grouting agents for mines and tunnels, a solution of the monomer being pumped into the ground where polymerization is allowed to occur. The monomer is neurotoxic, and exposure may occur during its manufacture or in the polymerization process. Most cases of acrylamide toxicity occur by inhalation or cutaneous absorption. Acrylamide can be formed by cooking various carbohydrate-rich foods at high temperatures, but consumption is unlikely to be sufficient for neurotoxicity. The acrylamide is distributed widely throughout the body and is excreted primarily through the kidneys. The mechanism responsible for its neurotoxicity is unknown, but it has been related to an inhibitory effect on presynaptic function (LoPachin and Gavin, 2012), by damage to the nerve terminal involving membrane fusion mechanisms and tubulovesicular alterations (Pennisi et al., 2013), and to abnormalities of kinesin-based fast axonal transport. Axonal swellings due to accumulations of neurofilaments relate to impaired retrograde axonal transport. Clinical manifestations of acrylamide toxicity depend on the severity of exposure. Acute high-dose exposure results in confusion, hallucinations, reduced attention span, drowsiness, and other encephalopathic changes. A peripheral neuropathy of variable severity may occur after acute high-dose or prolonged low-level exposure. The neuropathy is a length-dependent axonopathy involving both sensory and motor fibers. Hyperhidrosis and dermatitis may develop before the neuropathy is evident clinically in those with repeated skin exposure. Ataxia from cerebellar dysfunction also occurs and relates to degeneration of afferent and efferent cerebellar fibers and Purkinje cells. Neurological examination reveals distal sensorimotor deficits and early loss of all

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Allyl Chloride

Carbon Disulfide Carbon disulfide is used as a solvent or soil fumigant, in perfume production, in certain varnishes and insecticides, in the cold vulcanization of rubber, and in manufacturing viscose rayon and cellophane films. Toxicity occurs primarily from inhalation or ingestion but also may occur transdermally. The pathogenetic mechanism is uncertain but may involve an essential metal-chelating effect of carbon disulfide metabolites, direct inhibition of certain enzymes, or the release of free radicals following cleavage of the carbon–sulfur bond. Most reported cases have been from Europe and Japan. Acute inhalation of concentrations exceeding 300–400 ppm leads to an encephalopathy, with symptoms that vary from mild behavioral disturbances to drowsiness and, ultimately, to respiratory failure. Behavioral disturbances may include explosive behavior, mood swings, mania or depression, confusion, and other psychiatric disturbances. Long-term exposure to concentrations between 40 and 50 ppm may produce similar disturbances. Minor affective or cognitive disturbances may be revealed only by neuropsychological testing. Long-term exposure to carbon disulfide may lead also to extrapyramidal (parkinsonian) or pyramidal deficits, impaired vision, absent pupillary and corneal reflexes, optic neuropathy, and a characteristic retinopathy. A small-vessel vasculopathy may be responsible (Huang, 2004). Neuroimaging may reveal cortical—especially frontal—atrophy, as well as lesions in the globus pallidus and putamen. Computed tomography (CT) angiography and perfusion studies have revealed decreased

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cerebral blood flow in total brain parenchyma and basal ganglia, decreased cerebral blood volume in the basal ganglia, and a prolonged mean transit time in the total brain parenchyma and the territories of the internal carotid artery, basal ganglia, and occipital lobe. Such findings have been held to support the presence of a microangiopathy (Chuang et al., 2007). A clinical or subclinical polyneuropathy develops after exposure to levels of 100–150 ppm for several months or to lesser levels for longer periods and is characterized histologically by axonal loss, focal axonal swellings, and neurofilamentary accumulations. Clinically there is stocking-glove impairment of all sensory modalities together with distal weakness and absent ankle reflexes. The concurrence of neuropathy and parkinsonism should suggest the possibility of carbon disulfide intoxication. No specific treatment exists other than the avoidance of further exposure. Recovery from the peripheral neuropathy generally follows the discontinuation of exposure, but some central deficits may persist.

Carbon Monoxide Occupational exposure to carbon monoxide occurs mainly in miners, gas workers, and garage employees. Other modes of exposure include poorly ventilated home heating systems, stoves, and suicide attempts. The neurotoxic effects of carbon monoxide relate to intracellular hypoxia. Carbon monoxide binds to hemoglobin with high affinity to form carboxyhemoglobin; it also limits the dissociation of oxyhemoglobin and binds to various enzymes. Acute toxicity leads to headache, disturbances of consciousness, and a variety of other behavioral changes. Motor abnormalities include the development of pyramidal and extrapyramidal deficits. Seizures may occur, and focal cortical deficits sometimes develop. Treatment involves prevention of further exposure to carbon monoxide and administration of pure or hyperbaric oxygen. New therapies aimed at the inflammatory effects and oxidative stress induced by carbon monoxide poisoning or helping remove carbon monoxide from the body, as with porphyrin complexes or modified globin proteins, are under study (Rose et al., 2017). Neurological deterioration may occur several weeks after partial or apparently full recovery from the acute effects of carbon monoxide exposure, with recurrence of motor and behavioral abnormalities. The degree of recovery from this delayed deterioration is variable; full or near-full recovery occurs in some instances, but other patients lapse into a persistent vegetative state or severe parkinsonism. Neuroimaging may show lesions in the periventricular white matter, globus pallidus, and elsewhere. There may be diffuse brain atrophy. Pathological examination shows hypoxic and ischemic damage in the cerebral cortex as well as in the hippocampus, cerebellar cortex, and basal ganglia. Lesions are also present diffusely in the cerebral white matter. The delayed deterioration has been related to a diffuse subcortical leukoencephalopathy, but its pathogenesis is uncertain.

Ethylene Oxide Ethylene oxide is used to sterilize heat-sensitive medical equipment and as an alkylating agent in industrial chemical synthesis. A by-product, ethylene chlorohydrin, is highly toxic. Operators of sterilization equipment should wear protective ventilatory apparatus to prevent occupational exposure. Acute exposure to high levels produces headache, nausea, and a severe, reversible encephalopathy, with seizures and disturbances of consciousness. Respiration may be impaired. Treatment is supportive. Long-term exposure to ethylene oxide or ethylene chlorohydrin—as can occur, for example, in operating-room nurses and sterilizer workers—may lead to a peripheral sensorimotor axonopathy and mild cognitive changes. Recovery generally follows the cessation of exposure. Neuropathy may be produced in rats by exposure to ethylene oxide, and the residual ethylene oxide in sterilized dialysis tubing

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may contribute to the polyneuropathy occurring in patients undergoing chronic hemodialysis.

Hexacarbon Solvents The hexacarbon solvents n-hexane and methyl-n-butyl ketone are both metabolized to 2,5-hexanedione, which is responsible in large part for their neurotoxicity. This neurotoxicity is potentiated by methyl ethyl ketone, which is used in paints, lacquers, printer’s ink, and certain glues. n-Hexane is used as a solvent in paints, lacquers, and printing inks and is used especially in the rubber industry and in certain glues. Workers involved in the manufacturing of footwear, laminating processes, and cabinetry, especially in confined, unventilated spaces, may be exposed to excessive concentrations of these substances. Methyl-nbutyl ketone is used in the manufacture of vinyl and acrylic coatings and adhesives and in the printing industry. Exposure to either of these chemicals by inhalation or skin contact leads to a progressive distal sensorimotor axonal polyneuropathy; partial conduction block may also occur. Optic neuropathy or maculopathy and facial numbness also have followed n-hexane exposure. The neuropathy is related to a disturbance of axonal transport, and histopathological studies reveal giant multifocal axonal swelling and accumulation of axonal neurofilaments, with distal degeneration in peripheral and central axons. Myelin retraction and focal demyelination are found at the giant axonal swellings. Acute inhalation exposure may produce feelings of euphoria associated with hallucinations, headache, unsteadiness, and mild narcosis. This has led to the inhalation of certain glues for recreational purposes, which causes pleasurable feelings of euphoria in the short term but may lead to a progressive, predominantly motor neuropathy and symptoms of dysautonomia after high-dose exposure and a more insidious sensorimotor polyneuropathy following chronic use. Electrophysiological findings include increased distal motor latency and marked slowing of maximal motor conduction velocity, as well as small or absent sensory nerve action potentials and electromyographic (EMG) signs of denervation in affected muscles. The conduction slowing relates to demyelinating changes and is unusual in other toxic neuropathies. A reduction in the size of sensory nerve action potentials may occur in the absence of clinical or other electrophysiological evidence of nerve involvement. Central involvement may result in abnormalities of sensory evoked potentials. The cerebrospinal fluid (CSF) is usually normal, but a mildly elevated protein concentration is sometimes found. Despite cessation of exposure, progression of the neurological deficit may continue for several weeks or, rarely, months (coasting) before the downhill course is arrested and recovery begins. Clinical and electrophysiological recovery of the peripheral neuropathy may take several years and may not be complete when involvement is severe (Little and Albers, 2015). As the polyneuropathy resolves, previously masked signs of central dysfunction, such as spasticity, may become evident.

Methyl Bromide Methyl bromide has been used as a refrigerant, insecticide, fumigant, and fire extinguisher, but its use has been banned in many countries because of its ozone-depleting properties. Its high volatility may lead to work-area concentrations sufficient to cause neurotoxicity from inhalation. Following acute high-level exposure, an interval of several hours or more may elapse before the onset of symptoms. Because methyl bromide is odorless and colorless, subjects may not even be aware that exposure has occurred, so chloropicrin, a conjunctival and mucosal irritant, is commonly added to methyl bromide to warn of inhalation exposure. Acute methyl bromide intoxication leads to an encephalopathy with convulsions, delirium, hyperpyrexia, coma,

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pulmonary edema, and death. Acute exposure to lower concentrations may result in conspicuous mental changes, including confusion, psychosis or affective disturbances, headache, nausea, dysarthria, tremulousness, myoclonus, ataxia, visual disturbances, and seizures. The electroencephalogram (EEG) may show frontally predominant slow waves or polyspike-wave complexes, while magnetic resonance imaging (MRI) reveals involvement of the dentate nucleus, brainstem, and splenium of the corpus callosum (De Souza et al., 2013). Long-term, low-level exposure may lead to a polyneuropathy in the absence of systemic symptoms. Distal paresthesias are followed by sensory and motor deficits, loss of tendon reflexes, and an ataxic gait. Visual disturbances, optic atrophy, and upper motor neuron deficits may occur also. Calf tenderness is sometimes conspicuous. The CSF is unremarkable. Electrodiagnostic study results reveal both sensory and motor involvement. Gradual improvement occurs with cessation of exposure. The basis of the neurotoxicity is uncertain but methyl phosphates formed in cells may contribute to its neuron-specific toxicity via cholinesterase inhibition (Bulathsinghala and Shaw, 2014). Treatment is symptomatic and supportive. Hemodialysis may help in removing bromide from the blood. Chelating agents are of uncertain utility.

Organochlorine Pesticides The organochlorine pesticides include aldrin, dieldrin, and lindane, as well as the once-popular insecticide dichlorodiphenyl-trichloroethane, commonly called DDT. Exposure is typically through inhalation or ingestion. Tremor, convulsions, and coma may follow acute high-level exposure, but the effects of chronic low-level exposure are uncertain. Chlordecone, which belongs to this group, may produce a neurological disorder characterized by “nervousness,” tremor, clumsiness of the hands, gait ataxia, slurred speech, and opsoclonus. Minor cognitive changes, memory loss, and benign intracranial hypertension may occur. The signs may reverse over months or longer. The pathophysiology of the disorder has not been established. The risk of developing Parkinson disease (PD) is reportedly increased by exposure to organochlorine insecticides but the involved mechanisms are unclear (Costa, 2015).

Organophosphates Organophosphates are used mainly as pesticides and herbicides but are also used as petroleum additives, lubricants, antioxidants, flame retardants, and plastic modifiers. Most cases of organophosphate toxicity result from exposure in an agricultural setting, not only among those mixing or spraying the pesticide or herbicide but also among workers returning prematurely to sprayed fields. Absorption may occur through the skin, by inhalation, or through the gastrointestinal tract. Organophosphates inhibit acetylcholinesterase by phosphorylation, with resultant acute cholinergic symptoms, with both central and neuromuscular manifestations. Symptoms include nausea, salivation, lacrimation, headache, weakness, and bronchospasm in mild instances and bradycardia, tremor, chest pain, diarrhea, pulmonary edema, cyanosis, convulsions, and even coma in more severe cases. Death may result from respiratory or heart failure. Treatment involves intravenous (IV) administration of pralidoxime (1 g) together with atropine (1 mg) given subcutaneously every 30 minutes until sweating and salivation are controlled. Pralidoxime accelerates reactivation of the inhibited acetylcholinesterase, and atropine is effective in counteracting muscarinic effects, although it has no effect on the nicotinic effects, such as neuromuscular cholinergic blockade with weakness or respiratory depression. It is important to ensure adequate ventilatory support before atropine is given. The dose of pralidoxime can be repeated if no obvious benefit occurs, but in refractory cases, it may

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need to be given by IV infusion, the dose being titrated against clinical response. Cardiac and respiratory function must be supported and seizures controlled pharmacologically. Functional recovery may take approximately 1 week, although acetylcholinesterase levels take longer to reach normal levels. Measurement of paraoxonase status may be worthwhile as a biomarker of susceptibility to acute organophosphate toxicity; this liver and serum enzyme hydrolyzes a number of organophosphate compounds and may have a role in modulating their toxicity (Costa et al., 2005). Carbamate insecticides also inhibit cholinesterases but have a shorter duration of action than organophosphate compounds. The symptoms of toxicity are similar to those described for organophosphates but are generally milder. Treatment with atropine is usually sufficient. Certain organophosphates cause a delayed polyneuropathy that occurs approximately 2–3 weeks after acute exposure even in the absence of cholinergic toxicity. In the past, contamination of illicit alcohol with tri-ortho cresyl phosphate (“Jake”) led to large numbers of such cases. There is no evidence that peripheral nerve dysfunction follows prolonged low-level exposure to organophosphates (Vale and Lotti, 2015). Paresthesias in the feet and cramps in the calf muscles are followed by progressive weakness that typically begins distally in the limbs and then spreads to involve more proximal muscles. The maximal deficit usually develops within 2 weeks. Quadriplegia occurs in severe cases. Although sensory complaints are typically inconspicuous, clinical examination shows sensory deficits. The Achilles reflex is typically lost, and other tendon reflexes may be depressed also; however, in some instances, evidence of central involvement is manifested by brisk tendon reflexes. Cranial nerve function is typically spared. With time, there may be improvement in the peripheral neuropathy, but upper motor neuron involvement then becomes unmasked and often determines the prognosis for functional recovery. There is no specific treatment to arrest progression or hasten recovery. Electrodiagnostic studies reveal an axonopathy with partial denervation of affected muscles and small compound muscle action potentials but normal or only minimally reduced maximal motor conduction velocity. The delayed syndrome follows exposure only to certain organophosphates, such as tri-ortho cresyl phosphate, leptophos, trichlorfon, and mipafox. The neurological disturbance relates in some way to phosphorylation and inhibition of the enzyme, neuropathy target esterase (NTE), which is present in essentially all neurons and has an uncertain role in the nervous system (Lotti and Moretto, 2005). In addition, “aging” of the inhibited NTE (loss of a group attached to the phosphorus, leaving a negatively charged phosphoryl group attached to the protein) must occur for the neuropathy to develop. The precise cause of the neuropathy is uncertain, however, as is the role of NTE in axonal degeneration. No specific treatment exists to prevent the occurrence of neuropathy following exposure, but the measurement of lymphocyte NTE has been used to monitor occupational exposure and predict the occurrence of neuropathy. Moreover, the ability of any particular organophosphate to inhibit NTE in hens may predict its neurotoxicity in humans. Three other syndromes related to organophosphate exposure require brief comment. The intermediate syndrome occurs in the interval between the acute cholinergic crisis and the development of delayed neuropathy, typically becoming manifest within 4 days of exposure and resolving in 2–3 weeks (Abdollahi and Karami-Mohajeri, 2012). It reflects excessive cholinergic stimulation of nicotinic receptors and is characterized clinically by respiratory and bulbar symptoms as well as proximal limb weakness. Symptoms relate to the severity of poisoning and to prolonged inhibition of acetylcholinesterase activity but not to the development of delayed neuropathy. The syndrome of dipper’s

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flu refers to the development of transient symptoms such as headache, rhinitis, pharyngitis, myalgia, and other flulike symptoms in farmers exposed to organophosphate sheep dips. Vague sensory complaints (but no objective abnormalities on sensory threshold tests) may also occur (Pilkington et al., 2001). Whether these complaints relate to mild organophosphate toxicity is uncertain. Similarly uncertain is whether chronic effects (persisting behavioral and neurological dysfunction) may occur in the absence of acute toxicity or follow acute exposure to organophosphates as a result of the respiratory and cardiac complications that sometimes occur (Vale and Lotti, 2015). A meta-analysis of well-designed studies, however, did find an association between lowlevel exposure and impaired neurobehavioral function (Ross et al., 2013). Evaluation of reports is hampered by incomplete documentation and the variety of agents to which exposure has often occurred. Carefully controlled studies may clarify this issue in the future.

Pyrethroids Pyrethroids are synthetic insecticides that affect voltage-sensitive sodium channels. Their neurotoxicity in mammals may also relate to their effect on sodium channels but voltage-gated calcium and chloride channels have been implicated as alternative or secondary sites of action for certain pyrethroids (Soderlund, 2012). Occupational or residential exposure is increasing, is mainly through the skin but may also occur through inhalation, and has led to paresthesias that have been attributed to repetitive activity in sensory fibers as a result of abnormal prolongation of the sodium current during membrane excitation. The paresthesias affect the face most commonly and are exacerbated by sensory stimulation such as scratching; they typically resolve within a day. Local application of a cool cloth or of a cream containing vitamin E may help relieve the sensory complaints. Treatment is otherwise purely supportive. Coma and convulsions may result if substantial amounts of pyrethroids are ingested, however, necessitating urgent hospitalization. In laboratory animals, two syndromes relating to neurotoxicity have been described, but these are poorly defined in humans. The first syndrome (type I) is characterized by reflex hyperexcitability and fine tremor, whereas the second (type II) consists of choreoathetosis, salivation, and seizures.

Pyriminil Exposure to pyriminil (Vacor), a rodenticide, has led to severe autonomic dysfunction accompanied by a usually milder sensorimotor axonopathy following its ingestion. The mechanism by which this develops is unclear, but it may relate to an impairment of fast anterograde axonal transport. Acute diabetes mellitus also results from necrosis of the beta islet cells of the pancreas.

Solvent Mixtures In the 1970s, a number of reports from Scandinavia suggested that house painters, in particular, developed an irreversible disturbance of cognitive function that related to long-term exposure to mixtures of organic solvents. Many studies of exposed workers since then have documented the occurrence of cognitive symptoms (impaired memory, difficulty in concentration, poor attention span), affective complaints, and changes in personality, with impaired motivation and ease of fatigue. The symptoms are generally nonspecific in nature. The neurological examination is typically normal or reveals minor nonspecific abnormalities, as do neuroimaging and electrophysiological tests. However, other studies (including cases previously diagnosed with the disorder) have failed to validate the earlier reports, which, in many instances, were methodologically flawed. Furthermore, workers performing the same basic tasks in different companies have highly variable levels of solvent exposure, and solvent mixtures vary in different

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occupational settings, complicating the interpretation of published studies. Because of these factors and the nonspecific character of symptoms, the existence of so-called painter’s (or chronic solvent) encephalopathy in those exposed to low levels of organic solvents for a prolonged period has been questioned. Nevertheless, the World Health Organization has published diagnostic criteria for this syndrome, later refined by a commission of the European Union and by others (Sainio, 2015; van Valen et al., 2018), and it is accepted as an occupational disease by the International Labour Organization. Certain neurodegenerative diseases, including Parkinson and Alzheimer diseases, have been related to occupational exposure to organic solvents in some but not other studies. Difficulties in interpreting individual studies relate to methodological factors such as the manner in which exposure is estimated, varying diagnostic criteria, and the presence of confounding risk factors. Certain neurodegenerative disorders are not homogeneous but consist of a heterogeneous group of conditions with a similar clinical phenotype, complicating still further the interpretation of different epidemiological studies concerning their possible association with solvent exposure.

Styrene Styrene is used for manufacturing reinforced plastic and certain resins. Occupational exposure occurs by the dermal or inhalation routes and is typically associated with exposure to a variety of other chemicals, thereby making it difficult to define the syndrome that occurs from styrene exposure itself. Exposure (inhalation or dermal) occurs particularly among those working in industries manufacturing or using styrene, those exposed to automobile exhaust or cigarette smoke, and those using photocopiers. Styrene may also be ingested in drinking water or certain foods. Further details and allowable limits are provided by the Agency for Toxic Substances and Disease Registry (2007). Acute exposure to high concentrations of styrene has led to cognitive, behavioral, and attentional disturbances. Less clear are the consequences of exposure to chronic low levels of styrene. Abnormalities in psychomotor performance have been reported, but there is little compelling evidence of persisting neurological sequelae in this circumstance. Visual abnormalities (impaired color vision and reduced contrast sensitivity) also occur.

Toluene Toluene is used in a variety of occupational settings. It is a solvent for paints and glues and is used to synthesize benzene, nitrotoluene, and other compounds. Exposure, usually by inhalation or transdermally, occurs in glue-sniffers and among workers laying linoleum, spraying paint, and working in the printing industry, particularly in poorly ventilated locations. Chronic high exposure may lead to cognitive disturbances and to central neurological deficits with upper motor neuron, cerebellar, brainstem, and cranial nerve signs and tremor (Filley et al., 2004). An optic neuropathy may occur, as may ocular dysmetria and opsoclonus. Disturbances of memory and attention characterize the cognitive abnormalities, and subjects may exhibit a flattened affect. The cerebellar dysfunction, which may be permanent, may lead to dysarthria, action tremor, gait ataxia, and occasionally downbeat nystagmus (Manto, 2012). MRI shows cerebral atrophy and diffuse abnormalities of the cerebral white matter; symmetrical lesions may be present in the basal ganglia and thalamus and the cingulate gyri. Thalamotomy may ameliorate the tremor if it is severe. Lower levels of exposure lead to minor neurobehavioral disturbances.

Trichloroethylene Trichloroethylene is an industrial solvent and degreaser that is used in dry cleaning and the manufacture of rubber. It also has anesthetic

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properties. Recreational abuse has occurred because it may induce feelings of euphoria. Acute low-level exposure may lead to headache and nausea but claims that an encephalopathy follows chronic lowlevel exposure are unsubstantiated. Higher levels of exposure lead to dysfunction of the trigeminal nerve, with progressive impairment of sensation that starts in the snout area and then spreads outward. This has been particularly associated with rebreathing anesthetic circuits where the trichloroethylene is heated by the carbon dioxide absorbent. With increasing exposure, facial and buccal numbness is followed by weakness of the muscles of mastication and facial expression. Ptosis, extraocular palsies, vocal cord paralysis, and dysphagia may occur also, as may signs of parkinsonism (Gash et al., 2008; Goldman et al., 2012) or an encephalopathy, but the occurrence of a peripheral neuropathy is uncertain. The clinical deficit relates to neuronal loss in the cranial nerve nuclei and nigrostriatal dopaminergic system and degeneration in related tracts. Upon discontinuation of exposure, the clinical deficit generally resolves, sometimes over 1–2 years, but occasional patients are left with residual facial numbness or dysphagia.

OCCUPATIONAL EXPOSURE TO METALS Aluminum Aluminum exposure is responsible for dialysis encephalopathy, which is characterized by speech disturbances, cognitive decline, seizures, and myoclonus. Some reports suggest that workers exposed to aluminum dust or aluminum-containing welding fumes may develop depression and mild cognitive dysfunction, but whether this relates to the occupational exposure is unclear; individual studies are difficult to interpret because of methodological and other issues. A role for aluminum in the pathogenesis of Alzheimer disease is disputed (Virk, 2015; Wang, 2016).

Arsenic Arsenic poisoning can result from ingestion of the trivalent arsenite in murder or suicide attempts. Large numbers of persons in areas of India, Pakistan, and certain other countries are chronically poisoned from naturally occurring arsenic in groundwater. Traditional Chinese and Tibetan medicinal herbal preparations may contain arsenic sulfide and mercury and are a source of chronic poisoning. Uncommon sources of accidental exposure include burning preservative-impregnated wood and storing food in antique copper kettles. Exposure to inorganic arsenic occurs in workers involved in smelting copper and lead ores. With acute or subacute exposure, nausea, vomiting, abdominal pain, diarrhea, hypotension, tachycardia, and vasomotor collapse occur and may lead to death. Obtundation is common, and an acute confusional state may develop. Arsenic neuropathy takes the form of a distal axonopathy, although a demyelinating neuropathy is found soon after acute exposure. The neuropathy usually develops within 2–3 weeks of acute or subacute exposure, although the latent period may be as long as 1–2 months. Symptoms may worsen over a few weeks despite lack of further exposure, but they eventually stabilize. With low-dose chronic exposure, the latent period is more difficult to determine. In either circumstance, systemic symptoms are also conspicuous. With chronic exposure, similar but less severe gastrointestinal disturbances develop, as may skin changes such as melanosis, keratoses, and malignancies. Mees lines are white transverse striations of the nails (striate leukonychia) that appear 3–6 weeks after exposure (Fig. 86.1). As a nonspecific manifestation of nail matrix injury, Mees lines can be seen in a number of other conditions, including thallium poisoning, chemotherapy, and a variety of systemic disorders. The neuropathy involves both large- and small-diameter fibers. Initial symptoms are typically of distal painful dysesthesias and are followed by distal weakness. Proprioceptive loss may be severe, leading

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Fig. 86.1 Mees Lines in Arsenic Neuropathy. (From Johnston, R., 2012. Weedon’s Skin Pathology Essentials, first ed. Churchill Livingstone, Elsevier.)

to marked ataxia. The severity of weakness depends on the extent of exposure. The respiratory muscles are sometimes affected, and the disorder may simulate Guillain-Barré syndrome both clinically and electrophysiologically. Electrodiagnostic studies may initially suggest a demyelinating polyradiculoneuropathy, but the changes of an axonal neuropathy subsequently develop. Arsenic levels in hair, nail clippings, or urine may be increased, especially in cases of chronic exposure. Detection of arsenic in urine is diagnostically useful within 6 weeks of a single large-dose exposure or during ongoing low-level exposure. Total inorganic arsenic urinary excretion should be measured over 24 hours. Methods are available in reference laboratories for distinguishing between inorganic (toxic) and organic (seafood-derived) arsenic compounds. Arsenic bound to keratin can be detected in hair or nails months to years after exposure. Pubic hair is preferable to scalp hair for examination because it is less liable to environmental contamination. Levels exceeding 10 µg/g of tissue are abnormal. Other abnormal laboratory features include aplastic anemia with pancytopenia and moderate CSF protein elevation. Nerve conduction studies in chronic arsenic neuropathy reflect the changes of distal axonopathy with low-amplitude or unelicitable sensory and motor evoked responses and preserved conduction velocities. EMG typically shows denervation in distal extremity muscles. In the subacute stages, however, some electrophysiological features such as partial motor conduction block, absent F responses, and slowing of motor conduction velocities are suggestive of demyelinating polyradiculoneuropathy. Progressive slowing of motor conduction velocities sufficient to invoke consideration of segmental demyelination has been reported in the first 3 months after massive exposure. Biopsies of peripheral nerves show axonal degeneration in chronic cases. Arsenite compounds react with protein sulfhydryl groups, interfere with formation of coenzyme A and several steps in glycolysis, and are potent uncouplers of oxidative phosphorylation. These biochemical reactions are responsible for the impaired neuronal energy metabolism, which in turn results in distal axonal degeneration. Chelation therapy with water-soluble derivatives of dimercaprol (DMSA or DMPS) is effective in controlling the systemic effects of acute arsenic poisoning and may prevent the development of neuropathy if it is started within hours of ingestion. There is little evidence that chelation in the later stages of arsenic neuropathy promotes clinical recovery. The neuropathy itself often improves gradually over the course of many months, but depending on the severity of the deficit when exposure is discontinued, a substantial residual neurological deficit is common.

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Lead Occupational exposure to lead occurs in workers in smelting factories and metal foundries and those involved in demolition, ship breaking, manufacturing of batteries or paint pigments, and construction or repair of storage tanks. Occupational exposure also occurs in the manufacture of ammunition, bearings, pipes, solder, and cables. Nonindustrial sources of lead poisoning are home-distilled whiskey, Asian folk remedies, earthenware pottery, indoor firing ranges, and retained bullets. Lead has been used to artificially increase the weight of illicit marijuana and has then been inhaled with it (Busse et al., 2008). Artificial turf may also pose an exposure threat to unhealthy levels of lead: the lead is released in dust that may be ingested or inhaled, but whether there is a sufficient amount to cause neurotoxicity is unclear. Lead neuropathy reached epidemic proportions at the end of the 19th century because of uncontrolled occupational exposure but now is rare because of strict industrial regulations. Exposure also may result from ingestion of old lead-containing paint in children with pica and consumption of illicit spirits by adults. Absorption is commonly by ingestion or inhalation but occasionally occurs through the skin. The toxic effects of inorganic lead salts on the nervous system commonly differ with age, producing acute encephalopathy in children and polyneuropathy in adults. Children typically develop an acute gastrointestinal illness followed by behavioral changes, confusion, drowsiness, reduced alertness, focal or generalized seizures, and (in severe cases) coma with intracranial hypertension. At autopsy, the brain is swollen, with vascular congestion, perivascular exudates, edema of the white matter, and scattered areas of neuronal loss and gliosis. In adults, an encephalopathy is less common, but behavioral and cognitive changes are sometimes noted. In adults, lead produces a predominantly motor neuropathy, sometimes accompanied by gastrointestinal disturbances and a microcytic, hypochromic anemia. The neuropathy is manifest primarily by a bilateral wrist drop sometimes accompanied by bilateral footdrop or by more generalized weakness that may be associated with distal atrophy and fasciculations. Sensory complaints are usually minor and overshadowed by the motor deficit when the neuropathy develops subacutely following relatively brief exposure to high lead concentrations, but they are more conspicuous when the neuropathy develops after many years of exposure. The tendon reflexes may be diminished or absent. Older reports describe a painless motor neuropathy with few or no sensory abnormalities and distinct patterns of weakness affecting wrist extensors, finger extensors, and intrinsic hand muscles. Preserved reflexes, fasciculations, and profound muscle atrophy may simulate amyotrophic lateral sclerosis. A rare sign of lead exposure is a blue line at the gingival margin in patients with poor oral hygiene. Hypochromic microcytic anemia with basophilic stippling of the red cells, hyperuricemia, and azotemia should stimulate a search for lead exposure. Prognosis for recovery from the neuropathy is good when the neuropathy is predominantly motor and evolves subacutely, but it is less favorable when the neuropathy is motorsensory in type and more chronic in nature. Lead intoxication is confirmed by elevated blood and urine lead levels. Blood levels exceeding 70 µg/100 mL are considered harmful, but even levels greater than 40 µg/100 mL have been correlated with minor nerve conduction abnormalities. Subjects should be removed from further occupational exposure if a single blood lead concentration exceeds 30 µg/100 mL or if two successive blood lead concentrations measured over a 4-week interval equal or exceed 20 µg/100 mL (Kosnett et al., 2007). Discontinuation of lead exposure should be considered when exposure control measures over an extended period do not reduce blood lead concentrations to less than 10 µg/dL or if selected medical conditions exist that increase the risk of continued exposure. It has been recommended that medical surveillance should

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include quarterly blood lead measurements for individuals with blood lead concentrations between 10 and 19 µg/dL and semiannual measurements when sustained blood lead concentrations are less than 10 µg/dL (Kosnett et al., 2007). Lead inhibits erythrocyte δ-aminolevulinic acid dehydratase and other enzymatic steps in the biosynthetic pathway of porphyrins. Consequently, increased red cell protoporphyrin levels emerge together with increased urinary excretion of δ-aminolevulinic acid and coproporphyrin. Excess body lead burden, confirming past exposure, can be documented by increased urinary lead excretion after a provocative chelation challenge with calcium ethylenediaminetetraacetic acid. Only a few electrophysiological studies have been reported in patients with overt lead neuropathy. These investigations indicate a distal axonopathy affecting both motor and sensory fibers. These observations corroborate changes of axonal degeneration seen in human nerve biopsies. Contrary to the findings in humans, lead produces segmental demyelination in animals. The biochemical mechanisms leading to neurotoxicity remain unknown but may include oxidative stress, disruption of calciumdependent cell signaling, inhibition of nitric oxide synthase, and changes in glutamatergic signaling (Caito and Aschner, 2015). Lead encephalopathy is managed supportively, but corticosteroids are given to treat cerebral edema. Chelating agents (dimercaprol or 2,3-dimercaptopropane sulfonate) are also prescribed for patients with symptoms of lead toxicity (Kosnett et al., 2007). No specific treatment exists for lead neuropathy other than prevention of further exposure to lead. Chelation therapy does not hasten recovery. It is continued until a steady-state level of lead excretion is reached. With large lead stores in bone, chelation may be followed by movement of lead back into the blood and soft tissues, and thus by a rebound increase in blood lead level after an initial decline. Chelation therapy should not be used as attempted prophylaxis against rising blood levels in workers with continuing lead exposure.

Manganese Manganese miners may develop neurotoxicity following inhalation for prolonged periods (months or years) of dust containing manganese. Headache, behavioral changes, and cognitive disturbances (“manganese madness”) are followed by the development of motor symptoms such as dystonia, parkinsonism, retropulsion, and a characteristic gait called cock-walk, manifested by walking on the toes with elbows flexed and the spine erect. There is usually no tremor, and the motor deficits rarely improve with l-dopa therapy. MRI may show changes in the globus pallidus, and this may be helpful in distinguishing manganese-induced parkinsonism from classic PD. Any relationship between welding and the development of PD itself is disputed. Manganese intoxication has been reported in miners, smelters, welders, and workers involved in the manufacture of dry batteries, after chronic accidental ingestion of potassium permanganate, and from incorrect concentration of manganese in parenteral nutrition. Manganese toxicity also may occur with chronic liver disease and longterm parenteral nutrition. Manganese intoxication may be associated with abnormal MRI (abnormal signal hyperintensity in the globus pallidus and substantia nigra on T1-weighted images). In contrast to PD, fluorodopa positron emission tomography (PET) studies are usually normal in patients with manganese-induced parkinsonism, and raclopride (D2 receptor) binding is only slightly reduced in the caudate and normal in the putamen. Neuronal loss occurs in the globus pallidus and substantia nigra pars reticularis, as well as in the subthalamic nucleus and striatum. There is little response to l-dopa of the extrapyramidal syndrome, which may progress over several years. Myoclonic jerking may occur, sometimes without extrapyramidal accompaniments.

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Chelation therapy is of uncertain benefit in patients with manganese toxicity, although claims of improvement in parkinsonism among small series of manganese-exposed subjects have been made.

compounds may lead to headache, drowsiness, a metallic taste, hypohidrosis, rashes and skin discoloration, and a curious odor resembling garlic on the breath. Recovery generally occurs spontaneously.

Mercury

Thallium

The neurotoxic effects of elemental mercury (mercury vapor), inorganic salts, and short-chain alkyl-mercury compounds predominantly involve the central nervous system (CNS) and dorsal root ganglion sensory neurons. Inorganic mercury toxicity may result from inhalation during industrial exposure, as in thermometer and battery factories, mercury processing plants, and electronic applications factories. In the past, exposure occurred particularly in the hat-making industry. No evidence exists that the mercury contained in dental amalgam imposes any significant health hazard. The extent to which mercury exposure accounts for differences in health and cognitive function between dentists and control subjects is unclear. Clinical consequences of exposure include cutaneous erythema, hyperhidrosis, anemia, proteinuria, glycosuria, personality changes, intention tremor (“hatter’s shakes”), and muscle weakness. The personality changes (“mad as a hatter”) consist of irritability, euphoria, anxiety, emotional lability, insomnia, and disturbances of attention with drowsiness, confusion, and ultimately stupor. A variety of other central neurological deficits may occur but are more conspicuous in patients with organic mercury poisoning. A few cases presenting with peripheral neuropathy or a predominantly motor neuronopathy resembling amyotrophic lateral sclerosis have been described in association with intense exposure to elemental mercury vapors. The effects of methyl mercury (organic mercury) poisoning have come to be widely recognized since the outbreak that occurred in Minamata Bay (Japan) in the 1950s, when industrial waste discharged into the bay led to a contamination of fish that were then consumed by humans. Outbreaks have also occurred following the use of methyl mercury as a fungicide, because intoxication occurs if treated seed intended for planting is eaten instead. Methyl and ethyl mercury compounds have been used as fungicides in agriculture and in the paper industry. Methyl mercury and elemental mercury are potent neurotoxins that cause neuronal degeneration in the cerebellar granular layer, calcarine cortex, and dorsal root ganglion neurons. The mechanisms involved in methyl mercury toxicity may include increased oxidative stress; inhibition of proteins involved in calcium homeostasis, glutamate transport, and γ-aminobutyric acid (GABA) synthesis; and alterations in several cell signaling pathways (Caito and Aschner, 2015). The characteristic features of chronic methyl mercury poisoning are sensory disturbances, constriction of visual fields, progressive ataxia, tremor, and cognitive impairment. Electrophysiological studies have shown that these symptoms relate to central dysfunction. Sensory disturbances result from dysfunction of sensory cortex or dorsal root ganglia rather than peripheral nerves, and the visual complaints also relate to cortical involvement. Pathological studies reveal neuronal loss in the cerebral cortex, including the parietal and occipital regions, as well as in the cerebellum. The diagnosis of elemental or inorganic mercury intoxication usually can be confirmed by assaying mercury in urine. Monitoring blood levels is recommended for suspected organic mercury poisoning. Chelating agents increase urinary excretion of mercury, but the evidence is incomplete that chelation increases the rate or extent of recovery.

Thallium has been used until recently as a rodenticide and insecticide. It has also been used as a depilatory and in various industrial contexts. It is absorbed through the skin and also by ingestion or inhalation. Thallium exposure causes mitochondrial damage and impairs energy production. It leads to increased oxidative stress, changes in the physical properties of cell membranes, and the activation of antioxidant mechanisms (Osorio-Rico et al., 2017). There are changes in antiapoptotic and proapoptotic proteins, cytochrome c, and caspases (OsorioRico et al., 2017). The toxic effects of thallium have been related to the binding of sulfhydryl groups or displacement of potassium ions from biological membranes. Thallium salts cause severe neuropathy and CNS degeneration that has led to their discontinued use as rodenticides and depilatories. Most intoxications result from accidental ingestion, attempted suicide, or homicide. After consumption of massive doses, vomiting, diarrhea, or both occur within hours. Neuropathic symptoms, heralded by limb pain and severe distal paresthesia, are followed by progressive limb weakness within 7 days. Cranial nerves, including optic nerves, may be involved. Ptosis is common. In severe cases, ataxia, chorea, confusion, and coma, as well as ventilatory and cardiac failure, may ensue. Alopecia, which appears 2–4 weeks after exposure, provides only retrospective evidence of acute intoxication. A chronic progressive, mainly sensory neuropathy develops in patients with chronic low-level exposure. In this form, hair loss is a helpful clue. Electrocardiographic findings of sinus tachycardia, U waves, and T-wave changes of the type seen in potassium depletion are related to the interaction of thallium and potassium ions. Electrophysiological findings are characteristic of distal axonal degeneration. Autopsy study results confirm a distal axonopathy of peripheral and cranial nerves. Studies in animals show an accumulation of swollen mitochondria in distal axons before wallerian degeneration of nerve fibers. The diagnosis is confirmed by the demonstration of thallium in urine or bodily tissues. High levels are found in CNS gray matter and myocardium. With acute ingestion, gastric lavage and cathartics are given to remove unabsorbed thallium from the gastrointestinal tract. Oral potassium ferric ferrocyanide (Prussian blue), which blocks intestinal absorption, together with IV potassium chloride, forced diuresis, and hemodialysis, has been used successfully in acute thallium intoxication.

Tellurium Tellurium is used in the manufacture of various alloys, the production of rubber, the manufacture of thermoelectric devices, and the coloring of glass, ceramics, and metalware. Inhalation of volatile tellurium

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Tin Although ingested inorganic tin usually produces little or no systemic or neurological complications, organic tin compounds used in various industrial processes have definite neurotoxicity. Intoxication with trimethyl tin leads to multifocal central dysfunction with conspicuous behavioral disturbances, emotional lability, confusion, disorientation, cognitive disturbances, sleep dysfunction, headaches, and visual disturbances. Triethyl tin may lead to severe cerebral edema with headache, papilledema, and behavioral abnormalities that generally resolve some weeks after discontinuation of exposure.

EFFECTS OF IONIZING RADIATION Electromagnetic and particulate radiation may lead to cell damage and death. Radiation therapy affects the nervous system by causing damage to cells (particularly their nuclei) in the exposed regions; these cells include neurons, glia, and the blood vessels supplying neural structures. As a late carcinogenic effect, radiation therapy may

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also produce tumors, particularly sarcomas, that lead to neurological deficits. Neurological injury is proportional to both the total dose and the daily fraction of radiation received. The combination of radiation therapy with chemotherapy may increase the risk of radiation damage. Preclinical studies are investigating whether certain growth factors or metalloporphyrin antioxidants can prevent damage or hasten the recovery of neural structures from radiation injury (Pearlstein et al., 2010). Neurological deficits may also arise as a secondary consequence of radiation (e.g., from vertebral osteoradionecrosis), leading to pain or compression of the spinal cord or nerve roots.

Encephalopathy Radiation encephalopathy is best considered according to its time of onset after exposure (Grimm and DeAngelis, 2008). Acute radiation encephalopathy occurs within a few days of exposure and is characterized by headache, nausea, and a change in mental status. It may be related to increased intracranial pressure from breakdown of the blood–brain barrier due to the immediate effects of the energy dispersal in the nervous tissue. It typically occurs after exposure of a large brain volume to more than 3 Gy. Treatment with high-dose corticosteroids usually provides relief. Early delayed radiation encephalopathy is probably caused by demyelination and occurs between 2 weeks and 4 months after irradiation. Headache and drowsiness are features, as is an enhancement of previous focal neurological deficits. Symptoms resolve after several weeks without specific treatment. A brainstem encephalopathy that manifests as ataxia, nystagmus, diplopia, and dysarthria also may develop if the brainstem was included in the irradiated field. Spontaneous recovery over a few weeks is usual, but the disorder sometimes progresses to obtundation, coma, or death. Delayed radiation encephalopathy occurs several months or longer after cranial irradiation, particularly when doses exceed 35 Gy. It may be characterized by diffuse cerebral injury (atrophy) or focal neurological deficits. Slowness of executive function may occur, and there may be marked alterations of frontal functions such as in attention, judgment, and insight. Some patients develop a progressive disabling disorder with cognitive and affective disturbances and a disorder of gait approximately 6–18 months after whole-brain irradiation. Verbal and spatial memory become impaired, as does problem-solving ability. Cognitive deficits increase with time, leading to dementia. Such a disturbance may occur more commonly in elderly patients after irradiation. Pathological examination in some instances has shown demyelinating lesions. Radiation-induced late effects have been attributed to dynamic interactions between multiple cell types within the brain, including glial cells, neurons, and endothelial cells, and include inflammatory responses, radiation-induced neuronal loss, vascular changes, and changes in neuronal function, particularly synaptic plasticity (Greene-Schloesser et al., 2013). The precise mechanisms involved are unclear. Bevacizumab, a monoclonal antibody that inhibits vascular endothelial growth factor A, may help in some instances. Therapeutic strategies to prevent these disorders are focusing experimentally on stem cell or drug-based anti-inflammatory therapies (including blockade of the renin–angiotensin system; Greene-Schloesser et al., 2013).

Myelopathy A myelopathy may result from irradiation involving the spinal cord. Transient radiation myelopathy usually occurs within the first year or so after incidental spinal cord irradiation in patients treated for lymphoma and neck and thoracic neoplasms. Paresthesias and the Lhermitte phenomenon characterize the syndrome, which is self-limiting and probably relates to demyelination of the posterior columns. A delayed severe radiation myelopathy may occur 1 or more years after

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the completion of radiotherapy, especially with total doses exceeding 60 Gy to the spinal cord. The size of individual treatment fractions is also important, but it is unclear whether concomitant chemotherapy influences the risk. Patients present with a focal spinal cord deficit that progresses over weeks or months to paraplegia or quadriplegia. This may simulate a compressive myelopathy or paraneoplastic subacute necrotizing myelopathy, but the changes on MRI are usually those of a focal increased T2-weighted myelomalacia with cord atrophy in the originally irradiated field. The CSF is usually normal, although the protein concentration is sometimes elevated. Corticosteroids may lead to temporary improvement or slow progression, but no specific treatment exists. Anecdotal reports of benefits from hyperbaric oxygen are not supported by more detailed studies. The utility of bevacizumab is being studied. The disorder is caused by necrosis and atrophy of the cord, with an associated vasculopathy. Occasional patients develop sudden back pain and leg weakness several years after irradiation, with MRI revealing hematomyelia; symptoms usually improve with time. Inadvertent spinal cord or cauda equina involvement, usually by irradiation directed at the para-aortic nodes, sometimes leads to a focal lower-limb lower motor neuron syndrome. The neurological deficit may progress over several months or years but eventually stabilizes, leaving a flaccid asymmetrical paraparesis. Recovery does not occur.

Plexopathy A radiation-induced plexopathy may rarely occur soon after radiation treatment for neoplasms, particularly of the breast and pelvis, and must be distinguished from direct neoplastic involvement of the plexus (Dropcho, 2010). Paresthesias, weakness, and atrophy typify the disorder, which tends to plateau after progressing for several months. The plexopathy may develop 1–3 years or longer after irradiation that involves the brachial or lumbosacral plexus. In this regard, doses of radiation exceeding 60 Gy, use of large daily fractions, involvement of the upper part of the brachial plexus, lymphedema, induration of the supraclavicular fossa, and the presence of myokymic discharges on EMG all favor a radiation-induced plexopathy. Although radiation plexopathy is often painless, a point favoring this diagnosis rather than direct infiltration by neoplasm, pain is conspicuous in some patients. Symptoms progress at a variable rate. The plexopathy is associated with small-vessel damage (endarteritis obliterans) and fibrosis around the nerve trunks.

EFFECTS OF NONIONIZING RADIATION Nonionizing radiation that strikes matter is transformed to heat, which may lead to tissue damage. Ultraviolet radiation is produced by the sun, incandescent and fluorescent light sources, welding torches, electrical arc furnaces, and germicidal lamps. Ultraviolet radiation is absorbed primarily by proteins and nucleic acids. Susceptibility to it is increased by certain drugs such as chlorpromazine and tolbutamide and by certain plant substances such as materials from figs, lemon and lime rinds, celery, and parsnips, which contain furocoumarins and psoralens. Short-term exposure to ultraviolet light can damage the retina and optic nerve fibers. A severe central scotoma may result from macular injury. Prevention requires the use of goggles and face masks in work environments where exposure to high-intensity ultraviolet radiation is likely to occur. Infrared radiation is found in various industrial settings or where lasers or arc lamps are used, with a range of wavelengths between microwaves and visible light. By heating the eyes, infrared radiation can cause cataracts, cornea damage, and retina burns. Protection is afforded by wearing filters or reflective coatings.

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Exposures to laser radiation can also induce ocular damage. This is particularly a problem when the wavelength of the laser beam is not in the visible portion of the electromagnetic spectrum, because the patient may not be aware of the exposure. Protection may be provided by safety goggles for those known to be at risk. Microwaves have frequencies ranging from 1 to 300 GHz. Exposure to modulated electromagnetic energy in this frequency range can cause the perception of audible noises or actual speech within the head. This has been suggested as the cause for the symptoms developed by certain US diplomats in Cuba and China in 2017. Concern has been raised that occupational or environmental exposure to high-voltage electric power lines may lead to neurological damage from exposure to high-intensity electromagnetic fields. However, the effects of such exposure are uncertain and require further study. Nonionizing radiation at the radiofrequency used by cellular telephones has been reported to cause brain tumors or accelerate their growth (Hardell et al., 2013; Morgan et al., 2015), but the evidence is conflicting, and a clear theoretical basis for such an association with brain tumors is lacking. Most safety standards for exposure to radiofrequency radiations relate to the avoidance of harmful heating or electrostimulatory effects. There are case reports of burning sensations or dull aches of the face or head on the side that the telephone is used. Radiofrequency radiations have also been associated with dysesthesias, generally without objective neurophysiological evidence of peripheral nerve damage (Westerman and Hocking, 2004). The basis of such symptoms is unclear. High-intensity noise in the acute setting may lead to tinnitus, vertigo, pain in the ear, and hearing impairment. Chronic exposure to high-intensity noise of any frequency leads to focal cochlear damage and impaired hearing.

ELECTRIC CURRENT AND LIGHTNING Electrical injuries (whether from manufactured or naturally occurring sources) are common. Their severity depends on the strength and duration of the current and the path in which it flows. Electricity travels along the shortest path to ground. Its passage through humans can often be determined by identifying entry and exit burn wounds. When its path involves the nervous system, direct neurological damage is likely among survivors. With the passage of the current through tissues, heat is produced, which is responsible at least in part for any damage, but nonthermal mechanisms may also contribute (Winkelman, 2014). In addition, neurological damage may result from circulatory arrest or trauma related to falling or a shock pressure wave. A large current that passes through the head leads to immediate unconsciousness, sometimes associated with ventricular fibrillation and respiratory arrest. Confusion, disorientation, seizures, and transient focal deficits are common in survivors, but recovery generally occurs within a few days. Some survivors develop a cerebral infarct after several days or weeks, attributed to thrombotic occlusion of cerebral blood vessels. Residual memory and other cognitive disturbances are also common. Weaker currents lead only to headaches or other mild symptoms for a brief period. When the path of the current involves the spinal cord, a transverse myelopathy may occur immediately or within 7 days or so, and may progress for several days. The disorder eventually stabilizes, after which partial or full recovery occurs in many instances (Lakshminarayanan et al., 2009). Upper and lower motor neuron deficits and sensory disturbances are common, but the sphincters are often spared. Unlike traumatic myelopathy, pain is not a feature. Autopsy studies show demyelination of long tracts, loss of anterior horn cells, and areas of necrosis in the spinal cord.

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Segmental muscle atrophy may occur within a few days or weeks of electrical injury of the spinal cord. Whether this relates to focal neuronal damage or has an ischemic basis is uncertain. The current pathway is typically across the cervical cord from one arm to the other, and the resulting muscle atrophy in the arms may be accompanied by an upper motor neuron deficit in the legs. Sensory disturbances (in upper or lower limbs) and sphincter dysfunction also occur. Occasional reports have suggested the occurrence of a progressive disorder simulating amyotrophic lateral sclerosis after electrical injury. Peripheral or cranial nerve injury in the region of an electrical burn is often reversible, except when high-tension current is responsible and when the damage is severe, in which case thermal coagulation necrosis is likely. Care must be taken to distinguish such neuropathies from compartment or entrapment neuropathies, which are suggested by severe pain and a delay between injury and development of the neuropathy. Compartment syndromes develop because of muscle swelling and necrosis, and entrapment syndromes because of swelling of tissues in confined anatomical spaces. Immediate decompression of the compartment is indicated in these cases. For uncertain reasons, occasional patients have developed hemorrhagic or thrombotic stroke after electrical injuries. Venous sinus thrombosis has also been described. Suggested mechanisms include coagulation necrosis of part of the vascular wall, with aneurysmal distention and rupture or intramural thrombosis. Intense vasospasm, acute hypertension, intramural dissections, or transient circulatory arrest may also contribute. Trauma resulting from the electrical injury (e.g., falls) may lead to intracranial hemorrhage, subdurally, epidurally, or in the subarachnoid space. Long-term consequences of electrical injuries include neuropsychological symptoms such as fatigue, impaired concentration, irritability and emotional lability, and posttraumatic stress disorder (Ritenour et al., 2008).

VIBRATION Exposure to vibrating tools such as pneumatic drills has been associated with both focal peripheral nerve injuries such as carpal tunnel syndrome and vascular abnormalities such as Raynaud phenomenon (Sauni et al., 2009). The mechanism of production is uncertain but presumably reflects focal damage to nerve fibers. The designation of hand-arm vibration syndrome has been applied to a combination of vascular, neurological, and musculoskeletal symptoms and signs that may occur in those using handheld vibrating tools such as drills and jackhammers. There may be blanched, discolored, swollen, or painful fingers; paresthesias or weakness of the fingers; pain and tenderness of the forearm; and loss of manual dexterity (Weir and Lander, 2005). The pathophysiological basis of the syndrome is poorly understood, and treatment involves the avoidance of exposure to cold or vibrating tools.

HYPERTHERMIA Exposure to high external temperatures may lead to heat stress disorders. Heat stroke, the most severe condition, sometimes has an exertional basis, and disturbances of thermoregulatory sweating may be contributory. Classic heat stroke occurs, especially in older persons, with chronic disorders such as diabetes or obesity and in hypermetabolic states such as thyrotoxicosis. Anticholinergic or diuretic drugs and dehydration predispose to heat stroke because they impair sweating and thereby limit heat dissipation. Hyperthermia leads to thirst, fatigue, nausea, weakness, and muscle cramps and eventually to confusion, delirium, obtundation, or coma,

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but coma can develop without any prodrome. Seizures are frequent, focal neurological deficits are sometimes present, and papilledema may occur. With recovery, symptoms and signs generally clear completely, but cognitive changes or focal neurological deficits may persist. Cataracts have been attributed to dehydration. Cardiac output is reduced, pulmonary edema may occur, and adult respiratory distress syndrome is sometimes conspicuous. Other systemic manifestations include a respiratory alkalosis and often a metabolic acidosis, hypokalemia or hyperkalemia, hypoglycemia, other electrolyte disturbances, and various coagulopathies. Rhabdomyolysis is common, and acute renal failure may occur in exertional heat stroke. The prognosis depends on the severity of hyperthermia and its duration before the initiation of treatment. With proper management, the mortality rate is probably about 5%. Treatment involves control of the body temperature by cooling, rehydration of the patient, correction of the underlying cause of the hyperthermia, and prevention of complications. When excessive muscle activity is responsible, neuromuscular blockade may be necessary. In the malignant hyperthermia syndrome, the responsible anesthetic agent is discontinued, the patient is vigorously cooled, oxygenation is ensured, and IV dantrolene is administered. In the neuroleptic malignant syndrome, the responsible neuroleptic and other psychotropic agents should be stopped and the patient should be treated supportively; fever is reduced with cooling blankets, cardiorespiratory function is maintained, and agitation is controlled with benzodiazepines. Among other conditions predisposing to hyperthermia are thyrotoxicosis and pheochromocytoma. Thyrotoxic crisis is treated with thyroid-blocking drugs. Patients with pheochromocytoma are treated with α-adrenergic antagonists. Cooling is achieved by evaporation or direct external cooling, as by immersion of the patient in cold water. The skin should be massaged vigorously to counteract the cutaneous vasoconstriction that results from external cooling and impedes heat removal from the core. Antipyretic agents are unhelpful. Hypotension is treated by fluid administration rather than vasoconstrictor agents, which should be avoided if possible. High doses of mannitol and use of diuretics may be required to promote urinary output. Electrolyte and glucose abnormalities also require treatment. Patients who received 915-MHz hyperthermia treatment together with ionizing radiation for superficial cancers and developed nonspecific burning, tingling, and numbness in the territory of an adjacent nerve have been described (Westerman and Hocking, 2004). Once the symptoms developed, they occurred with the application of power without any time lag and ceased as soon as power was removed, suggesting that they were not a thermal effect. Dysesthesias have also been reported after accidental exposures in faulty microwave ovens (Westerman and Hocking, 2004). The precise neurophysiological basis for such symptoms has not been elucidated.

declines, respiratory requirements diminish, cardiac output falls, and significant hypotension and cardiac arrhythmias ultimately develop. Neurologically, there is increasing confusion, psychomotor retardation, and obtundation until consciousness is eventually lost. The tendon reflexes are reduced and muscle tone increases, but extensor plantar responses are not usually found. The EEG slows and ultimately shows a burst suppression pattern or becomes isoelectric with increasing hypothermia. At core temperatures below 32°C, the appearance of brain death may be simulated clinically and electroencephalographically, but complete recovery may follow appropriate treatment. Management involves the slow rewarming of patients and preventing complications such as aspiration pneumonia and metabolic acidosis. Hypotension may occur from dehydration but can usually be managed by fluid replacement. Plasma electrolyte concentrations must be monitored closely, especially because of the risk of developing cardiac arrhythmias. With recovery, there are usually no long-term sequelae. Nerve damage may occur as a consequence of the tissues becoming frozen by the cold (frostbite). This involves the extremities and is usually irreversible.

HYPOTHERMIA

Neurotoxins of animals, insects, plants, and fungi are of great scientific interest. Many of them serve as important tools used by neuroscientists to probe the workings of the nervous system. One of the oldest and best-known examples is curare, a plant toxin that was used in Claude Bernard’s classical experiments on neuromuscular transmission. α-Bungarotoxin from the venom of the banded krait is a competitive blocker of the acetylcholine receptor that has been invaluable in studies of the neuromuscular junction. Venoms are used by animals or insects to defend against predators and to immobilize prey. Each contains a wide range of incompletely characterized enzymes that may include metalloproteinases, phospholipases, acetylcholinesterases, collagenases, phosphodiesterases, and others. The composition varies not only from species to species but

A core temperature below 35°C may occur in very young or elderly persons with environmental exposure, coma, hypothyroidism, malnutrition, severe dermatological disorders (due to excessive heat loss and inability to regulate cutaneous vasoconstriction), and alcoholism. Alcohol promotes heat loss by vasodilation and may directly lead to coma or predispose impaired individuals to trauma, with resultant environmental exposure to cold. Hypothermia also occurs in persons exposed to low temperatures in the working environment, such as divers, skiers, and cold-room workers. The usual compensatory mechanism for cooling is shivering, but this fails at body temperatures below 30°C or so. As the temperature

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BURNS Following common usage, the term thermal burn refers to a burn caused by direct contact with heat or flames. Patients with severe burns may have associated disorders such as anoxic encephalopathy from carbon monoxide poisoning, head injury, or respiratory dysfunction from smoke inhalation. Central neurological disorders may occur later during hospitalization and are secondary to various systemic complications. Metabolic encephalopathies may relate to anoxia, liver or kidney failure, and hyponatremia, and central pontine myelinolysis may occur also. Infections (meningitis or cerebral microabscesses) are common, especially in the second or third week after the burn. Vascular complications, including multiple strokes, may result from septic infarction, disseminated intravascular coagulation, venous thrombosis, hypotension, or intracranial hemorrhage. Imaging studies are therefore important in clarifying the underlying disorder. Peripheral complications of burns are also important. Nerves may be damaged directly by heat, leading to coagulation necrosis from which recovery is unlikely. A compartment syndrome may arise from massive swelling of tissues and mandates urgent decompressive surgery. In other instances, neuropathies result from compression, angulation, or stretching due to incorrectly applied dressings or improper positioning of the patient. A critical illness polyneuropathy and myopathy is now well recognized in patients with multiorgan failure and sepsis, including patients with burns, and is discussed in Chapters 106–109.

NEUROTOXINS OF ANIMALS AND INSECTS

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also according to season and geographical region, so the clinical effects of venomous injuries are highly variable. In addition to their effects on the nervous system, most venoms possess hemorrhagic, necrotic, inflammatory, and coagulopathic properties, and are capable of inducing tissue necrosis and systemic cardiovascular collapse. Despite their biological potency, death from venoms is uncommon in developed countries. The rarity is in part a result of the healthy respect most people have for snakes, spiders, and scorpions. Moreover, most injuries result in a small amount of envenomation that is usually below lethal dosage. Mortality is more likely in children and the elderly.

Snakes More than 5 million snakebites occur worldwide per year, with half of them venomous, resulting in about 400,000 amputations and up to 138,000 deaths. About 6800 cases with fewer than 10 deaths are reported in the United States each year (Langley, 2008). In contrast, cases are far more common in Africa, Asia, and Latin America, with mortality and morbidity particularly high in impoverished rural communities (Gutierrez et al., 2017; Williams et al., 2010). The majority of venomous snakebites are inflicted by snakes from the families Viperidae (true vipers and pit vipers) and Elapidae. Pit vipers (Crotalinae), so named because of an identifiable heat-sensing foramen, or “pit,” between each eye and nostril, include rattlesnakes (genera Crotalus and Sistrurus), fer-de-lances or lanceheads (Bothrops), and bushmasters (Lachesis). Moccasins (Agkistrodon), including cottonmouths and copperheads, account for up to half of pit viper envenomations in the United States. The true vipers (Viperinae) include the puff adder, rhinoceros-horned viper and Gaboon viper (Bitis), and Russell viper (Daboia russelii), and are important venomous snakes worldwide. Important venomous snakes of the Elapidae family include cobras, mambas, kraits, coral snakes, and sea snakes. Low-molecular-weight polypeptides in snake venoms have neurological activities on both pre- and postsynaptic elements of the neuromuscular junction. Some toxins may be directly myotoxic, resulting in rhabdomyolysis and compartment syndromes. Just as important are the diverse systemic effects that affect platelets, endothelial cells, coagulation cascade, and other organs. As many as 25% to 50% of venomous snakebites are “dry” and do not result in envenomation. When envenomation occurs, signs and symptoms vary and depend on the venom composition of the local snakes. Bites by the same species may cause primarily neuromuscular paralysis in one region and coagulopathy and hemorrhage in another area. In general, snakes from the family Viperidae induce mostly coagulopathies, bleeding, and local tissue damage, while the family Elapidae are more likely to produce neuromuscular toxicity. Patients typically present with local pain, swelling, and erythema after a snakebite. Early indications of envenomation include tender regional lymph nodes, nausea, and a metallic, rubbery, or minty taste in the mouth. Systemic symptoms appear over the ensuing 12–24 hours and consist of a variable combination of perioral or limb paresthesias, muscle fasciculations, weakness, hypotension, and shock. Ptosis, oculomotor palsies, dysphagia, diffuse weakness, areflexia, and respiratory suppression may develop. If weakness is present, the pattern generally resembles myasthenia gravis, with predilection for the neck flexors, ocular, bulbar, and proximal limb and respiratory muscles. Clinical outcome principally depends on the availability and sophistication of emergency medical care. Initial laboratory evaluation should include complete blood cell and platelet counts, coagulation panel, fibrinogen, fibrin split products, serum chemistries, creatine kinase, and urinalysis. In patients with weakness, nerve conduction studies with repetitive stimulation may reveal a pattern of either pre- or postsynaptic blockade. The

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observed changes consist of reduced amplitude of compound muscle action potentials, decremental response to low-frequency repetitive stimulation, and postexercise and posttetanic facilitation. Treatment includes calming and supportive measures. Even in the absence of life-threatening symptoms, a patient should be monitored for at least 6–12 hours if bitten by a venomous snake. Antivenom immunoglobulin is the only effective antidote. If available for the specific snake responsible for envenomation, antivenom should be administered as soon as possible (Gutierrez et al., 2017; Warrell, 2010). Patients should be monitored closely for anaphylactic and infusion reactions to antivenom. Additional supportive measures to counter organ and circulatory failure are equally important. In survivors of snakebites, the main source of disability is local tissue necrosis, which may lead to disfigurement or limb amputation.

Spiders Of the commonly encountered spiders, few produce significant symptoms in humans. The female widow spider (Latrodectus sp.) is the most important to the neurologist. Of the approximately 2600 widow bites reported annually in the United States, 13 had major health consequences, and no fatality occurred (Langley, 2008). Black widow spider (Latrodectus mactans) venom contains α-latrotoxin, a potent neurotoxin capable of inducing release and blocking reuptake of neurotransmitter at presynaptic cholinergic, noradrenergic, and aminergic nerve endings. Venom of Phoneutria banana spiders from South America and Atrax funnel-web spiders from Australia also causes neurotoxicity. Another clinically important spider, the brown recluse spider (Loxosceles reclusa), is responsible for local tissue damage and systemic symptoms that rarely may include disseminated intravascular coagulation, hemolysis, shock, and multisystem failure. Although the latrotoxins found in widow spider venom are more potent than the neurotoxins found in snake venom, most spider bites lead to only a small volume of envenomation. Children are most vulnerable, although symptoms are usually minor (Glatstein et al., 2018). Sometimes a characteristic erythematous ring surrounding a paler center (“target” or “halo” lesion) develops around the site of the spider bite. In the rare instances with sufficient envenomation, pain and involuntary muscle spasms spread from the bite site and appear in abdominal muscles and distant limb musculature (so-called latrodectism). Symptoms may appear as early as 30–60 minutes, and spread to distant muscles, usually by 3–4 hours. Tachycardia, hypertension, piloerection, and diaphoresis may be present. Other associated symptoms include priapism, salivation, bronchospasm, and bronchorrhea. Serum creatine kinase may be elevated. In very rare instances, respiratory failure can result from diaphragmatic muscle involvement. Treatment begins with careful monitoring of vital signs and intensive care support if necessary. Benzodiazepines and opioids are used to control spasmodic effects and pain. Muscle spasms may also be treated with slow infusion of calcium gluconate or methocarbamol. Antivenom may be beneficial, but there are no vigorous clinical trial data.

Scorpions Of the approximately 1400 scorpion species, about 25 are of neurological importance with venom that may be deadly to humans. Scorpion envenomation is second only to snakebites as a public health problem in the tropics and North Africa. In Mexico alone, 100,000–200,000 scorpion bites occur annually, resulting in 400–1000 fatalities. In the United States, approximately 17,000 scorpion bites are reported annually, with the majority from Arizona, followed by Texas, Nevada, and Southern California (Kang, 2017). The Arizona bark scorpion (Centruroides sculpturatus) is of particular concern because of its

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neurotoxic venom. The venoms contain a wide range of polypeptides with molecular targets at the voltage-gated sodium and potassium channels. Small children are especially prone to developing neurological complications, and as many as 80% of bites are symptomatic. Presenting symptoms are highly variable, from local pain to serious systemic complications. Paresthesias are common and usually experienced around the site of the bite but also may be felt diffusely. Autonomic symptoms of sympathetic excess (tachycardia, hypertension, and hyperthermia) are often present, but parasympathetic symptoms including the SLUD syndrome (salivation, lacrimation, urination, and defecation) may be present as well. Muscle fasciculations, spasms, limb flailing, dysconjugate roving or rotary ocular movements, dysphagia, and other cranial nerve signs are sometimes seen. With severe envenomation, encephalopathy may result from direct CNS toxicity or secondary to uncontrolled hypertension. Symptom control, cardiovascular and respiratory support, and antivenom administration are the mainstays of treatment. Centruroides scorpion antivenom appeared to be effective in a small, randomized control trial in children with neurotoxicity (Boyer et al., 2009). Efficacy was reaffirmed when a subsequent larger treated cohort was compared to historical controls (Boyer et al., 2013).

Tick Paralysis Tick paralysis is caused by envenomation during tick bites. The vast majority of reported cases occur during the spring-summer breeding seasons in Australia and North America. Ixodes species are largely responsible in Australia, and Dermacentor are in America. Most cases in North America appear in the Pacific Northwest and Rocky Mountains, and only a few in the eastern United States (Diaz, 2015). Paralysis is due to inoculation of a toxin during the tick bite. Continuing attachment of the tick for 1 or more days is necessary before clinical symptoms appear. In most cases, the tick is eventually found on the scalp and neck, or around the ear. Other areas where a tick may go undetected for days are the ear and nose canals and the genital areas. Children are the most likely victims. Girls outnumber boys in the United States, perhaps because a tick is harder to find in longer hair. The clinical presentation of tick paralysis often mimics Guillain–Barré syndrome. Weakness typically starts in the legs and spreads to the arms and eventually to the bulbar and respiratory muscles. Gait ataxia or limb incoordination may be the first sign in young children. Examination shows limb weakness (most prominent in the legs), hypoactive or unobtainable stretch reflexes, and normal or mildly impaired sensation. Respiratory muscle weakness, if present, manifests as rapid shallow breathing and diminished forced vital capacity. Mechanical ventilation was necessary in 11% of US cases and 3% of Australian cases (Diaz, 2015). There are reports of atypical presentations such as cranial neuropathy, encephalopathy, autonomic dysfunction, and brachial plexopathy. Electrodiagnostic findings are likely to be nonspecific during the acute phase of the disease, although only limited data are available. Lowamplitude compound muscle action potentials may be the only abnormality (Vedanarayanan et al., 2002). Motor nerve conduction velocities, sensory nerve conduction studies, and repetitive nerve stimulation are typically normal. There is a case report of unilateral conduction block at the lower trunk of the brachial plexus from a tick bite in the ipsilateral axilla (Krishnan et al., 2009). CSF is usually normal. The key to diagnosis is to find the culpable tick by careful inspection of the patient’s skin. The tick can then be removed, leading to clinical improvement that may start within a few hours and complete in 1–2 days.

NEUROTOXINS OF PLANTS AND FUNGI Pharmacologically active agents are present in thousands of plants and fungal species. Although fatal poisoning is rare, many of the commonly

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encountered species are capable of inducing serious neurological symptoms. Toxicity occurs in several circumstances. Approximately 75% of cases occur in children younger than age 6 as a result of accidental ingestion. Adult poisoning may happen when toxic plants or mushrooms are mistaken for edible species. Another category arises with intentional consumption by those seeking drug-induced mood effects from plants such as Jimson weed. Plant identification is difficult and should be left to a trained botanist or mycologist. Common names of plants are inadequate, and botanical names should be used whenever possible. Even without a definitive identification, the history of ingestion and recognition of a characteristic syndrome are often sufficient for a tentative diagnosis. Initial treatment is usually empirical, consisting of gastric lavage or catharsis and supportive measures. With the exception of anticholinergic poisoning, there are few specific antidotes. A comprehensive review of the numerous botanical toxins is impossible. Table 86.1 lists several major categories and the commonly associated plants in each category. Omitted are plants that do not have direct toxicity on the nervous system, such as those containing cardiac glycosides, coumarin, oxalates, taxines, andromedotoxin, colchicine, and phytotoxins. Secondary neurological disturbances may result from these toxins because some can cause electrolyte abnormalities, cardiovascular dysfunction, or coagulopathy.

Jimson Weed Jimson weed (Datura stramonium), first grown by early settlers in Jamestown from seeds brought from England, was initially used to treat asthma. The plant is now found throughout the United States. Intoxication primarily occurs among young people who intentionally ingest the plant for its psychic effects. The chief active ingredient is the alkaloid hyoscyamine, with lesser amounts of atropine and scopolamine. Symptoms of anticholinergic toxicity appear within 30–60 minutes after ingestion and often continue for 24–48 hours because of delayed gastric motility. The clinical picture can include hyperthermia, delirium, hallucinations, seizures, and coma. Autonomic disturbances such as mydriasis, cycloplegia, tachycardia, dry mouth, and urinary retention are often present. Treatment includes gastrointestinal decontamination with or without the induction of emesis. Supportive measures and symptom relief should be provided, but physostigmine should be reserved for severe or life-threatening intoxications.

Poison Hemlock The dangers of ingesting poison hemlock (Conium maculata) have been known since ancient times. This was reportedly the method used to execute Socrates. The Old Testament describes rhabdomyolysis in Israelites who ate quail fed on hemlock (coturnism). The highest concentration of toxin is in the root of this plant that may be mistaken for wild carrots. Alkaloid toxins structurally similar to nicotine initially cause CNS activation and general autonomic stimulation. In severe cases, a depressant phase may then ensue, presumably secondary to acetylcholine receptor depolarization blockade. Death is usually secondary to respiratory paralysis.

Water Hemlock Water hemlock (Cicuta maculata) is a highly toxic plant found primarily in wet, swampy areas and is sometimes mistakenly ingested as wild parsnips or artichokes. Although related to poison hemlock, its clinical toxidrome is quite different. The principal toxin, the long-chain aliphatic alcohol cicutoxin, is a highly potent noncompetitive GABA receptor antagonist (Uwai et al., 2000). Symptoms consist of initial gastrointestinal effects (abdominal pain, salivation, and diarrhea) followed by generalized convulsions, obtundation, and coma. Mortality

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TABLE 86.1

Neurotoxicity of Plants

Principal Toxins

Plants (Representative Examples)

Tropane (belladonna) alkaloids

Jimson weed (Datura stramonium); deadly nightshade (belladonna, Atropa Mydriasis, cycloplegia, tachycardia, dry mouth, hyperbelladonna); matrimony vine (Lycium halimifolium); henbane (Hyoscyamus niger); pyrexia, delirium, hallucinations, seizures, coma mandrake (Mandragora officinarum); jasmine (Cestrum spp.) Woody nightshade (bittersweet, Solanum dulcamara); black nightshade (S. nigrum); As above Jerusalem cherry (S. pseudocapsicum); wild tomato (S. gracile); leaves and roots of the common potato (S. tuberosum) Tobacco (Nicotiana spp.); golden chain (Laburnum anagyroides); mescal bean Variable sympathetic and parasympathetic hyperactiv(Sophora spp.); Scotch broom (Cytisus spp.); poison hemlock (Conium maculatum) ity, hypotension, drowsiness, weakness, hallucinations, seizures Water hemlock (Cicuta maculata) Diarrhea, abdominal pain, salivation, seizures, coma Chinaberry (Melia azedarach) Confusion, ataxia, dizziness, stupor, paralysis, seizures Buckthorn (Karwinskia humboldtiana) Ascending paralysis; polyneuropathy Chickling pea and others (Lathyrus spp.); cycad (Cycas rumphii); false sago palm Possible chronic myelopathy with spasticity and motor (Cycas circinalis) neuron degeneration

Solanine alkaloids

Nicotine-like alkaloids (e.g., cytisine) Cicutoxin Triterpene Anthracenones Excitatory amino acid agonists

Main Clinical Features

is secondary to refractory status epilepticus; seizures are treated with standard protocols.

Peyote Peyote (Lophophora williamsii) is a small cactus native to the southwestern United States and Mexico, but it can be cultivated anywhere. The principal agent is mescaline, which has actions similar to those of the hallucinogenic indoles. A peyote button, the top portion of the cactus, contains about 45 mg of mescaline; approximately six to nine buttons are sufficient to be hallucinogenic. Dizziness, drowsiness, ataxia, paresthesias, sympathomimetic symptoms, nausea, and vomiting are frequent accompanying clinical features. Ingestions are rarely life threatening.

Morning Glory The active agents in morning glory (Ipomoea tricolor) seeds are various amides of lysergic acid. The seeds are consumed for purposes of drug abuse. The neuropsychological effects are similar to those of lysergic acid diethylamide (LSD) and consist of hallucinations, anxiety, mood changes, depersonalization, and drowsiness. Acute clinical effects may also include mydriasis, nausea, vomiting, and diarrhea.

Medicinal Herbs Treatment of illness with herbal remedies, either purchased over the counter at health food stores or procured from practitioners of traditional medicine, may lead to undesired toxicity. The labels, if present, may not fully represent the myriad of compounds contained within. Potentially harmful ingredients may be included as contaminants or intentionally added to increase a desired effect. Contamination of products with Atropa belladonna (deadly nightshade), Datura spp., and Mandragora officinarum (mandrake) have been reported. Common herbal preparations such as kava-kava (Piper methysticum) and St. John’s wort (Hypericum perforatum) have neurotoxic potential, particularly if combined with other herbal or standard pharmaceuticals. Mayapple (Podophyllum peltatum), widely used in Chinese herbal medicine, is potentially neurotoxic.

Excitatory Amino Acids Various Lathyrus species, including Lathyrus sativus (chickling pea), Lathyrus clymenum (Spanish vetch), and Lathyrus cicera (flat-podded pea), are responsible for lathyrism. These hardy plants are an important part of the diet of people in India, Africa, China, and some parts of Europe. Epidemics of lathyrism often coincide with periods

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of famine or war, probably a result of excessive dietary dependency on these legumes. The putative toxin is β-N-oxalylamino-l-alanine (l-BOAA), an amino acid with potent agonist activity at the (RS)-αamino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subclass of glutamate receptors. l-BOAA is capable of inducing lathyrism in several animal models. Clinically affected patients present with subacute or insidious onset of upper motor neuron signs and gait instability. Muscle aching and paresthesias may be present, but the sensory examination is largely normal. Cognition and cerebellar functions are spared. Partial recovery after discontinuation of Lathyrus intake is possible, but interestingly, there are reports of deterioration without further exposure many years later. Another excitatory amino acid, β-methylamino-l-alanine (BMAA), is found in cycad seeds, a dietary staple of the Chamorro people of Guam. When given in sufficient quantity, BMAA can induce neurotoxicity in primates. An unusually high incidence of amyotrophic lateral sclerosis, parkinsonism, and dementia was observed in the Chamorros around the Second World War, and it has been postulated that BMAA may play an etiological role (Bradley and Mash, 2009). A causal relationship in humans, however, is difficult to prove.

Mushroom Poisoning Of the more than 5000 varieties of mushrooms, approximately 100 are known to be toxic to humans. Accidental poisoning is common because poisonous mushrooms often closely resemble edible varieties. Aside from accidental ingestion, mushrooms such as Psilocybe spp., Panaeolus, Amanita muscaria, and Amanita pantherina are popular among drug users for their psychoactive effects. The common mushrooms associated with neurological morbidity are listed in Table 86.2. Supportive care and decontamination are the mainstays of treatment. This can be further supplemented by specific treatments such as infusion of pyridoxine (gyromitrin poisoning), atropine (muscarine poisoning), or physostigmine (ibotenic acid and muscimol poisoning) as needed.

MARINE NEUROTOXINS Descriptions of marine food poisoning date back to ancient times. A carving on the tomb of the Egyptian Pharaoh Ti (c. 2700 bc) depicts the toxic danger of the puffer fish. Ciguatera intoxication was known during the T’ang Dynasty (618–907 ad) in China. It was later described by early Spanish explorers and in the journals of Captain Cook’s expedition in 1774 (Doherty, 2005). George Vancouver recognized

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Neurological Diseases and Their Treatment

Poisonous Mushrooms Mushrooms (Representative Examples)

Principal Toxins Monomethylhydrazines (gyromitrin)

Mode of Action

Time of Onset/Main Clinical Features

Gyromitra spp. (“false morels”)

Functional pyridoxine deficiency; GABA deficiency (through decreased GAD activity) Coprinus atramentarius (“inky cap”) and Inhibition of aldehyde dehydrogenase other Coprinaceae (disulfiram-like) Clitocybe and Inocybe genera Cholinergic agonist Amanita muscaria (“fly agaric”), A. GABA receptor agonist; glutamate gemmata, A. pantherina (“the panther”), receptor agonist; anticholinergic A. cothurnata Psilocybe caerulipes, Psilocybe cubenStructural analog of serotonin (5-HT); sis, Panaeolus foenisecii, Gymnophilus actions resemble LSD spectabilis, Psathyrella foenisecii

Coprine Muscarine Isoxazoles (muscimol, ibotenic acid) Indoles (psilocybin, psilocin)

6–10 h: GI symptoms, hemolysis; seizures respond to pyridoxine 20–120 min: Flushing, palpitations, and headache after alcohol ingestion 15–120 min: Cholinergic hyperactivity 30–90 min: Ethanol-like intoxication; euphoria, hallucinations, dysarthria, ataxia, myoclonic jerks, seizures, and coma 30–60 min: Euphoria, hallucinations, mydriasis, tachycardia, seizures (in children)

GI, Gastrointestinal; GABA, γ-aminobutyric acid; GAD, glutamic acid decarboxylase; 5-HT, 5-hydroxytryptamine; LSD, lysergic acid diethylamide.

paralytic shellfish poisoning (PSP) in the Pacific Northwest toward the end of the 18th century. Most marine toxins originate from microorganisms, typically unicellular flagellated algae (dinoflagellates). The proliferation of toxin-producing algae depends on environmental and seasonal factors. During periods of intense algal proliferation (“blooms”), high concentrations of toxins accumulate in fish or shellfish, which then act as transvectors for human disease. Outbreaks may also lead to widespread mortality of fish, shellfish, or marine mammals. One of the algal blooms familiar to residents of the United States is the so-called red tide, which refers to the reddish-brown discoloration of seawater. All the common marine toxins are colorless, tasteless, and odorless. They are often stable to heat, acid, and normal food preparation procedures, making them particularly dangerous to unsuspecting consumers. Many of these toxins affect the Na+ channels in peripheral nerves, causing disorders that range from mild sensory symptoms to life-threatening weakness. The diagnosis depends on a history of ingestion and recognition of the appropriate clinical features. Whenever possible, the contaminated food should be retrieved and tested, as assays for many toxins are available.

Ciguatera Fish Poisoning The ciguatera toxins are produced by algae that thrive in the tropical or subtropical coral reef ecosystem, mainly in the Indo-Pacific and the Caribbean waters between latitudes 35°N and 35°S. The algae are consumed by small herbivorous fish that in turn are eaten by carnivorous ones. As a result, predatory fish such as barracuda, eel, sea bass, grouper, red snapper, and amberjack are likely to be more toxic, although practically any reef fish eaten in significant quantity can cause ciguatera. Outbreaks can also occur in residents of temperate areas after a return from travel or from consumption of imported fish. The prevalence of ciguatera ranges from 0.1% in residents of large continents to 50% or more in those living in South Pacific and Caribbean islands (Dickey and Plakas, 2010). A number of toxins are responsible for ciguatera, including ciguatoxins and maitotoxin. Ciguatoxins are a group of lipid-soluble molecules that act on tetrodotoxin-sensitive voltage-gated Na+ channels in nerve and muscle, leading to increased Na+ permeability at rest and membrane depolarization. Maitotoxin is the most potent nonproteinaceous toxin known. It is a water-soluble compound that increases Ca2+ influx through voltage-independent Na+ channels. Gambierol and palytoxin have also been implicated in ciguatera poisoning.

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Symptoms are typically dose-dependent, with more severe poisonings occurring after consumption of the toxin-rich head, liver, and viscera of contaminated fish. Abdominal pain, nausea, vomiting, and diarrhea first appear within hours of ingestion. Bradycardia and hypotension may accompany the initial acute symptoms. Neurological symptoms then follow (Lewis, 2006). Patients develop centrifugal spread of paresthesias, involving the oral cavity, pharynx, limbs, trunk, genitalia, and perineum. Particularly characteristic is cold allodynia and a paradoxical temperature reversal when cold is perceived as burning, tingling, or unbearably hot. Less frequently, warm is perceived as cold. Headache, weakness, fatigue, arthralgia, myalgia, metallic taste, and pruritus are common. Symptoms may be worsened by alcohol consumption, exercise, sexual intercourse, or diets. Some patients are referred to psychiatrists by clinicians unfamiliar with the disease. Cold allodynia in the distal limbs is a common finding on neurological examination (Schnorf et al., 2002). Some patients have findings of a mild sensory neuropathy. Weakness is generally not present, though rare cases of polymyositis have been reported. Most neurological symptoms remit in approximately 1 week, although some degree of paresthesias, asthenia, weakness, and headache may persist for months to years. Ciguatera can be rarely life threatening, with serious complications such as seizure, coma, and respiratory failure (Chan, 2016). Diagnosis is based on a history of ingestion and the characteristic gastrointestinal, cardiovascular, and neurological disturbances. Clustering of cases in people who consumed the same fish helps with the diagnosis, though there is variation in individual susceptibility. An assay for ciguatoxins in fish is commercially available. Nerve conduction studies may show slowing of both sensory and motor conduction velocities, with prolongation of the absolute refractory, relative refractory, and supernormal periods. Although the chief neurological symptoms are attributable to the peripheral nerves, brain MRI may show reversible white-matter abnormalities (diffusion-weighted imaging [DWI] hyperintensity and apparent diffusion coefficient [ADC] reduction) in the corpus callosum, pyramidal tracts, and cerebellar peduncles (Yalachkov et al., 2019). Gastric lavage may be beneficial if the patient presents soon after ingestion. Intravenous mannitol (20%; 1 g/kg at 500 mL/h) has been used for treatment of acute ciguatera poisoning. The mechanism of action is postulated to be reduction of edema in Schwann cells. The efficacy of mannitol is supported only by uncontrolled case series that report dramatic neurological improvement, especially if mannitol is given soon after symptom onset. One small controlled trial in 50 patients found no difference in outcome between mannitol and saline placebo (Schnorf et al., 2002), although many of the patients were

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treated over 24 hours after symptom onset. Supportive care during acute disease may include fluid replacement, control of bradycardia, and symptomatic treatment of anxiety, headache, and pain. Calcium gluconate, anticonvulsants, and corticosteroids have been tried with varying results. The chronic symptoms of ciguatera poisoning are difficult to treat. Gabapentin, pregabalin, amitriptyline, or other tricyclic antidepressants may provide partial relief of neuropathic pain.

Puffer Fish Poisoning Tetrodotoxin (TTX) is the causative agent in puffer fish poisoning. Puffer fish (family Tetraodontidae) have a worldwide distribution in both fresh and salt waters but are most commonly found in Japan and China. Other sources of TTX include the ocean sunfish, toadfish, parrotfish, Australian blue-ringed octopus, gastropod mollusk, horseshoe crab (eggs), atelopid frogs (skin), newts (genus Taricha), and some salamanders. Imported dried puffer fish has also been reported as a source of poisoning. TTX concentrations are especially high in the skin, liver, roe, and gonads, and relatively low in the muscles. Fugu refers to a preparation of puffer fish in Japan that is considered a delicacy. Specially trained and certified fugu chefs fillet the fish in such a way to avoid contamination by the deadly viscera. Despite these precautions, fugu poisoning accounts for approximately half of the fatal food poisonings in Japan, with up to 50 deaths each year. Tetrodotoxin is a heat-stable, water-soluble small molecule that selectively blocks voltage-gated Na+ channels in excitable membranes. It interferes with the inward (excitatory) flow of Na+ current that occurs during an action potential, blocks impulse conduction in somatic and autonomic nerve fibers, reduces the excitability of skeletal and cardiac muscles, and has profound effects on vasomotor tone and central mechanisms involved in respiration. A dose of 1–2 mg of purified TTX can be lethal. Toxicity has been documented with the consumption of as little as 1.4 ounces (39.69 g) of fugu. Lip, tongue, and distal limb paresthesias appear within minutes to about 2 hours of ingestion. Nausea, vomiting, diarrhea, and abdominal pain are common. Perioral paresthesias and progressive ascending weakness are apparent in moderately severe cases. Dysphonia, dysphagia, hypoventilation, bradycardia, and hypotension develop in severe intoxications. Coma and seizures may be seen. Fatality rates are high in severely affected individuals due to respiratory insufficiency, cardiac dysfunction, and hypotension (Chowdhury et al., 2007). Diagnosis may be made on the basis of the patient’s ingestion history and clinical features on presentation. Liquid chromatography may detect TTX in serum or urine. Electrophysiological tests of nerve excitability sometimes show a characteristic elevation in electrical threshold (Kiernan et al., 2005). There may be mild to moderate slowing of nerve conduction velocities, especially in the sensory nerves and in the more severely affected patients (Liu et al., 2011). Treatment is supportive. Gastric lavage and charcoal are indicated if presentation is early. Neostigmine has been used with anecdotal success. Patients who survive the acute period of intoxication (approximately the first 24 hours) often recover without neurological sequelae.

Shellfish Poisoning Three neurological syndromes result from consumption of shellfish contaminated by toxins: PSP, neurotoxic shellfish poisoning (NSP), and amnestic shellfish poisoning (ASP; James et al., 2010). All of them are primarily associated with the ingestion of bivalve mollusks (clams, mussels, scallops, oysters)—filter feeders that can accumulate toxic microalgae. Rarely, poisoning is seen after consumption of other seafood such as predator crabs that may have eaten contaminated shellfish. Outbreaks are more frequent during the summer months, especially during periods of red tides, but they may occur in any month

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and in the absence of red tides. Shellfish may remain toxic for several weeks after the bloom subsides.

Paralytic Shellfish Poisoning PSP occurs in the United States along the coasts of New England, the Pacific Northwest, and Alaska. It is the most common and most severe of the shellfish intoxications. Mortality rates range from 1% to 12%, with higher rates in areas without advanced life support capabilities. Children appear to be more sensitive than adults. Saxitoxin (STX) is a heat-stable toxin that binds reversibly to voltage-gated Na+ channels in nerve and muscle membrane. Its action is similar to tetrodotoxin. Symptoms usually appear within 30 minutes to 3 hours of ingestion. Paresthesias develop and initially involve the perioral areas, oral cavity, face, and neck. These symptoms spread to the limbs and trunk in severe cases. Other manifestations may include dysarthria, dysphagia, headache, gait ataxia, limb incoordination, ophthalmoplegia, and pupillary abnormality. Despite the name of this syndrome, muscle paralysis does not develop in every patient. If present, weakness may involve muscles of the face, jaw, swallowing, respiration, and the upper and lower limbs. Respiratory paralysis appears within 2–12 hours and is the primary cause of death in PSP. Spontaneous recovery begins after 12 hours and is usually complete within a few days. Weakness, however, may persist for weeks. There is no antidote, and treatment is supportive. Initial diagnosis depends largely on recognizing the history and clinical features. Nerve conduction studies may show reduced amplitude of the sensory and motor-evoked responses and prolonged latencies with slowed nerve conduction velocities. Unlike acute demyelinating neuropathies in which electrophysiological abnormalities lag behind clinical findings, the electrophysiological abnormalities in PSP are most prominent at symptom onset and improve over a few days as clinical symptoms resolve. STX may be detected by high-performance liquid chromatography (HPLC) or enzyme-linked immunosorbent assay (ELISA). A mouse bioassay is commonly employed to monitor commercial shellfish production in many parts of the world. A mouse unit is the minimum amount needed to produce the death of a mouse in 15 minutes. The lethal dose for humans is approximately 5000–20,000 mouse units.

Neurotoxic Shellfish Poisoning NSP is more restricted geographically than PSP and is found primarily in the Gulf of Mexico, the Caribbean Sea, and the waters around New Zealand (Watkins et al., 2008). The responsible toxins are brevetoxins that cause activation of voltage-gated Na+ channels, leading to nerve membrane depolarization and spontaneous action potential firing. These toxins are probably more toxic to wildlife than humans, as red tides from blooms of Gymnodinium breve are typically associated with massive fish, invertebrate, and seabird kills. Clinical presentation is characterized by the simultaneous onset of gastrointestinal and neurological symptoms within minutes to hours after ingestion. Nausea, vomiting, and diarrhea are common. Numbness and tingling appear around the mouth and face, as well as the extremities. Some patients may develop slurred speech, ataxia, headache, and limb weakness. Reversal of hot and cold sensation, similar to that in ciguatera poisoning, has been reported. No human deaths have been associated with NSP. The toxin may be detected by HPLC, radioimmunoassay (RIA), or ELISA are also available. There is also a mouse bioassay.

Amnestic Shellfish Poisoning Amnestic shellfish poisoning (ASP) was first described in 1987 in Canadians who ate blue mussels harvested off the Prince Edward Island coast (Pulido, 2008). Gastrointestinal symptoms were followed by cognitive dysfunction and headache. The putative toxin is domoic

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acid, which has since been found in mussels, clams, and other shellfish in many coastal regions worldwide. Domoic acid is an analog of kainic acid and acts as a potent excitatory neurotransmitter. Neurological disease results from its excitotoxic actions, especially on the limbic system. Symptoms appear within a few hours of ingestion, with diarrhea, vomiting, or abdominal cramps. Roughly half of patients experience headaches, and approximately 25% have memory loss, disorientation, mutism, seizures, myoclonus, or coma. Two patients were reported to have a unique alternating hemiparesis and complete external ophthalmoplegia. Gradual improvement occurs over a 3-month period. Those with residual deficits often have anterograde amnesia with relative preservation of intellect and other higher cortical functions. Some patients develop temporal lobe epilepsy. In the only reported outbreak, the mortality rate was 3%, all occurring in elderly patients. Autopsy

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revealed neuronal loss in the amygdala and hippocampus. Treatment is primarily symptomatic. Diagnosis may be established by the identification of domoic acid with HPLC. A surveillance program is now routine in high-risk regions of the United States and Canada to monitor commercial shellfish operations. Low levels of domoic acid are persistent in some shellfish yearround. In a study of Native Americans in the Pacific Northwest, a high level of consumption of razor clams appeared to negatively impact everyday memory (Grattan, 2018). Further studies are needed to clarify the clinical significance of repeated low-level exposure to domoic acid. The complete reference list is available online at https://expertconsult. inkling.com.

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87 Effects of Drug Abuse on the Nervous System John C.M. Brust

OUTLINE Drugs of Dependence, 1319 Opioids, 1319 Psychostimulants, 1320 Sedatives, 1321 Marijuana, 1322 Hallucinogens, 1323 Inhalants, 1323 Phencyclidine, 1323 Anticholinergics, 1323

Neurological Complications, 1323 Trauma, 1323 Infection, 1323 Seizures, 1324 Stroke, 1324 Cognitive Effects, 1324 Fetal Effects, 1325 Miscellaneous Effects, 1325

Drug dependence is of two types. Psychic dependence (addiction) refers to craving and drug-seeking behavior. Physical dependence refers to an adaptive state in which abrupt cessation of drug use results in somatic withdrawal symptoms. Tolerance refers to the need for increasing doses of a drug to produce a desired effect or to avoid withdrawal. Abuse refers to the perception that use of a drug, or the manner in which it is used, whether licit or illicit, is harmful. Worldwide, numerous drugs, licit and illicit, are used recreationally, resulting in different patterns of intoxication and withdrawal. Symptoms and signs can be confusing. Polydrug users might experience intoxication from one agent while simultaneously withdrawing from another (Brust, 2004). In 2016, a national epidemiological survey of American adults reported a 9.9% lifetime prevalence of DSM-5 drug use disorder (not including ethanol or tobacco) (Grant, 2016).

Desomorphine, a designer opioid, has become increasingly popular in Eastern Europe. Termed “crocodile” for the green-black skin lesions found on parenteral users, the drug is made by cooking crushed codeine pills with household hydrocarbons such as gasoline or paint thinner. Vascular damage causes gangrene and multiorgan failure, and average life expectancy in users is estimated at 2 years (Gahr et al., 2012). Since 2013, undocumented reports of crocodile use in North America have appeared (Grund et al., 2013). Kratom, obtained from a Southeast Asian tree, contains mitragynine, which has opioid-like as well as serotonergic and noradrenergic effects. Usually smoked, Kratom produces stimulatory effects at low doses and opioid effects at higher doses (Rosenbaum et al., 2012). Fatal overdose has been reported (Gershman et al., 2019). At desired levels of intoxication, opioid agonists produce drowsy euphoria, analgesia, cough suppression, miosis, and often a variety of other symptoms and signs (Box 87.2). Taken parenterally or smoked, heroin produces a “rush,” a brief ecstatic feeling followed by euphoria and either “nodding” or garrulous hyperactivity. Heroin overdose causes coma, respiratory depression, and pinpoint but reactive pupils; hypotension, if present, is usually secondary to hypoventilation. Treatment of overdose, including naloxone and ventilator support, depends on the degree of respiratory depression (Box 87.3). Fentanyl, fentanyl analogs, and novel synthetic opioids, some of which are thousands of times more potent than morphine, require larger and often repeated doses of naloxone to reverse respiratory depression. In response to the opioid epidemic, naloxone is now available over the counter as a nasal spray or an auto-injector. Opioid agonist withdrawal produces a characteristic syndrome (Box 87.4). Seizures and delirium are not features, and their presence mandates identification of another cause (e.g., cocaine overdose or ethanol withdrawal). Craving is intense and is not explained by the unpleasantness of the somatic symptoms. Opioid withdrawal in adults is seldom life-threatening and can usually be prevented or treated with methadone 20 mg taken once or twice daily. With morphine or heroin, withdrawal symptoms usually appear several hours after the last dose,

DRUGS OF DEPENDENCE Opioids Opioids include agonists, antagonists, and mixed agonist–antagonists (Box 87.1). In the past, the opioid most often used recreationally was heroin (diacetylmorphine), which is classified by the US Drug Enforcement Agency (DEA) as Schedule I (high potential for abuse, no accepted medical use). Beginning in the 1990s, the United States and other countries experienced a steady rise in the use of prescription opioids to treat chronic noncancer pain (Han et al., 2017; Volkow et al., 2018). There soon emerged an epidemic of recreational use of these products (Walsh and Babalonis, 2017; Vadivelu et al., 2018), which in turn was followed by an epidemic of illicit opioid use, including heroin, fentanyl, and “designer opioids” (principally fentanyl analogs and novel synthetic opioids) (Frisoni et al., 2018; Karila et al., 2019). These agents are often taken with other drugs, including cocaine, benzodiazepines, and ethanol. Of 72,306 drug overdose deaths in the United States during 2017, 84% were opioid-related (Seth et al., 2018; CDC Wonder, 2018).

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BOX 87.1

Neurological Diseases and Their Treatment

Commonly Used Opioids

BOX 87.4

Withdrawal

Agonist Camphorated tincture of opium (paregoric) Morphine Meperidine (Demerol) Methadone Fentanyl Hydromorphone (Dilaudid) Oxycodone Hydrocodone Propoxyphene (Darvon) Heroin

Drug craving Anxiety, irritability Lacrimation Rhinorrhea Yawning Sweating Mydriasis Myalgia, muscle spasms Piloerection Anorexia, nausea, vomiting Diarrhea Abdominal cramps Productive coughing Hot flashes Fever Tachycardia Tachypnea Hypertension Erection, orgasm

Antagonist Naloxone (Narcan) Naltrexone Mixed Agonist–Antagonist Pentazocine (Talwin) Butorphanol (Stadol) Buprenorphine (Buprenex)

BOX 87.2

Acute Effects of Opioid Agonists

“Rush” Euphoria or dysphoria Drowsiness, “nodding” Analgesia Nausea, vomiting Miosis Dryness of the mouth Sweating Pruritus Cough suppression Respiratory depression Hypothermia Postural hypotension Constipation Biliary tract spasm Urinary retention

BOX 87.3

Symptoms and Signs of Opioid

Commonly Used Psychostimulants

BOX 87.5

Dextroamphetamine Methamphetamine Ephedrine Pseudoephedrine Methylphenidate (Ritalin) Pemoline (Cylert) Phenmetrazine (Preludin) Phentermine 3, 4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”) Cocaine Cathinone, methcathinone

Treatment of Opioid Overdose

Respiratory support If hypotension does not respond promptly to ventilation, IV fluids (pressors rarely needed) Consider prophylactic intubation If respiratory depression, naloxone, 2 mg IV, IM, or SC, and then 2–4 mg repeated as needed up to 20 mg. If no respiratory depression, naloxone 0.4–0.8 mg IV, IM, or SC, and if no response, 2 mg repeated as needed Hospitalization and close observation, with additional naloxone as needed Consider additional drug overdose, e.g., alcohol or cocaine

or paregoric. Phenobarbital can be added for intractable seizures or if additional drug withdrawal is suspected. Opioid dependence is treated pharmacologically with maintenance doses of methadone or buprenorphine (Hser et al., 2013; Mattick et al., 2014). Treatment failure is most often attributable to inadequate dosage. Despite US Food and Drug Administration (FDA) approval, oral treatment with the opioid antagonist naltrexone has limited usefulness in treating opioid dependence (O’Connor and Fiellin, 2000; Walley, Wakerman, and Eng, 2019). Proposed alternative therapies include injectable extended-release naltrexone (Krupitsky et al., 2013), slow-release oral morphine (Ferri et al., 2013), injectable heroin (Byford et al., 2013), acupuncture (Cui et al., 2013), and deep brain stimulation (Kuhn et al., 2013). Treatment with the West African hallucinogenic alkaloid ibogaine has been associated with sudden cardiac death (Jalal et al., 2013).

Psychostimulants peak at 24–72 hours, and last a week or two. With methadone, symptoms appear at 12–24 hours and can last several weeks. In newborns, untreated opioid withdrawal is severe, protracted, and often fatal. Seizures and myoclonus are described but can be difficult to tell from jitteriness. Treatment is with titrated doses of methadone

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Psychostimulants comprise a large number of licit and illicit drugs that include cocaine and amphetamine-like agents (Box 87.5). Cocaine is an alkaloid present in the South American plant Erythroxylon coca. Unlike other psychostimulants, cocaine is also a local anesthetic. As a street drug, cocaine hydrochloride is sniffed or

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CHAPTER 87 Effects of Drug Abuse on the Nervous System

Acute Toxic Effects of Cocaine and Amphetamine-Like Psychostimulants

BOX 87.6

Psychiatric Anxiety, insomnia, paranoia, agitation, violence, depression, suicide, hallucinations, psychosis Neurological Dizziness, syncope, vertigo, mydriasis, headache, paresthesias, tremor, stereotypy, bruxism, chorea, dystonia, myoclonus, seizures, coma, ischemic or hemorrhagic stroke Cardiopulmonary Chest pain, dyspnea, palpitations, sweating, pulmonary edema, cardiac arrhythmia, myocardial infarction, cardiac arrest Other Nasal congestion, nausea, vomiting, abdominal pain, fever, chills, myalgia, rhabdomyolysis, myoglobinuria

BOX 87.7

Overdose

Treatment of Psychostimulant

Sedation with intravenous benzodiazepine Oxygen Sodium bicarbonate for acidosis Anticonvulsants Antihypertensives (nitroprusside or α-adrenergic blockers; avoid β-adrenergic blockers) Ventilatory support Blood pressure support Cardiac monitoring and treatment of cardiac arrhythmia Treatment of hyperthermia For rhabdomyolysis: vigorous hydration, sodium bicarbonate

injected. An alkaloidal preparation (“crack”) is smoked, thereby avoiding complications of parenteral use and allowing sustained administration of very large doses. Methamphetamine (“speed,” “crystal meth”) is easily manufactured from commercially available pseudoephedrine. In the United States it is especially popular in midwestern and rural areas. Methamphetamine can be taken orally, sniffed, injected, or, as “ice,” smoked. During 2010 it was estimated that worldwide 17.9 million people were dependent on amphetamine-like psychostimulants and 6.7 million on cocaine (Degenhardt et al., 2014). Intended effects of cocaine and methamphetamine include alert euphoria with increased motor activity and endurance. Taken parenterally or smoked, they produce a rush distinguishable from that of opioids. With repeated use there is stereotypic activity progressing to bruxism and dyskinesias and paranoia progressing to frank hallucinatory psychosis. Cocaine or methamphetamine overdose causes psychiatric, cardiopulmonary, and neurological symptoms, which can progress to shock, coma, and death (Box 87.6). Malignant hyperthermia and disseminated intravascular coagulation occur. Treatment includes sedation, cooling, anticonvulsants, antihypertensives, and cardiac monitoring (Box 87.7). Withdrawal from these agents produces fatigue, hunger, craving, and depression. Objective signs are few, but depression can be suicidal. The phenylalkylamine 3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”), popular on college campuses, appears to combine the psychostimulant properties of amphetamine-related agents and the hallucinogenic properties of drugs such as d-lysergic acid diethylamide (LSD). Many analogs of MDMA are marketed for oral

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use. At low doses, MDMA reportedly facilitates communication and empathy. Undesired effects include anxiety, tremor, muscle tightness, sweating, profuse salivation, blurred vision, and ataxia. As with methamphetamine, overdose causes hypertensive crisis, hyperthermia, tachyarrhythmia, psychosis, delirium, seizures, and rhabdomyolysis. Treatment is similar to that for psychostimulant toxicity. Khat, a shrub indigenous to East Africa and the Arabian Peninsula, contains an amphetamine-like compound, cathinone, and the plant’s leaves are chewed for their stimulant effects. During the past decade “designer” analogs of cathinone have become popular recreational drugs in Europe and North America. Purchased through the Internet as “legal highs” and collectively marketed as “bath salts,” dozens of compounds are available, including methcathinone (ephedrone), mephedrone, methylone, and methylenedioxypyrovalerone (MDPV) (Angoa-Perez et al., 2017; Benzer et al., 2013; Glennon, 2014; Iverson et al., 2014; Miotto et al., 2013; Rech et al., 2015; Valente et al., 2014). Overdose is similar to what is encountered with methamphetamine. Numerous fatalities have been reported (Karila et al., 2019). In addition to cathinone derivative, a wide array of novel designer psychostimulants have appeared on European and North American markets. Chemically characterized as aminoindanes, piperazines, and pipradrol, these agents have varying degrees of noradrenergic, dopaminergic, and serotonergic activity, and some are used as MDMA substitutes in products sold as Ecstasy (Iverson et al., 2014; Rosenbaum et al., 2012; Simmler et al., 2014). Phenylpropanolamine, an amphetamine-like compound, was present in decongestants and diet pills and also available on the Internet as a “legal high” until a case-control study demonstrated it carried a risk for stroke. It was withdrawn from the US market in 2000 (Kernan et al., 2000). Dietary supplements containing ephedra alkaloids (“ma huang”) were available in “health food” stores until stroke and seizure risk led to their withdrawal in 2003 (Haller and Benowitz, 2000). Despite clinical trials involving dozens of agents, an effective pharmacotherapy for psychostimulant dependence does not exist. Studies have involved dopamine, serotonin, opioid agonists and antagonists (Bidlack, 2014), GABAergic agents (modify effects of γ-aminobutyric acid [GABA]), glutamate inhibitors (Li et al., 2013a), sigma receptor ligands (Matsumoto et al., 2014), calcium channel blockers, ketamine (Dakwar et al., 2014), glial modulators (Beardsley and Hauser, 2014), bupropion (Carroll et al., 2014), guanfacine (Fox and Sinha, 2014), metyrapone (Goeders et al., 2014), salvinorin A analogs (Kivell et al., 2014), N-acetylcysteine (Berk et al., 2013; Corbit et al., 2014), orexin antagonists (Merlo Pich and Melotto, 2014), and deep brain stimulation (Yadid et al., 2013).

Sedatives Sedative drugs include barbiturates, benzodiazepines, and miscellaneous products (Chen et al., 2011) (Boxes 86.8–86.10). Intended effects and overdose resemble ethanol intoxication, but respiratory depression is much less with benzodiazepines than with barbiturates. Treatment of overdose includes ventilator support. For severe benzodiazepine poisoning, a specific antagonist flumazenil can reverse coma, but its action is brief and it can trigger seizures. As with ethanol, sedative withdrawal causes tremor, seizures, or delirium tremens; treatment can require intensive care and very high-titrated doses of a benzodiazepine. “Designer benzodiazepines” began appearing early in the 21st century, and it is estimated that worldwide over 3000 such compounds have been synthesized. Biological half-lives of these agents vary widely, and they are difficult to detect using standard assays (Carpenter et al., 2019; Moosman and Auwarter, 2018).

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BOX 87.8

Neurological Diseases and Their Treatment

Commonly Used Barbiturates

Intermediate-Acting Amobarbital Butalbital (only in mixtures, e.g., Fioricet) Short-Acting Pentobarbital Secobarbital Ultra-Short-Acting Methohexital Thiopental

Commonly Used Benzodiazepines

BOX 87.9

Marijuana

Marketed as Tranquilizers Alprazolam Clorazepate Chlordiazepoxide Diazepam Lorazepam Oxazepam Marketed as Hypnotics Flurazepam Temazepam Triazolam Marketed as Anticonvulsants Clonazepam Marketed for Anesthesia Induction and for Treatment of Status Epilepticus Midazolam

Miscellaneous Sedatives

Buspirone Chloral hydrate Paraldehyde Diphenhydramine Ethchlorvynol Glutethimide Hydroxyzine Meprobamate Methaqualone (no longer produced in the United States) Zolpidem (Ambien, Stilnox, Niotal) Zaleplon (Sonata) γ-Hydroxybutyric acid (Xyrem)

γ-Hydroxybutyric acid (GHB) and its precursors, γ-butyrolactone and 1,4-butanediol, are GABAergic sedatives. Classified as Schedule III, GHB is approved in the United States for treating narcolepsy. Notorious as “date-rape” drugs, these agents produce ethanol-like intoxication and withdrawal symptoms.

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Acute Effects of Marijuana

Relaxation, euphoria, jocularity Jitteriness, anxiety, paranoia, panic Depersonalization, subjective time-slowing Dizziness, sensation of floating Impaired coordination and balance Impaired memory and judgment Conjunctival injection, decreased salivation Urinary frequency Tachycardia Systolic hypertension and postural hypotension Bradycardia, hypotension Increased appetite and thirst Decreased intraocular pressure Analgesia Auditory and visual illusions or hallucinations Psychosis

Long-Acting Phenobarbital Barbital Primidone

BOX 87.10

BOX 87.11

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Consisting of leaves and flowers of the hemp plant Cannabis sativa, marijuana is usually smoked but can be eaten. The plant contains more than 60 cannabinoid compounds, of which δ-9-tetrahydrocannabinol (δ-9-THC) is the principal psychoactive ingredient. Hashish, prepared from resin covering the leaves, has a much higher concentration of δ-9-THC. In the United States, pure δ-9-THC (dronabinol) and a close analog (nabilone) are FDA-approved for anorexia and chemotherapy-induced nausea but not for neurological disease (Koppel et al., 2014). A nonpsychoactive cannabinoid, cannabidiol (CBD), is FDAapproved for treating seizures in patients with Dravet or LennoxGastaut syndrome (Gaston and Szaflarski, 2018). A 2014 systematic review from the American Academy of Neurology found evidence for efficacy of oral cannabis extracts containing combinations of δ-9THC and CBD in treating spasticity, central pain, painful spasms, and urinary frequency in patients with multiple sclerosis. Evidence of benefit in a variety of other neurological conditions was lacking, as was evidence of benefit from smoked marijuana in any neurological disorder (Bowen and McRae Clark, 2018; Koppel et al., 2014; Torres-Moreno et al., 2018; Rice and Cameron, 2018). Nonetheless, as of 2018, 30 states and Washington, DC had approved the use of marijuana or cannabinoid compounds for a variety of disorders, most with little or no evidence of efficacy, and putting users in violation of federal law. The discovery of cannabinoid receptors with endogenous ligands in the brain led to the pharmaceutical development of synthetic receptor agonists. A number of these soon became popular recreational agents, marketed as “Spice” and “K2” (Brust, 2013; Seely et al., 2012). Up to 200 times more potent than δ-9-THC, dozens of these compounds, with ever-changing formulations, are available through the Internet. “K2” products are currently the second most popular illicit drug (after marijuana) among US high school students (Johnson et al., 2011). Smoked marijuana produces dreamy euphoria, often with jocularity and disinhibition, plus an array of somatic symptoms (Box 87.11). Sometimes there is dysphoria or panic. Incoordination and impaired judgment increase the risk of traffic accidents, and because δ-9-THC is taken up by fat and slowly released, subtle effects on cognition can last more than 24 hours. High doses cause auditory or visual hallucinations, confusion, and psychosis, but fatal overdose has not been documented. Withdrawal symptoms are usually mild, with headache,

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CHAPTER 87 Effects of Drug Abuse on the Nervous System jitteriness, sleep difficulty, and anorexia, but psychic dependence can be marked. The lifetime dependence risk of marijuana users is 9% but doubles for those who use it before age 17 (Bostwick, 2012; Kilmer, 2017; Volkow et al., 2014). Synthetic cannabinoids (“K2,” “Spice”) frequently produce serious adverse effects, including psychosis, hallucinations, self-mutilation, cardiac arrhythmia, myocardial infarction, vertigo, hypertension, protracted vomiting, convulsive seizures, acute kidney injury, stroke, and death (Adams et al., 2017; Armenian et al., 2017a; Branchoff et al., 2018; Cooper, 2016; Courts et al., 2016; Fattore, 2016; Langford and Bolton, 2018; Mills et al., 2015; Paul et al., 2018; Riederer et al., 2016; Tait et al., 2016). Similarly, withdrawal symptoms are more severe than with marijuana, and dependence liability is greater (Nacca et al., 2013). Synthetic cannabinoids are not identified in toxicology screens, and there is no antidote for overdose.

TABLE 87.1

Hallucinogens

Anesthetics

Dozens of hallucinogenic plants are used ritualistically and recreationally around the world. In the United States, the most popular hallucinogenic agents are the phenylalkylamine mescaline from peyote cactus, the indolealkylamines psilocin and psilocybin from different mushroom species, dimethyltryptamine (DMT) in ayahuasca, and the synthetic ergot LSD (Graddy et al, 2018; Feng et al, 2017; Nichols, 2016). Increasingly popular is the herb Salvia divinorum, which contains the kappa opioid receptor agonist salvinorin A (Pourmand et al., 2018; Ranganathan et al., 2012; Rech et al., 2015; Rosenbaum et al., 2012). Numerous designer hallucinogens are available, with such street names as “Fly” and “Bromodragonfly” (Hill and Thomas, 2011). “2C drugs” are phenylethylamines with hallucinogenic properties (Weaver et al., 2015). Acute effects are perceptual (visual distortions or hallucinations, often formed and elaborately beautiful), psychological (depersonalization or altered mood), and somatic (dizziness, paresthesias, or tremor). Some users experience paranoia or panic, and some have “flashbacks,” a spontaneous recurrence of symptoms in the absence of drug use. High doses can cause seizures or stupor but fatalities are usually attributable to accidents or suicide. Treatment of overdose usually requires no more than calm reassurance. Withdrawal symptoms do not occur.

“Room odorizers”

Inhalants Recreational inhalant use is a worldwide phenomenon, especially popular among children and adolescents. A wide variety of products containing different volatile compounds are available (Table 87.1). Despite chemical diversity, intended effects are similar to ethanol intoxication; symptoms usually last only 30 minutes or so, leading to repeated use over many hours. Overdose can cause respiratory depression, hallucinations, psychosis, seizures, and coma; death has resulted from cardiac arrhythmia, accidents, aspiration of vomitus, and asphyxiation during sniffing from plastic bags. Treatment consists of respiratory and cardiac monitoring. There is no predictable withdrawal syndrome other than craving.

Phencyclidine Developed as an anesthetic, phencyclidine (PCP) was withdrawn because it caused psychosis. As a recreational drug (PCP, “angel dust”), it is easily manufactured by kitchen chemists and usually smoked. Also used recreationally are the related agents ketamine and dextromethorphan (Majlesi et al., 2011). Among a variety of PCP analogs, methoxetamine has a much longer duration of action than ketamine (Corazza et al., 2012).

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Inhalants

Products

Contents

Aerosols

Fluorinated hydrocarbons, propane, isobutane Chlorinated hydrocarbons, naphtha Toluene, acetone, benzene, trichloroethylene, n-hexane, xylene Toluene, methylene chloride, aliphatic acetates Aliphatic and aromatic hydrocarbons Bromochlorodifluoromethane Methane, ethane, propane, butane Many aliphatic and aromatic hydrocarbons Nitrous oxide, diethyl ether, halothane, chloroform, trichloroethylene Amyl, butyl, and isobutyl nitrite

Cleaning fluids, furniture polish Glues, cements Paints, enamels, paint thinners Lighter fluid Fire extinguishing agents Natural gas Petroleum

Low doses of PCP produce relaxation and euphoria, but sometimes dysphoria predominates, and with higher doses symptoms progress to agitation, violent behavior, hallucinations, psychosis, myoclonus, seizures, coma, respiratory depression, and shock. Unlike psychostimulants, PCP reproduces both positive and negative symptoms of schizophrenia, including catatonia. Treatment includes a calm environment, benzodiazepine sedation, and restraints as needed. Psychic dependence occurs but withdrawal symptoms are usually limited to nervousness and tremor.

Anticholinergics Worldwide, a number of plants contain atropine and scopolamine. In North America, Datura stramonium (“jimson weed”) grows abundantly, and ingestion of its seeds (or, less often, leaves and roots) is popular among adolescents. Less often used recreationally are antiparkinsonian anticholinergics and the tricyclic antidepressant amitriptyline. The result is a predictable intoxication that includes delirium, fever, and dilated unreactive pupils. Treatment includes physostigmine, gastric lavage, and, if necessary, anticonvulsants. Neuroleptics, which have anticholinergic properties, are contraindicated, and sedatives should be used cautiously. There is no withdrawal syndrome.

NEUROLOGICAL COMPLICATIONS Trauma Drug intoxication can result in trauma; for example, driving accidents with marijuana, acts of violence with psychostimulants, or self-mutilation with hallucinogens. Among users of illicit drugs, trauma is most often related to the illegal activities necessary to distribute and procure them.

Infection Parenteral drug abusers are subject to local and systemic infections that affect the nervous system. Hepatitis can result in encephalopathy or hemorrhagic stroke. Cellulitis and pyogenic myositis can lead to peripheral nerve damage, vertebral osteomyelitis with radiculopathy or myelopathy, and meningoencephalitis. Tetanus affecting injectors is often severe. Botulism can originate at injection sites or, in cocaine snorters, in paranasal sinuses. Endocarditis, bacterial or fungal, can cause meningitis, brain abscess, infarction, and septic (“mycotic”) aneurysm.

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Drug injection is a major risk factor for human immunodeficiency virus (HIV) infection, and acquired immunodeficiency syndrome (AIDS) in this population is associated with the same neurological complications that affect nondrug users. Especially notable are syphilis and tuberculosis, including drug-resistant forms. Promiscuity and associated sexually transmitted diseases put nonparenteral cocaine users at increased risk for AIDS (DesJarlais et al., 2014; Centers for Disease Control and Prevention, 2018). Progressive myelopathy occurs in parenteral drug users infected with either human T-cell lymphotropic virus (HTLV) I HTLV II. During 2009–10, 199 cases of anthrax, many fatal, were reported in Europe as a result of contaminated heroin (Hanczaruk et al., 2014).

Seizures Some drugs cause seizures as a toxic effect. With amphetamine-like psychostimulants seizures are usually accompanied by other symptoms of intoxication such as fever, hypertension, or delirium. With cocaine, seizures are more likely to occur in the absence of obvious overdose. Cocaine-related seizures have a “kindling” effect—repeated use progressively reduces seizure threshold. Opioids lower seizure threshold, but seizures in someone with heroin overdose mandate search for an alternative cause such as concomitant cocaine intoxication or ethanol withdrawal. Meperidine more often causes seizures or myoclonus, attributable to its metabolite normeperidine. Like ethanol, sedative drugs, including barbiturates, benzodiazepines, and GHB, cause seizures as a withdrawal phenomenon. A case-control study found that marijuana use was protective against the development of incident seizures (Ng et al., 1990). In animals the nonpsychoactive cannabinoid CBD is anticonvulsant. Its efficacy in treating human epilepsy is uncertain.

Stroke Illicit drug users often smoke tobacco or abuse ethanol, increasing their risk for ischemic or hemorrhagic stroke. Parenteral drug abusers are additionally at risk for stroke related to endocarditis, hepatitis, and AIDS. Heroin nephropathy carries risk for stroke. Heroin users are at risk for ischemic stroke in the absence of systemic disease or other stroke risk factors; an immunological mechanism has been proposed (Brust, 2011). Magnetic resonance imaging (MRI) studies in heroin users found reduced perfusion in anterior cingulate cortex, medial prefrontal cortex, and insula (Denier et al., 2013a). Pulse wave analysis revealed “advanced vascular stiffness and ageing” among opioid-dependent subjects compared with controls (Reece and Hulse, 2014). With amphetamine-like psychostimulants (including MDMA) hemorrhagic stroke has occurred in the setting of overdose, often with severe hyperthermia. Ischemic stroke attributed to large- and smallvessel vasculitis is also described in amphetamine/methamphetamine users, although the diagnosis of vasculitis has often been based on angiographic “beading,” a nonspecific sign. Over 600 cases of stroke have been reported in cocaine users, roughly half ischemic and half hemorrhagic (Brust, 2011), and epidemiological data confirm that cocaine is a significant stroke risk factor (Westover et al., 2007). Cerebral vasculitis is rare in cocaine users, in whom hemorrhagic stroke is probably most often caused by hypertensive surges (often with an underlying saccular aneurysm or vascular malformation). Ischemic stroke is most often associated with direct cerebrovascular constriction. Cocaine affects platelets and other coagulation factors, and some of its metabolites are pharmacologically active, plausibly accounting for strokes occurring hours or even days after use.

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Anecdotal reports describe stroke temporally associated with marijuana smoking in young people without other vascular risk factors (Wolff et al., 2013). Marijuana users are also at risk for myocardial infarction and Buerger-like peripheral vascular disease. A population-based study of hospitalized patients reported an adjusted odds ratio of 1.76 for marijuana exposure and ischemic stroke (Westover et al., 2007). Another population survey, adjusting for covariates, found that subjects who used marijuana at least weekly had 4.7 times the rate of stroke compared with nonusers (Hemachrandra et al., 2016). Proposed mechanisms for stroke include postural hypotension with impaired autoregulation, cardioembolism, and reversible cerebral vasoconstriction syndrome. Of 48 consecutive young people with acute ischemic stroke, marijuana use was associated with “multiple intracranial stenosis” in 10 (Wolff et al., 2011). A number of reports describe ischemic stroke in synthetic cannabinoid users (Bernson-Leung, 2014; Brust, 2013; Freemen et al., 2013; Khan et al., 2018; Pacher et al., 2018; Rose et al., 2015; Takematsu et al., 2014). A review of 98 cases of cannabinoid-related stroke (87% ischemic, 8% hemorrhagic) identified 85 following marijuana use and 13 following synthetic cannabinoid use (Wolff and Jouvanis, 2017). LSD and PCP are vasoconstrictive, and ischemic and hemorrhagic strokes have followed use (Brust, 2011).

Cognitive Effects Chronically altered mentation in drug users might be related to ethanol, infection (e.g., AIDS dementia), malnutrition, or trauma. Determining whether the drugs themselves cause lasting cognitive or behavioral abnormality has been difficult; intoxication or withdrawal effects can persist for uncertain durations, and baseline cognitive performance prior to drug use is seldom available. A meta-analysis of studies addressing “neuropsychological consequences of chronic opioid use” (including prescription analgesics and methadone maintenance therapy) identified significant impairments in verbal working memory, verbal fluency, and “cognitive impulsivity,” but the authors stressed methodological problems in the studies reviewed (Baldacchino et al., 2012). Structural and functional imaging studies have demonstrated reduced cerebral gray-matter density and decreased white-matter fractional anisotropy in heroin users (Bora et al., 2012; Denier et al., 2013a, 2013b; Goldstein and Volkow, 2011; Guihua et al., 2013; Li et al., 2013a, 2013b; Qiu et al., 2013a, 2013b; Wang et al., 2012, 2013; Yuan et al., 2009; Wollman et al., 2015). Abnormal connectivity patterns are described in both heroin users (Liu et al., 2009) and recreational users of oxycodone and hydrocodone (Upadhyay et al., 2010). In animals and humans, dextroamphetamine damages dopaminergic nerve terminals, methamphetamine damages both dopaminergic and serotonergic nerve terminals, and MDMA damages serotonin nerve terminals. The effects are partially reversible, but regeneration can lead to aberrant pathways. Abnormal cognition and behavior, as well as functional MRI abnormalities, are described in methamphetamine and MDMA users (Murphy et al., 2009). In a study of MDMA, subjects were matched on neuropsychological testing and functional imaging prior to taking up drug use and re-examined after 12–36 months. Those who had used MDMA during that interval, even in small doses, had decreased verbal memory and abnormal fractional anisotropy in the thalamus, globus pallidus, and cerebral white matter (deWin et al., 2008). Serotonin transporter binding was decreased in the cerebral cortex of abstinent MDMA users who, although “grossly behaviorally normal,” demonstrated abnormalities on trials of attention, memory, and executive function (Kish et al., 2010).

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CHAPTER 87 Effects of Drug Abuse on the Nervous System Cocaine is not neurotoxic to axon terminals, but cognitive impairment is described. High doses of cocaine decrease hippocampal neurogenesis and impair working memory in rats (Sudai et al., 2011). Lasting cognitive impairment and structural alterations in frontostriatal systems are described in heavy cocaine users (Ersche et al., 2011; Lucantonio et al., 2012; Tau et al., 2014). Cocaine-treated rats demonstrate abnormal dendritic spines on neurons in the nucleus accumbens, and in both rodents and humans, diffusion tensor imaging shows abnormal fractional anisotropy in cerebral white matter (Moeller et al., 2007; Narayana et al., 2009; Shen et al., 2009; Wang et al., 2013). Rhesus monkeys self-administering cocaine developed abnormal central nervous system (CNS) myelin composition (Smith et al., 2014). Reduced resting state functional connectivity between amygdala and prefrontal cortex predicted relapse in abstinent cocaine addicts (McHugh et al., 2014). Reduced frontal gray matter volume and increased striatal volume are described in users of either cocaine or amphetamine (Crunelle et al., 2014; Ide et al., 2014; Mackey and Paulus, 2013; Moreno-Lopez et al., 2012). In rodents, cocaine alters N-methyl-d-aspartate (NMDA) receptor subunit composition and redistributes the assembled protein at the synapse (Ortinski, 2014). A meta-analysis of neuroimaging studies in “stimulant-dependent individuals” found consistent reduction of prefrontal gray matter,” which was plausibly linked to impaired “self-regulation and self-awareness.” Direction of causality, however, remained open to question (Ersche et al., 2013). A review of studies describing the long-term cognitive effects of cocaine concluded, “The current evidence does not support the view that cocaine use is associated with broad cognitive deficits” (Frazer et al., 2018). Another review during the same period concluded, “Long-term effects of cocaine show a wide array of deteriorated cognitive function” (Sprunk et al., 2018). Clinical, imaging, and animal studies provide persuasive evidence that marijuana and synthetic cannabinoid use, especially during adolescence, causes lasting behavioral and cognitive alteration (Batalla et al., 2013; Battistella et al., 2014; Broyd et al., 2016; Brust, 2012; Bolla et al., 2002; Cohen and Weinstein, 2018; Davidson et al., 2017; Gilman et al., 2014; Greydenus et al., 2013; Hall, 2015; Pujol et al., 2014; Steel et al., 2014; Volkow et al., 2014). In the New Zealand Dunedin cohort study, which followed individuals from birth to age 38 years, heavy marijuana use by adolescents and young adults was associated with neuropsychological decline across multiple domains of functioning. The most persistent users had an average IQ drop of eight points from childhood to adulthood, and impairment was still evident after cessation for a year or more (Meier et al., 2012). Functional imaging during testing of executive function found abnormal patterns of activation after several weeks of abstinence from marijuana (Bolla et al., 2005; Eldreth et al., 2004). Diffusion-weighted MRI and connectivity mapping identified microstructural alterations affecting axonal pathways in long-term marijuana users (Pujol et al., 2014). Volume reductions in brain regions rich in CB1 receptors have also been observed (Battistella et al., 2014; Gilman et al., 2014). Animal studies have reproduced such findings (Steel et al., 2014; Verrico et al., 2014). Epidemiological studies offer compelling evidence that marijuana is a significant risk factor for schizophrenia (Le Bec et al., 2009; van Winkel and Kuepper, 2014). Sedative drugs cause reversible dementia in the elderly and delayed learning in small children. Controversial is whether psychostimulants predispose to depression or whether PCP predisposes to schizophrenia. Leukoencephalopathy and dementia are described in toluene sniffers. Lead encephalopathy is described in gasoline sniffers.

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Fetal Effects Adverse effects of in utero exposure to drugs are difficult to disentangle from inadequate prenatal care, concomitant ethanol or tobacco, malnutrition, and home environment. Fetal exposure to prescription opioids is associated with decreased gestational size, respiratory distress, and, later, cognitive impairment (Broussard et al., 2011). In utero exposure to methamphetamine is significantly associated with restricted fetal growth, depressed arousal in neonates, and in older children, lower verbal memory, spatial memory, working memory, attention, and visual-motor integration. Lasting metabolic and structural changes affect frontostriatal circuitry (Roussotte et al., 2011; Thompson et al., 2009). A 10-year prospective study controlling for such confounders as additional drugs and environmental influences concluded that first trimester exposure to cocaine conferred risk for reduced height, weight, and head circumference and for lower sociability and increased withdrawn behavior (Richardson et al., 2013). A systematic review of 27 studies concluded that prenatal cocaine exposure “increases the risk for small but significantly less favorable adolescent functioning,” including behavior, language, and memory. Eight studies reported morphological abnormalities of brain structure (Buckingham-Howes et al., 2013). A meta-analysis of studies of newborns exposed to cocaine found “clear evidence that crack cocaine contributes to adverse perinatal outcome,” including reduced head circumference (dos Santos et al., 2018). A review of “congenital cocaine syndrome” concluded, “…maternal cocaine use during pregnancy…is associated with a host of neurological and developmental abnormalities in the offspring,” including microcephaly, perinatal cerebral infarction, brain abnormalities on MR diffusion tensor imaging, and lower volumes of cortical grey matter (Todd et al., 2018). Human and animal studies offer evidence that in utero exposure to marijuana carries risk for later cognitive impairment (Dinieri and Hurd, 2012; Gilbert et al., 2016; Richardson et al., 2016). Long-term cohort studies have demonstrated impaired performance on tasks of attention and visual memory as well as greater impulsivity and smaller head size, persisting into adolescence (Fried et al., 2002, 2003; Richardson et al., 2002). In animals, prenatal exposure disrupts cortical development by interfering with cytoskeletal dynamics critical for axonal connectivity between neurons (Tortoriello et al., 2014). A literature review concluded that although marijuana use is not teratogenic in the sense of causing morphological abnormalities, it does have negative long-term effects on executive functioning (Grant, 2018). Organic solvents are teratogenic in animals.

Miscellaneous Effects Guillain-Barré polyneuropathy and brachial or lumbosacral plexopathy, probably immunological in origin, are described in heroin users. Severe axonal sensorimotor polyneuropathy affects sniffers of glue containing n-hexane. Rhabdomyolysis, myoglobinuria, and renal failure have followed use of heroin, psychostimulants, and PCP (as well as ethanol) (Adrish et al., 2014). Myeloneuropathy indistinguishable from cobalamin deficiency and combined systems disease affects sniffers of nitrous oxide. Vitamin B12 levels are often normal. The mechanism is inactivation of the cobalamin-dependent enzyme methionine synthetase. Severe irreversible parkinsonism affected Californians exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), an unintended by-product in the manufacture of a synthetic meperidine-like opioid.

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“Chasing the dragon” consists of heating heroin mixture on metal foil and inhaling the fumes. Such practice is associated with dementia, ataxia, dystonia, quadriparesis, blindness, and death as a result of a spongiform leukoencephalopathy most often affecting the posterior cerebrum and internal capsule. The responsible toxin has never been identified (Cordova et al., 2014; Alambyan et al., 2018). A similar spongiform encephalopathy has infrequently been reported from intravenous heroin (Pirompanich and Chankrachang, 2015). Refractory hydrocephalus is also described in dragon chasers (Bui et al., 2015). Irreversible extrapyramidal symptoms, including bradykinesia and dystonia, are described in users of methcathinone, a result of exposure to potassium permanganate used in preparing the drug (Steppins et al., 2014). Blindness occurred in a heroin user whose preparation contained large quantities of quinine. Cocaine users develop extrapyramidal symptoms progressing from repetitive stereotypic behavior (“punding”) to choreoathetosis and dystonia. Cocaine can precipitate or aggravate symptoms of Tourette syndrome (Brust, 2010). Marijuana inhibits follicle-stimulating and luteinizing hormones, causing reversible erectile dysfunction in men and menstrual irregularity in women.

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Toluene sniffers develop cerebellar white-matter lesions and ataxia. Sensorineural hearing loss has followed overdose with either heroin or methadone (Aulet et al., 2014; Saifan et al., 2013). Hallucinogen users not only experience flashbacks but also the visual phenomena—geometric shapes, objects in the peripheral field, flashes of color, enhanced color sensitivity, trailing and stroboscopic perception of moving objects, after images, halos, and macro/micropsia— can persist for years (“hallucinogen-persisting perception disorder”) (Hermle et al., 2012). US cocaine samples are frequently adulterated with the immunomodulatory drug levamisole, which has an amphetamine-like metabolite and causes leukopenia and vasculitis (Baptiste et al., 2015; Le Graff et al., 2016). An associated leukoencephalopathy has been described in a number of cocaine users (Cascio and Jun, 2018). The vitamin K anticoagulant brodifacoum, present in rodenticides, is a common adulterant in preparations of synthetic cannabinoids. Coagulopathy and spontaneous intracranial hemorrhage have been reported (Kelkar et al., 2018). The complete reference list is available online at https://expertconsult. inkling.com/.

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88 Brain Edema and Disorders of Cerebrospinal Fluid Circulation Gary A. Rosenberg

OUTLINE Brain Edema and Disorders of Cerebrospinal Fluid Circulation, 1327 Blood–Brain Interfaces, 1328 Cerebral Blood Vessels and the Neurovascular Unit, 1328 Production of Cerebrospinal Fluid and Interstitial Fluid, 1331 Water Molecules: Basis for Magnetic Resonance Imaging, 1331 Anatomical Sites of Central Nervous System Infection, 1331 Gap Junctions on Ependymal and Pial Surfaces, 1332 Arachnoid Granulations and Absorption of Cerebrospinal Fluid, 1332 Cerebrospinal Fluid Pressure, 1332 Composition of the Cerebrospinal Fluid, 1333 Brain Edema, 1333 Molecular Cascade in Injury, 1333 Neuroinflammation and Vasogenic Edema, 1333

Cytotoxic Brain Edema, 1334 Effect of Blood Pressure and Osmolality Changes on Brain Edema, 1335 Edema in Venous Occlusion and Intracerebral Hemorrhage, 1336 High-Altitude Cerebral Edema, 1338 Treatment of Brain Edema, 1338 Idiopathic Intracranial Hypertension, 1339 Clinical Features, 1339 Treatment, 1340 Brain Edema in Idiopathic Intracranial Hypertension, 1340 Hydrocephalus, 1340 Hydrocephalus in Children, 1340 Adult-Onset Hydrocephalus, 1341 Normal-Pressure Hydrocephalus, 1342

BRAIN EDEMA AND DISORDERS OF CEREBROSPINAL FLUID CIRCULATION

Cellular membranes preserve the compartmental structure with water in extracellular and intracellular spaces. When shifts in water from one compartment to another occur under pathological conditions, swelling in the various compartments leads to increased ICP. If the increased water is blocked from exiting the ventricles, hydrocephalus results with transependymal flow of water into the periventricular white matter, resulting in interstitial edema. Loss of energy stores results in cell swelling due to failure of the membrane pumps, which is called cytotoxic edema. Damage to blood vessels leads to leakage of fluid, which expands extracellular space with intact cell membranes, leading to vasogenic edema (Higashida et al., 2011; Simard et al., 2007). Hypoxia/ischemia and brain trauma initiate a series of molecular events that ultimately lead to cell death. Several molecules play key roles in the injury cascade: aquaporin forms pores in membranes that facilitate passive water movement; hypoxia inducible factor-1α (HIF1α) is another key molecule that plays a key role in brain injury and repair by activating a cassette of inflammatory and repair-promoting genes (Agre et al., 2003; Semenza, 2014). Cytokines, proteases, and free radicals amplify the tissue damage. Advances in magnetic resonance imaging (MRI) have improved the diagnosis of CSF disorders and brain edema. Although we understand the underlying molecular processes involved in edema formation and have better ways of observing its evolution, treatment of brain edema remains a major challenge. Brain edema represents a serious, often life-threatening consequence of many common brain disorders, including stroke, trauma, tumors, and infection. Early anatomists realized that the bony skull provided a rigid case that prevented expansion of the contents inside the skull and that such an expansion causes increases in ICP. Herniation

Increased intracranial pressure (ICP) and cerebral edema are life-threatening complications of shifts in water between cells and tissue that are final common pathways of injury in many neurological disorders. Separation of brain fluids from blood is maintained by a complex series of interfaces between the blood and brain tissues with the major one referred to as the neurovascular unit (NVU). The cerebrospinal fluid (CSF) is continuously formed mainly at the choroid plexus and absorbed at the arachnoid granulations. The interstitial fluid (ISF) bathes the brain cells delivering nutrients and removing waste. Early investigators realizing that the brain lacked a true lymphatic drainage system recognized that the ISF functioned as the lymphatic system and that the CSF and ISF were a continuous fluid. In 1925, Cushing and Weed named this the “third circulation” elevating it to the level of blood and lymph fluid. In 1885, Ehrlich injected blue dye into the bloodstream of mice. The dye stained all of the animals’ organs blue—except their brains. In a follow-up experiment in 1913, one of Ehrlich’s students injected the same dye directly into the brains of mice. This time, the brains turned blue, whereas the other organs did not. From these early studies the concept of a blood–brain barrier (BBB) emerged. It is now well established that at all the interfaces between the blood and brain tissues there are specialized proteins that form tight junctions. In addition to the tight junctions, the NVU has carrier molecules and electrolyte pumps to preserve the fluid balance, provide nutrients, and remove waste materials from metabolism (Iadecola et al., 2007).

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TABLE 88.1

Neurological Diseases and Their Treatment

Causes of Increased Intracranial Pressure

Site of Increased Intracranial Pressure

Diseases

Increased tissue volume Increased blood volume Cytotoxic edema Vasogenic edema Interstitial edema

Tumor, abscess Hypercapnia, hypoxia, venous sinus occlusion Ischemia, trauma, toxins, metabolic diseases Infections, brain tumors, hyperosmolar states, inflammation Hydrocephalus with transependymal flow

of brain tissues at several sites occurs when there is an increase in any of the three main brain compartments: brain tissue, blood, or CSF. Brain tumors and space-occupying infections damage cells because the mass distorts the surrounding tissues by compressing vital regions of the brain. Cell injury that occurs in cerebral ischemia, hypoglycemia, and some metabolic disorders causes tissue damage via cell swelling or breakdown of the BBB. It is important to appreciate the physiology of brain fluids as a basis for understanding the pathological changes encountered in clinical practice. The human nervous system has evolved mechanisms to provide a stable microenvironment for the normal functioning of neurons and other cells. The electrolyte and protein contents of the brain fluids are normally kept within a constant range, which differs greatly from the systemic circulation of blood and lymph. The key to maintaining this privileged environment is a series of interfaces at each of the sites of potential brain and blood interaction. Interfaces formed by endothelial cells, choroid plexuses, ependymal cells, and arachnoid have tight-junction proteins that restrict the transport of nonlipid soluble substances and large protein molecules. In the major site formed by the endothelial cells, other components are important, including astrocytes, pericytes, and the basal lamina. Energy is expended at these interfaces to preserve this balance, and functions that are unique to the brain have evolved to provide for a constant delivery of oxygen and glucose to brain cells as well as the removal of metabolic products. CSF fills the cerebral ventricles and subarachnoid spaces around the brain and spinal cord, serving along with the fluid between the cells, ISF, as a lymph-like fluid for brain tissue. ISF circulates between cells, draining into the CSF in the ventricle and subarachnoid space. Water moves into the extracellular space along osmotic gradients created at the capillary abluminal surface by the exchange of three sodium molecules for two molecules of potassium through the action of the sodium/ potassium-triphosphatase (Na+/K+-ATPase) pump. Once within the ventricles, CSF/ISF circulates through the foramina of Magendie and Luschka to return to the systemic circulation at the sagittal sinus by way of one-way valves at the arachnoid granulations. Examination of the CSF by lumbar puncture (LP) can provide unique information, aiding diagnosis and patient management. Increased ICP can only be determined by measurements made during removal of CSF; this information is critical in the diagnosis of raised CSF pressure in idiopathic intracranial hypertension (IIH). Studies of cells and proteins in the CSF provide information about infection and inflammation. Cancer cells can be detected and antibodies to infectious agents identified. When the BBB is disrupted, increased blood-derived proteins, mainly albumin that is produced in the liver, move into the CSF. Albumin levels in the blood are in the range of 3–5 g/dL, and in the CSF they are normally 15–60 mg/dL. CSF is critical in diagnosis of brain infection, such as meningitis, and in selection of appropriate treatment. Detection of cells in the CSF aids in the diagnosis of neuroinflammation. Detection of proteins in the CSF is important in the diagnosis of multiple sclerosis (MS): there are increased levels of myelin basic protein along with immunoglobulin (Ig)G endogenous production, which is expressed as an IgG index that is formed by dividing CSF albumin into IgG. When it

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is elevated, it suggests the IgG is formed in the brain rather than transported into the CSF across a damaged BBB. Patients with Alzheimer disease have low levels of amyloid-β1-42 (Aβ1-42), and elevated levels of phosphorylated tau. The ratio of Aβ1-42/Aβ1-40 is more accurate in identifying Alzheimer’s disease (AD) patients (Janelidze et al., 2016). Thus, LP to obtain CSF is one of the most cost-effective procedures in daily clinical practice, and when done correctly, it can provide critical diagnostic information that is only available from CSF. The recognition that the total volume of fluid and tissue contained within the skull of an adult is constant is called the Monro–Kellie doctrine, named after two early anatomists. Changes in volume of blood, CSF, or brain compartments produce compensatory changes in the others, with a resultant increase in CSF pressure. When CSF outflow pathways are blocked, enlargement of the ventricles or hydrocephalus follows, resulting in a buildup of pressure in the ventricles that forces the CSF to move transependymally into the periventricular white matter (Rosenberg et al., 1983). Masses enlarge the tissue space and compress CSF and blood spaces. When the compensatory mechanisms are overwhelmed, ICP increases and herniation of brain tissue occurs. Disruption of the blood vessels leads to vasogenic edema that moves through the more compliant extracellular space of the white matter. HIF-1α is another novel molecule that plays a key role in brain injury and repair matter. Finally, an increase in blood volume, as seen in hypercapnia and hypoxia, increases the ICP (Table 88.1).

BLOOD–BRAIN INTERFACES Cerebral Blood Vessels and the Neurovascular Unit The large surface area of capillary endothelial cells forms the major interface between the blood and brain. Other, less-extensive, interface surfaces include choroid plexuses and arachnoid granulations (Table 88.2). At each of the BBB interfaces, high-resistance junctions between cells, which make the surface into an epithelial-like structure, restrict transport. The epithelial sheets impede nonlipid-soluble substances, charged substances, or large molecules, whereas lipid-soluble substances, such as anesthetic gases and narcotics, pass easily through the cells. Water has an anomalous structure that allows it to pass rapidly through endothelial cells but with slight restrictions (Raichle et al., 1974). ISF surrounds brain cells. It is formed by capillaries via an active transport mechanism. It is similar in composition to CSF and circulates. This lymph-like ISF fluid is formed by cerebral blood vessels, which have electrolyte pumps that make fluid in a fashion similar to that of the epithelial cells. Flowing around cells, ISF brings nutrients such as glucose and oxygen to neurons and astrocytes and removes the products of metabolism. ISF is absorbed either into the blood via terminal capillaries and venules or into CSF for eventual absorption through the arachnoid granulations (Fig. 88.1). CSF from the subarachnoid space moves rapidly into the brain along paravascular routes surrounding penetrating cerebral arteries, exchanging with ISF and facilitating the clearance of interstitial solutes, which may be driven by arterial pulsation (Iliff et al., 2013). Measurements of movement of ISF

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TABLE 88.2

Brain Edema and Disorders of Cerebrospinal Fluid Circulation

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Characteristic Features of the Blood–Brain Interfaces

Interface

Tight-Junction Location

Functional Aspects

Blood–CSF CSF–blood Blood–brain

Choroid plexus cell Arachnoid membrane Capillary endothelial cell

Active secretion of CSF via ATPase and carbonic anhydrase Arachnoid granulations absorb CSF by one-way valve mechanism Active transport of ISF via ATPase; increased mitochondria and glucose transporters in capillary endothelial cells

ATPase, Adenosine triphosphatase; CSF, cerebrospinal fluid; ISF, interstitial fluid.

CSF

Neuropil

SDS

Na+

Na+

TJ

ISF

H2O

Arterial blood

Skull

SAS

Stroma

TJ

Na+ H2O

Venous sinus

TJ GJ

Choroid plexus

Capillary

GJ

Dura

PIA Arachnoid Ependyma Fig. 88.1 Illustration of the Third Circulation. Cerebrospinal fluid (CSF) is formed by the choroid plexuses in the ventricles, and interstitial fluid (ISF) is formed by cerebral capillaries. At both sites, the action of the Na+/ K+-ATPase pump creates the osmotic gradient that pulls water from the blood. Tight junctions (TJ) are found at each site of blood–brain interface. This includes the apical surface of the choroid plexus epithelial cells, the cerebral endothelial cells, and the arachnoid. Substances move between the brain and CSF across the gap junctions (GJ) on ependymal and pial surfaces. SAS, Subarachnoid space; PIA, pia mater; SDS, subdural space.

made with MRI indicate that inspiration facilitates the flow of ISF by its effect on the veins. Studies in mice have shown an influence of arterial pulse pressure on the movement of ISF into and out of the brain, but these studies need to be replicated in higher mammals. Brain extracellular space comprises 15%–20% of the total brain volume. Complex carbohydrates are found in the extracellular space, including hyaluronic acid, chondroitin sulfate, and heparan sulfate. Hyaluronic acid forms large water domains. These large extracellular matrix glycoproteins impede cell movement. After an injury, astrocytes secrete an extracellular molecule, hyaluron, which impedes movement of fluids in the extracellular space, slowing tissue repair. Treatment with hyaluronidase reduces hyaluron and improves regrowth of injured fibers (Back et al., 2005). Proteases are secreted during development, angiogenesis, and neurogenesis to clear a path for the growing cells, similar to the secretion of proteases by spreading cancer cells (Yong et al., 2001). Rather than a unitary endothelial BBB, transport between blood and brain is modulated by neurons, astrocytes, pericytes, and endothelial cells, forming an NVU. On the abluminal surface of the endothelial cells is a basal lamina composed of type IV collagen, fibronectin, heparan sulfate, laminin, and entactin. Entactin connects type IV collagen and laminin to add a structural element to the capillary. Fibronectin from the cells joins the basal lamina to the endothelium. Basal lamina provides structure through type IV collagen, charge barriers by heparan sulfate, and binding sites on the laminin and fibronectin molecules. Pericytes are embedded in the basal lamina; they are a combination of smooth muscle and macrophage. Pericytes are important in preserving the BBB. Loss of pericytes occurs in a number of neurodegenerative diseases (Bell et al., 2010). Astrocyte foot processes form a layer that surrounds the basal lamina. Glia limitans is found at the pial surface and at the interface between astrocytes and blood vessels (Owens et al., 2008; Fig. 88.2).

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Cerebral blood vessels have very low permeability and high electrical resistance, making them more similar to epithelial cells than systemic capillaries, which are passive structures with low electrical resistance and fenestrations that permit passage of large protein molecules. In addition, cerebral blood vessels have highly selective molecular transport properties. During development, cerebral blood vessels acquire the characteristics that distinguish them from systemic capillaries. Astrocytes are critical in this differentiation process, which involves interactions between blood vessels and astrocytes. The critical nature of the astrocytes in this process was shown in transplantation studies involving chicken and quail cells, which can be separated histologically. Quail brain grafts from 3-day-old quails transplanted into the coelomic cavity of chick embryos become vascularized by chick endothelial cells and form a competent BBB. On the other hand, when avascular embryonic quail coelomic grafts are transplanted into embryonic chick brain, chick endothelial cells form leaky capillaries and venules (Stewart et al., 1981). Astrocytes are critical in the differentiation process (Janzer et al., 1987). At the interface between the systemic circulation and brain cells there are specialized proteins that form the poorly permeable vessels. Tight-junction proteins have been isolated and cloned, permitting immunocytochemical studies of their location in the endothelial cells. Zona occludins tether the tight-junction proteins to actin within the endothelial cells; occludin and claudin form the actual tight junctions within the endothelial clefts. Occludin attaches to the zona occludins, while claudins attach to occludin and protrude into the clefts between cells. The extracellular tails of claudins from adjacent cells self-assemble to form the tight junctions that are “zip-locked” together (Hawkins et al., 2005). During an ischemic injury, the tight junction proteins are degraded, contributing to the disruption of the BBB (Yang et al., 2018). Tight junctions between the endothelial cells create the unique membrane properties of the cerebral capillaries by greatly increasing

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Astrocyte foot process

Pericyte AA

TJ Nuc

GT Basal lamina Type IV collagen Fibronectin Laminin Heparan sulfate

2K+ ATPase

Proteases H2O 3Na+ Free radicals Fig. 88.2 The Cerebral Capillary Is a Fluid-Secreting, Epithelial-Like Cell with a High Metabolic Rate. The Na+/K+-ATPase pump on the apical surface forms cerebrospinal fluid. Tight junctions (TJ) between the endothelial cells maintain the electrical resistance. A large number of mitochondria are seen in the capillary. Amino acid and glucose transporters are present. Around the cell is a basal lamina composed of type IV collagen, laminin, fibronectin, and heparan sulfate. Astrocytic end-feet surround cells. Pericytes, which are embedded in the basal lamina, are macrophage-like cells that have macrophage and smooth-muscle functions in the perivascular space.

BOX 88.1

Capillaries

Unique Features of Cerebral

Tight junctions create high electrical resistance Adenosine triphosphatase pumps on abluminal surfaces form interstitial fluid Increased numbers of mitochondria for high-energy needs Glucose transporters and amino acid carriers Basal lamina contributes to the barrier Pericytes act as perivascular macrophages Astrocytes maintain the tight junctions

electrical resistance, blocking transport of nonlipid-soluble substances (Box 88.1). Brain tissue has a very high demand for glucose and essential amino acids, which can be met by specialized molecules that transport glucose and amino acids across the BBB. Glucose transporters are densely distributed in the capillaries. At low levels of blood glucose, the carrier proteins function at full capacity to meet metabolic needs, but at higher levels of blood glucose, the carriers are saturated, and transport is dominated by diffusion rather than active transport (Vannucci et al., 1997). High concentrations of one isoform, GLUT1, are found on cerebral blood vessels. GLUT3 is found on neurons and GLUT5 in microglia. GLUT2 is found predominantly in the liver, intestine, kidney, and pancreas. Amino acid transporters carry essential amino acids into the brain. Competition for the amino acid transporters can lead to a deficiency state; serotonin uptake is decreased in patients with phenylketonuria, which competes for the transporter. Steady-state levels of brain electrolytes are preserved by transport mechanisms at the BBB. Potassium is maintained at a constant level in the CSF and brain by the BBB. This prevents fluctuations of electrolyte levels in the blood from influencing brain levels. Calcium is similarly regulated. Glutamate, which is an excitotoxin, is excluded from the brain. Highly lipid-soluble gases such as carbon dioxide

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and oxygen are rapidly exchanged across the capillary. Anesthetic gases are effective because they readily cross the BBB and enter the brain. The presence of the BBB creates a major impediment for the transport of drugs into the brain. For example, penicillin is restricted from entry into the brain; high doses are needed to achieve therapeutic brain levels. Newer generations of antibiotics, such as the cephalosporins, penetrate more readily, making them better agents for treatment of brain infections. Chemotherapy of brain tumors has been hampered by the poor lipid solubility of most agents; to overcome this impediment, chemotherapeutic agents can be injected intrathecally or into catheters implanted into the ventricles, with injection bulbs buried beneath the scalp. Drugs of addiction are often modified to allow them to more readily cross the BBB. For example, heroin, which is derived from morphine, has increased lipid solubility, which enhances its transport into the brain. Similarly, other addictive substances, such as nicotine and alcohol, are highly lipid soluble and easily transported into brain. Different rates for equilibration of various substances between blood and brain can cause paradoxical clinical situations. For example, to compensate for a metabolic acidosis, bicarbonate levels fall in both the blood and the brain. Metabolic acidosis is balanced by a respiratory alkalosis due to lowering of carbon dioxide by hyperventilation, which compensates for the acidosis; carbon dioxide is reduced in both the blood and CSF compartments, since it readily crosses the BBB, while bicarbonate is much more slowly exchanged between the two compartments. This adjustment results in a stable, albeit pathological, situation. However, when the metabolic acidosis is corrected by intravenous infusion of bicarbonate, there is a rapid adjustment of Pco2 as the hyperventilation stops and CO2 builds up. Bicarbonate adjusts very slowly because of the limited transport across the BBB, and the CO2 entering the brain causes a further fall in brain pH. This dangerous situation continues until the bicarbonate levels in the brain rise. Although treatment is necessary to correct the metabolic acidosis, patients may become worse due to brain acidosis if treatment is too rapid (Posner et al., 1967).

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Brain Edema and Disorders of Cerebrospinal Fluid Circulation

Production of Cerebrospinal Fluid and Interstitial Fluid Production of brain fluids comes from multiple sources including the choroid plexuses within the ventricles, the electrolyte pumps on the abluminal surface of the cerebral capillaries, and metabolism. The main source is the choroid plexuses, which form an important interface between CSF and blood. Choroid plexuses protrude into the cerebral ventricles; they are covered with a specialized type of ependymal cell that has tight junctions on the apical surface. Choroid plexus capillaries are fenestrated. Substances from the blood can cross into the stroma next to the ependymal cells. They are blocked from entering the CSF by tight junctions that form at the apical surface of the ependymal cells. Choroid plexus ependymal cells are enriched with mitochondria, Golgi complexes, and endoplasmic reticulum—suggesting a high rate of metabolic activity—and are covered with microvilli that increase their surface area. In humans, the volume of CSF in the ventricles and around the spinal cord is approximately 140 mL, with a rate of CSF production of 0.35 mL/min or about 500 mL/day, which explains why obstruction of CSF leads rapidly to life-threatening hydrocephalus. CSF production occurs at both choroidal and extrachoroidal sites, and estimates of the proportion of CSF from each site vary, depending on the species and the method of measurement. Removal of the choroid plexus in nonhuman primates only reduces CSF production by 40%, leaving 60% presumably from extrachoroidal production (Milhorat, 1969). Higher levels of sodium, chloride, and magnesium and lower levels of potassium, calcium, bicarbonate, and glucose are found in CSF than are expected from a plasma ultrafiltrate, which suggests that the CSF is actively secreted. An ATPase pump on the apical surface of the choroidal cells secretes three sodium ions in exchange for two potassium ions; osmotic water follows the increased sodium gradient. Carbonic anhydrase converts carbon dioxide and water into bicarbonate, which is removed along with chloride to balance the sodium charge. Production of CSF continues even when the ICP is high. Only acetazolamide, which inhibits carbonic anhydrase, can be used for the long-term reduction in CSF production. Experimentally, hypothermia, hypocarbia, hypoxia, and hyperosmolality have been shown to reduce production, but these are not practical to use for other than short periods. Osmotic agents such as mannitol and glycerol increase serum osmolality, lowering CSF production temporarily by about 50%. Agents that interfere with Na+/K+-ATPase reduce CSF production. Digitalis has an effect on the rate of CSF production, but ouabain, which is a more effective agent experimentally, is too toxic for use in patients. Recently, hypertonic saline has been shown to reduce CSF pressure; some of this effect may be due to a reduction in CSF production, but the mechanism of action remains to be clarified. Capillaries, which have Na+/K+-ATPase on the abluminal surface, are a source of extrachoroidal ISF production. Gray matter has a dense neuropil that impedes the flow of water, whereas white matter, being more regularly arranged, is a conduit for normal bulk flow of ISF as well as a route for movement of edema under pathological conditions. Normally the flow of ISF in the white matter is toward the ventricle, where it mixes with the CSF from the choroid plexus to be eventually drained across the arachnoid granulations that protrude into the sagittal sinus.

Water Molecules: Basis for Magnetic Resonance Imaging Water molecules have a magnetic moment that allows them to be aligned in a magnetic field. Such a field is created in a magnetic resonance scanner. Because brain tissue is 80% water, and water dipoles can be aligned by manipulating the magnetic fields, they can be made to resonate and the resonance signals from water protons can be

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detected by MRI; since water is the most abundant source of protons in the brain, water protons dominate the signals. MRI can detect water diffusion by the use of appropriate pulse sequences. The complex diffusion signals are obtained mainly from intracellular water, with some contribution from extracellular water. Water diffusion between cells in the extracellular space occurs normally. When there is cellular swelling and the extracellular space is compressed, the diffusion of water slows, and the apparent diffusion coefficient (ADC) shows a loss of signal, which appears black on the image. The diffusion-weighted image (DWI) has a bright signal. Because the DWI may show T2 shine-through that will be misinterpreted as restricted diffusion, both a darkened ADC and a bright DWI should be seen in the region of the infarct. In cerebral ischemia, the DWI is abnormal within minutes after the onset of the ischemia, making this an excellent diagnostic test for the presence of acute cerebral ischemia. Diffusion tensor imaging (DTI) reveals the patterns of white-matter tracts in three dimensions. Taking advantage of the directional flow of water protons along white matter, diffusion is measured in three planes, and the separate pathways for water movement between the fibers are traced. In patients with white-matter pathology, such as in vascular cognitive impairment and MS, injury patterns in the white matter can be revealed by DTI (Maillard et al., 2013). Contrast agents are important in determining injury to the BBB. Iodine-containing contrast agents are used in computed tomography (CT) scanning because they are radiopaque. When injected intravenously, contrast agents show the site of injury to the blood vessels by the appearance of the contrast agent on the scan. Iodine-containing contrast agents can cause anaphylactic reactions, however, particularly in individuals with allergy to shellfish. Contrast agents used in MRI studies are safer and more sensitive, making them the agents of choice. Gadoliniumcontaining compounds are used in MRI because they produce a paramagnetic effect. When they leak from the vessels into tissue, they cause a rapid relaxation of the protons that can be seen on T1-weighted images as a hyperintensity, compared to the pre-contrast scan. There is some retention of gadolinium in the brain, but the significance of this finding is uncertain. However, it has led to more cautious use of gadolinium.

Anatomical Sites of Central Nervous System Infection The terminology used to describe various types of central nervous system (CNS) infections is anatomically based (Table 88.3). An infection limited to the subarachnoid space, with inflammation of the meninges, is called meningitis. Meningeal signs of headache, stiff neck, and photophobia are present without focal findings that would indicate spread into the parenchyma. When the infection spreads contiguously from the subarachnoid space through the pial surface or along VirchowRobin spaces, crossing gap junctions, the brain parenchyma is infected, and the term meningoencephalitis is used. In addition to meningeal signs, there are focal findings and possibly impaired consciousness and seizures. An infection in the brain tissue that is most likely to spread via blood begins as a loose collection of invading cells referred to as a cerebritis; walling off of the infected brain tissue leads to an abscess. Finally, the term encephalitis is used to describe a more diffuse brain infection in both the gray and white matter, which is usually indicative of a viral infection. Occasionally the infection spreads in a potential space beneath the dura but outside the arachnoid; subdural empyema describes a life-threatening collection of pus over the brain surface that has often spread from an infected sinus through the venous plexus of the ethmoid or sphenoid sinuses into the subdural space. The presence of a subdural empyema should be suspected in a patient with sinus infection, fever, seizures, focal findings, and altered consciousness. Diagnosis of meningitis can be done by examination of CSF for signs of infection such as increased white blood cells or protein. Infections

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Terms Used to Describe Different Sites of Inflammation in the Central Nervous Symptoms

Site of Inflammation

Meningitis Meningoencephalitis Encephalitis Cerebritis/abscess

Fever, stiffness, photophobia, headache Meningeal symptoms with focal findings Headache, seizures, altered mental state Fever, seizures, focal findings

Subdural empyema

Fever, seizures, coma

Cells confined to subarachnoid space (SAS) SAS and brain inflammation Multiple sites of cellular response in brain tissue Cerebritis, early collection of inflammatory cells around vessels; abscess is the walled-off stage Diffuse collection of pus over the surface of the brain between the dura and arachnoid

that invade the brain are best diagnosed with MRI, which can readily demonstrate a meningoencephalitis, cerebritis, abscess, or encephalitis. Use of contrast agents increases the potential of reaching a correct diagnosis based on site of infection. Subdural empyema is the most difficult condition to diagnose because it may only be a thin layer of pus on the surface of the brain and be obscured by the skull. Diagnosis can be missed on LP or CT, and MRI is more sensitive.

Gap Junctions on Ependymal and Pial Surfaces Lining the cerebral ventricles (other than over the choroid plexus) is a layer of ciliated ependymal cells connected by gap junctions. Pial cells lining the surface of the brain, which form the limiting glial membrane, the glial limitans, also have gap junctions. Fluid, electrolytes, and large protein molecules move through the gap junctions, allowing exchange between the CSF and ISF. Intrathecal administration of antibiotics and chemotherapeutic agents has been used to bypass the BBB. Blood vessels penetrate the brain from the surface. As they enter the brain, they are invested with pia mater. The space between the penetrating blood vessels and the brain, prior to the point where only brain tissue surrounds the vessels, is called the Virchow-Robin space. After injection of substances intrathecally, the large proteins in the CSF space penetrate into the brain from the surface via the VirchowRobin spaces. These perivascular routes may be involved in the spread of infection into the brain from the subarachnoid space in meningitis.

Arachnoid Granulations and Absorption of Cerebrospinal Fluid Arachnoid granulations (pacchionian granulations) are the major sites for the drainage of CSF into the blood. They protrude through the dura into the superior sagittal sinus and act as one-way valves. As CSF pressure increases, more fluid is absorbed. When CSF pressure falls below a threshold value, the absorption of CSF ceases (Fig. 88.3). In this way, CSF pressure is maintained at a constant level, with the rate of CSF production as one determining factor. Although channels are seen in the arachnoid granulations, actual valves are absent. Tissue appears to collapse around the channel as the pressure falls, and the channels enlarge as pressure rises. Resistance to outflow across the arachnoid granulations leads to CSF pressure elevation. Substances can clog outflow channels and increase resistance to CSF absorption. Blood cells are trapped in the arachnoid villi, and subarachnoid hemorrhage causes a transient increase in CSF pressure and can occasionally lead to hydrocephalus. Similarly, white blood cells and increased protein from meningitis can block the arachnoid granulations and increase CSF pressure.

Cerebrospinal Fluid Pressure Measurement of CSF pressure is a critical part of the LP. Pressures should be measured with the patient in the lateral recumbent position,

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CSF pressure (mm H2O) Fig. 88.3 Schematic Drawing of the Relationship of Cerebrospinal Fluid Formation and Absorption to Pressure. Cerebrospinal fluid (CSF) is formed at a constant rate of 0.35 mL/min. Absorption begins above a threshold value that varies from person to person. Once CSF absorption begins, it is linear, as seen in a one-way valve. When formation rate equals absorption rate, the steady-state CSF pressure is determined. (Modified with permission from Cutler, R.W., Page, L., Galicich, J., et al., 1968. Formation and absorption of cerebrospinal fluid in man. Brain 91, 707–720.)

and a narrow-bore spinal needle should be used to minimize CSF leakage. Performing the LP with the patient in the sitting position, although easier for the physician, eliminates the possibility of obtaining an accurate CSF pressure. Whenever CSF pressure is a critical piece of information, such as in the diagnosis of IIH, the sitting position should not be used. The opening CSF pressure is measured with a manometer attached to the needle. Normal CSF pressure ranges from 80 to 180 mm H2O but may go as high as 200 mm H2O in obese patients or those who are not relaxed. Three components contribute to the measured pressure: volume of blood within the cranial cavity, amount of CSF, and the brain tissue. The CSF pressure recorded by the manometer represents the venous pressure transmitted from the right side of the heart through the venous sinuses. Small fluctuations from the cardiac systolic pulse and larger fluctuations from respirations can be seen in the column of fluid in the manometer. Pulsations in the manometer represent the fluctuations in the thin-walled veins. Arteries have thick elastic walls that dampen the pulsations from arteries. Deep respirations cause wide fluctuations in the CSF pressure, whereas changes in arterial pressure are barely visible. As ICP rises, tissue compliance falls and reserve capacity of the intracranial contents is lost. When tissue compliance is lost, small changes in fluid volume may lead to large increases in ICP.

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Patients with increased ICP can be continuously monitored with indwelling catheters in the ventricles or with a pressure sensor implanted over the dura. Both procedures are invasive and only used in critically ill patients. Pathological elevations in ICP cause plateau waves that increase in steps to 50 mm Hg, where they persist for up to 20 minutes before returning to baseline. Treatment of patients with raised ICP can be monitored at the bedside with pressure monitors. Monitoring is used to gauge response to osmotic agents and to determine the severity of head injury. Despite use of intracranial monitoring in patients with severe brain injury, clinical utility has not been shown.

Composition of the Cerebrospinal Fluid CSF resembles water; the protein content is low and no more than five lymphocytes and no neutrophils should be present. Glucose values are two-thirds of those in blood. Some IgG is produced in the brain, but in the absence of an inflammatory disease (e.g., MS), amounts should be very small. The IgG index can be used to determine the source of CSF IgG. While meningitis is the major disease diagnosed exclusively by detection of cells in the CSF, other neurological diseases result in abnormal levels of proteins. Acute MS attacks cause an increase in myelin basic protein, which represents breakdown of myelin; oligoclonal bands suggest a longer disease course (Noseworthy et al., 2000). The ratio of IgG to albumin in both the blood and brain is calculated according to the formula (CSF IgG × serum albumin)/(serum IgG × CSF albumin). Dividing the ratio in the brain by that in the blood indicates whether the IgG comes from the blood across a leaky BBB, in which case the ratio is low, or whether the source of IgG is the brain, in which case the IgG index is elevated. An IgG index above 0.6 generally indicates intrathecal IgG synthesis. Cells in the CSF provide an important indication of the underlying pathology. Bacterial infection typically leads to an increase in polymorphonuclear leukocytes; viruses cause a lymphocytosis. Large numbers of red blood cells in the CSF suggests a subarachnoid hemorrhage, which is confirmed by the presence of xanthochromia due to breakdown of blood products. In some forms of encephalitis, such as herpes encephalitis, there may be red blood cells in the CSF. Vasculitis can increase white blood cell numbers, as can an acute attack of MS. The presence of more than 50 cells increases the likelihood of vasculitis over MS. Parameningeal infections may not cause an increase in white blood cells but will increase CSF protein. CSF can aid in the diagnosis of neurodegenerative diseases.

BRAIN EDEMA Molecular Cascade in Injury Cerebral edema, which is the end result of many neurological diseases, is classified into cytotoxic or cellular swelling, ionic or extracellular edema that occurs in the presence of an intact BBB, vasogenic or vascular leakage, and interstitial edema, when the fluid accumulates in the interstitial spaces as occurs in hydrocephalus. Disruption of the BBB leads to vasogenic edema, which expands the extracellular space. Vasogenic edema moves more readily in between the linearly arranged fibers that form the white matter. The gray matter restricts water movement because of the dense mat-like nature of the neuropil, while the more loosely connected fiber tracts can be separated to allow edema fluid to flow. Cytotoxic edema, which results from pathological processes that damage cell membranes, constricts the extracellular spaces, constraining movement of fluid between the cells. Because of the lack of cell damage in vasogenic edema, once the damage to the blood vessel resolves, there may be a return to normal in the edematous tissue. This is generally not the case in cytotoxic edema, which is due to direct injury to cells. The resolution of interstitial edema from

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hydrocephalus is variable; some resolution may occur once the pressure in the expanded cerebral ventricle is reduced by insertion of a ventriculoperitoneal shunt. Cellular and blood vessel damage follows activation of an injury cascade. The cascade begins with depletion of energy and glutamate release into the extracellular space (Fig. 88.4). This occurs during a hypoxic, ischemic, or traumatic injury and causes cytotoxic damage. Release into the extracellular space of excessive amounts of the excitatory neurotransmitter glutamate opens calcium channels on cell membranes, allowing extracellular calcium to enter the cells. Because one calcium ion is exchanged for three sodium ions, the removal of excess calcium from the cell, which requires an intact cellular membrane, causes a buildup of sodium within the cell, creating an osmotic gradient that pulls water into the cell. While the cell membrane is intact, the increase in water causes dysfunction but not necessarily permanent damage. If the blood vessels are intact, this stage has been referred to as ionic edema (Simard et al., 2017). Accumulation of calcium ions within the cell activates intracellular cytotoxic processes, leading to cell death. An inflammatory response is initiated by the formation of immediate early genes (e.g., c-fos and c-jun) and cytokines, chemokines, and other intermediary substances. Microglial cells are activated and release free radicals and proteases, which contribute to the attack on cell membranes and capillaries. Irreversible damage to the cell occurs when the integrity of the membrane is lost. Free radicals are pluripotential substances produced in the ischemic brain and after traumatic injury. The arachidonic acid cascade produces reactive oxygen species such as superoxide ion, hydrogen peroxide, and hydroxyl ion. Release of fatty acids (e.g., arachidonic acid) provides a supply of damaging molecules. Superoxide dismutase-1 and catalase are the major enzymes that catalyze the breakdown of reactive oxygen species. Other defenses include glutathione, ascorbic acid, vitamin E, and iron chelators such as the 21-amino steroids. The role of oxygen radicals has been extensively studied. Transgenic mice that overexpress the superoxide dismutase-1 gene have smaller ischemic lesions than controls (Jung et al., 2009). Nitric oxide (NO) is another source of free radicals, which have both positive and negative effects. NO synthetase (NOS) has three forms: neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible or immunological NOS (iNOS). Macrophages and activated microglial cells form NO through the action of iNOS in response to ischemia, injury, and inflammatory stimuli. NO acts as both a normal vasodilator of blood vessels, by release of cyclic guanosine monophosphate in smooth muscle, and as a toxic compound under pathological conditions through the action of peroxynitrite anions (ONOO−), which are formed from the reaction of NO with superoxide anions (Endres et al., 2004). Manipulation of the NOS gene has helped reveal the action of the enzyme. nNOS produces toxic free radicals early in ischemic injury. Deletion of the nNOS gene in transgenic mice results in smaller infarcts from middle cerebral artery occlusion. On the other hand, eNOS causes vasodilatation and increases cerebral blood flow. Removing the eNOS genes leads to increased infarct size. Inflammation induces iNOS, which enhances injury and reaches a maximum at 24 hours (Iadecola, 1997).

Neuroinflammation and Vasogenic Edema Vasogenic edema occurs when there is damage to the cells of the NVU and subsequent disruption of the BBB. Protein and blood products enter brain tissue, increasing the oncotic pressure in the brain and exposing brain cells to toxic products from the blood. Opening of the BBB could occur by loosening of tight junctions, development of pinocytotic vesicles in the endothelial cell, or an alteration in the

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Stroke Trauma Inflammation Late effector genes (6–24 h)

(0–4 h) Chemokines Cytokines Free radicals Mononuclear cells

Glutamate release Ca2+ influx Energy depletion

Lysosomes Neutral proteases Endonucleases

Immediate early genes (0–6 h)

Necrosis Apoptosis

Fig. 88.4 Mechanisms of Ischemic-Hypoxic Injury Leading to Cell Swelling and Death. Chart shows the time course of early events involving glutamate release, immediate early gene production, and energy failure. This leads to changes in electrolytes and initiation of the inflammatory response. Cytokines continue the damage, which results in opening of the blood–brain barrier. Chemokines attract white blood cells to the injury site, where they release free radicals and proteases and enhance the injury. Finally, the proteases attack structural components, leading to membrane damage and cell death.

basal lamina surrounding the capillaries. Tight junctions in the endothelial cells are the first line of protection. Proteases and free radicals are the major substances that attack the capillaries (Candelario-Jalil et al., 2009). The layer of basal lamina around the capillary, containing type IV collagen, fibronectin, and laminin, is degraded by proteases. The proteases involved include the serine proteases, plasminogen activators/plasmin system, and matrix metalloproteinases (MMPs) (Cunningham et al., 2005). Free radicals activate the proteases and attack the membranes directly. Brain cells and infiltrating leukocytes are the sources of proteases and free radicals. Neutrophils contain prepackaged gelatinase B (MMP-9), which is released in an activated form at the injury site. Extracellular matrix undergoes remodeling by the action of MMPs during development and repair. The MMPs are a gene family of over 24 enzymes that are expressed constitutively during normal remodeling but are induced in an injury. MMPs are expressed in a latent form that requires activation. Constitutively expressed MMP-2 is normally expressed by astrocytic foot processes around cerebral blood vessels, where it modulates the permeability of the BBB. Membrane-type MMP (MT-MMP) is membrane bound and forms a trimolecular complex with tissue inhibitor to metalloproteinases 2 (TIMP-2) to activate MMP-2. This configuration keeps the action of MMP-2 close to the membrane where it can gradually remodel the extracellular matrix around the blood vessel (Liechti et al., 2014). Synaptic remodeling is an important feature of learning. MMP-9 is involved in the formation of the neural nets as part of the synapse formation. Treatment with MMP inhibitors blocks this critical process and impedes learning. The dual function of proteases, such as the MMPs, in perpetuating injury and facilitating repair illustrates the important concept that the beneficial effects of drugs in the early phases of injury is offset by the detrimental effects of blocking proteases during the repair process. Bacterial meningitis initiates an inflammatory response in the meninges caused by the invading organisms and by the secondary release of cytokines and chemokines. The secondary inflammatory response may aggravate the infection. Cytokines, including tumor necrosis factor (TNF)-α and interleukin (IL)-6, are elevated in the CSF of patients with bacterial meningitis and contribute to the secondary tissue damage. MMPs are increased in bacterial meningitis, and MMP inhibitors (e.g., doxycycline) block the damage secondary to infection

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(Lietchti et al., 2014). Steroids suppress the expression of MMPs and other inflammatory mediators. In children, treatment of bacterial meningitis with steroids along with the antibiotic reduces secondary injury. Use of steroids in adults with bacterial meningitis is more controversial. Doxycycline, a tetracycline derivative, suppresses MMP-9 expression and has a beneficial effect in reducing inflammation in meningitis when combined with another antibiotic (Meli et al., 2006).

Cytotoxic Brain Edema Stroke, trauma, and toxins induce cytotoxic edema. After a stroke, brain water increases rapidly owing to energy failure and loss of adenosine triphosphate (ATP). Cytotoxic edema begins soon after the onset of ischemia as shown by DWI, reaching a maximum between 24 and 72 hours, when the danger of brain herniation is greatest (Fig. 88.5). The initial cellular swelling due to an increase in water is the result of the accumulation of ions in the intracellular and extracellular spaces. This is referred to as ionic edema since the BBB remains intact. As the energy failure progresses there is further deterioration of the cell, threatening cell death. The next stage is the damage to the blood vessels, resulting in vasogenic edema, which occurs at multiple times depending on the cause of the injury. In brain trauma, there is an early opening of the BBB along with extensive damage to the brain tissue, and a mixture of cytotoxic and vasogenic edema leads to severe brain edema in the early stages after injury. Ischemic injuries with permanent occlusion of a blood vessel decrease blood flow to the vessel territory, and unless collateral vessels take over, there is infarction of the ischemic tissue. Greater damage occurs in transient ischemia, because the restoration of blood flow returns oxygen and white blood cells to the region, enhancing the damage. Reperfusion injury particularly damages the capillary, with disruption of the BBB seen in two phases: an early opening after several hours and a more disruptive secondary opening after several days (Kuroiwa et al., 1985). The initial opening, which is transient, is related to the activation of MMP-2, which is constitutively expressed and normally found in the latent form. Opening of the tight junctions is seen transiently after the onset of reperfusion, where disruption of tight-junction proteins is observed. A second, more disruptive, phase of injury to the capillary begins around 24–48 hours after the onset of reperfusion. This is related to activation of MMP-3 and MMP-9, along with cyclooxygenase-2, which are induced

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Fig. 88.5 Patient with Cytotoxic Edema Secondary to a Large Middle Cerebral Artery Infarction. A, Computed tomography (CT) shows early stages of infarction, with loss of definition of the insular stripe, an early sign of infarction. B, Diffusion-weighted image later that day shows restricted diffusion in region of infarct. C, One week after admission, CT shows mass effect and herniation, with hydrocephalus on contralateral side (arrow) due to obstruction of foramen of Monro.

from several cell types including microglia/macrophages during the amplification phase of the secondary inflammatory response. Emboli are more likely to lead to reperfusion injury than thrombosis because the breaking up of the clot can restore blood flow to a previously ischemic region. When that occurs, the risk of hemorrhage is increased (Fig. 88.6). Cerebrovascular diseases are the major cause of brain edema in the adult because of the high incidence of cerebral ischemia in the elderly, but other causes include acute hepatic failure, osmotic changes, exposure to toxins, and high altitude. In acute hepatic failure, cerebral edema may cause death. Patients with hepatic failure are often young and have an acute cause for liver failure. They may have overdosed on a drug that is toxic to the liver, such as acetaminophen, or they may have infectious hepatitis. Long-standing liver disease with cirrhosis and hepatic encephalopathy shows changes of astrocytes in the brain, but it is generally not complicated by cerebral edema (Norenberg et al., 2005). Reye syndrome, which is seen primarily in children after an influenza infection (particularly when they are treated with aspirin), has a high incidence of brain swelling. Parents are warned not to use aspirin for childhood fevers, and since warnings appeared and use of aspirin declined, the number of patients with Reye syndrome has decreased.

Effect of Blood Pressure and Osmolality Changes on Brain Edema Cerebral blood flow is tightly regulated in the waking state to ensure adequate flow to the brain. Loss of autoregulation occurs at both the lower and upper extremes of blood pressure, with resulting syncope and hypertensive encephalopathy, respectively. The normal level of autoregulation varies greatly between patients, depending on age, prior diseases such as hypertension and diabetes, and years of treatment for hypertension. The hypertensive blood vessel undergoes changes over a long period of time with the lumen becoming narrower and the outer wall thickening. This results in a noncompliant vessel that restricts blood flow and responds slowly to an increase in metabolic need (Rigsby et al., 2011). When a young patient with average blood pressures in the 100/60 range has an increase to 160/110, there may be hypertensive crisis, whereas in an older individual with long-standing hypertension, a blood pressure of 160/110 would most likely have no

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Fig. 88.6 Hemorrhagic Transformation and Enhancement of an Infarct. Patient presented with left-sided weakness of uncertain duration but probably less than 12 hours. Computed tomography (CT) without intravenous (IV) contrast (A) shows a posterior right temporo-occipital, cortically based area of low attenuation with smaller areas of higher attenuation. Magnetic resonance imaging (MRI) was performed the following day. The greater sensitivity of MRI for hemorrhage is illustrated by the areas of low T2 signal intensity on an axial spin-echo image (B) and even more prominently on a gradient-echo image (C). Follow-up CT showed very little change; difference is due primarily to differences in imaging technique and sensitivity, not further hemorrhage. Minimal foci of T1 hyperintensity are present before IV contrast administration (D). After gadolinium administration E, extensive enhancement within the area of infarct indicates breakdown of the blood–brain barrier.

adverse effects. When an individual with chronic hypertension has a stroke, the blood pressure may increase to 200/120 without producing a hypertensive crisis. In fact, lowering the blood pressure too rapidly may worsen the ischemia; a gradual reduction in blood pressure is safer. Therefore, it is critical to understand the normal range for the individual before deciding to treat. Rapid elevation of blood pressure causes hypertensive encephalopathy. In experimental animals, hyperemia is present, suggesting

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patients treated for diabetic ketoacidosis at risk for edema secondary to water shifts into the brain (Bohn and Daneman, 2002). Long-standing hyperosmolality leads to solute accumulation in the brain to compensate for hyperosmolar plasma levels. These idiogenic osmoles are thought to include taurine and other amino acids. During treatment of diabetic ketoacidosis, blood osmolality is reduced, and water moves into brain along the osmotic gradient, resulting in cerebral edema. Rapid reduction of serum hyperosmolality, as in diabetic ketoacidosis, should be avoided to prevent brain edema due to the residual idiogenic osmoles (Edge et al., 2001). Dialysis dysequilibrium also may be due to an osmotic imbalance that results from urea buildup in brain tissue. Rapid correction of chronic serum hyponatremia can cause central pontine myelinolysis (Murase et al. 2006). In this syndrome, patients have very low sodium, usually less than 120 mEq/L, secondary to a variety of causes including inappropriate secretion of antidiuretic hormone (ADH), excessive water drinking, anorexia nervosa, alcohol withdrawal, meningitis, and subarachnoid hemorrhage. When there is inappropriate secretion of ADH, serum osmolality is low in the face of high urine osmolality. Treatment involves water restriction. In other patients, there is a salt-wasting syndrome that is treated by careful salt replacement. Low serum sodium can develop over an extended time period and be remarkably well tolerated. Shifts of water during treatment can result in central pontine myelinolysis due to damage to the myelinated tracts, particularly in the brainstem, but extrapontine myelinolysis may also be present.

Fig. 88.7 Patient with Hypertensive Encephalopathy Secondary to Eclampsia, with the HELLP (Hemolysis, Elevated Liver Enzymes, and Low Platelets) Syndrome. A, T2-weighted magnetic resonance imaging shows extensive cerebral edema in posterior white-matter regions, with less involvement of the gray matter. B, A higher level of the same scan sequence as in A, showing some frontal lobe involvement. C and D, Diffusion-weighted images (DWIs), with only one small area of involvement. The lack of DWI changes is consistent with this being a vasogenic type of edema, and the patient had a good recovery without residual effects.

that the blood vessels are dilated and have increased permeability. Confusion, focal findings, seizures with papilledema, and increased CSF protein are present in some patients with hypertensive encephalopathy. MRI shows vasogenic edema, primarily in the posterior white matter of the brain (Fig. 88.7), a condition referred to by some as reversible posterior leukoencephalopathy syndrome. Common causes of rapid elevations of blood pressure are acute kidney disease, particularly in children with lupus erythematosus or pyelonephritis, and in eclampsia. Changes may be transient, and complete recovery is possible if treatment is instituted before hemorrhage or infarction occurs. A characteristic pattern of vasogenic edema without cytotoxic edema is present on MRI: there is extensive edema seen in the white matter, generally in the posterior regions, but spread in frontal regions can be seen, and an absence of DWI lesions indicating this is only vasogenic edema without tissue ischemia. Absence of signs of ischemia, such as a normal DWI in the face of marked white-matter edema, supports a good prognosis for recovery (Covarrubias et al., 2002). Rapid reduction in blood pressure is necessary. The reason for involvement of the posterior circulation is uncertain. Eclamptic patients have visual disturbances due to involvement of the occipital lobes; rarely is this a life-threatening condition, but when death occurs, on postmortem examination, petechial hemorrhages may be seen in the occipital lobes, explaining the visual symptoms. Another cause of cerebral edema is a rapid change in serum osmolality. For example, rapid reduction of plasma glucose and sodium puts

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Edema in Venous Occlusion and Intracerebral Hemorrhage Occlusion of the venous sinuses draining the brain can cause increased ICP and venous hemorrhagic infarction. When the superior sagittal sinus is involved, there may be hemorrhagic infarction in both hemispheres (Fig. 88.8). Dehydration and hypercoagulable states are often found in such patients. Early symptoms may be subtle, with headache due to vessel occlusion or increased ICP. However, as infarction develops, other symptoms such as seizures develop, leading to hemorrhagic conversion of the infarction, herniation, and death. A CT scan is usually unhelpful, and MRI may have subtle findings. Diagnosis can be made with an MR venogram showing the occluded veins. Partial occlusions resulting in increased ICP are underdiagnosed. Patients may recanalize the thrombosed superior sagittal sinus and have an excellent outcome (Fig. 88.9). Although still controversial, most studies suggest that anticoagulation of the patient with sagittal sinus thrombosis is indicated even when there is hemorrhage into the brain. Intracerebral hemorrhage (ICH) causes brain edema around the hemorrhagic mass. This edema is both cytotoxic (direct damage to cells) and vasogenic (inflammatory response induced by toxic blood products). Growth of hematoma was observed after 24 hours in 38% of patients who were imaged within 3 hours of hemorrhage onset and again within 24 hours (Brott et al., 1997). Determining the cause of the ICH is generally difficult because the origin of the intracranial bleeding is obscured by the tissue destruction following the bleed and cellular necrosis. In primary ICH, a vessel ruptures, releasing blood into the brain. Secondary hemorrhagic transformation can occur in an area of infarction, particularly when the ischemic region is large. Generally, the hemorrhagic transformation is found 24–72 hours after the insult. Primary ICH most commonly occurs in the region of the basal ganglia, where the lenticulostriate arteries are subjected to hypertensive changes. The pons and cerebellum are less common sites (Fig. 88.10). Accumulation of blood causes both mass effect on the surrounding tissues and release of toxic blood products into adjacent tissues. Mass effect can lead to herniation. Blood contains coagulation cascade enzymes such as thrombin and plasmin, which are pluripotential

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Fig. 88.8 Sagittal Sinus Occlusion in a 17-Year-Old with Severe Dehydration. A, Magnetic resonance venogram shows absence of sagittal sinus on coronal view (arrowhead). B, T2-weighted image shows extensive venous hemorrhagic infarction.

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Fig. 88.9 Patient with Sagittal Sinus Occlusion That Developed After Pregnancy. Images shown were obtained several months after the event and demonstrate ability to recover. At illness onset, there was papilledema and increased intracranial pressure. A, Sagittal sinus is intact in this coronal view from a magnetic resonance (MR) venogram. B, Lateral view from venogram, showing flow in sagittal sinus (arrow) and straight sinus (arrowhead). C, Region of prior venous infarction is shown on axial T2-weighted MR image. D, Same region as in C on the coronal T1-weighted image.

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Treatment of Brain Edema Fig. 88.10 Computed Tomography Scan Shows Intracerebral Hemorrhage with Rupture into the Ventricle. Contralateral ventricle is dilated as the result of compression of cerebrospinal fluid outflow.

molecules that can damage cells both directly by their toxic effects and indirectly by activation of other proteases. In experimental animals, injection of thrombin into the brain produces a focal increase in brain water content (Xi et al., 2006). In addition to proteases, free radicals are thought to be involved in hemorrhagic injury, but evidence of free radical involvement is indirect and comes from studies showing that free radical scavengers and spin trap agents reduce bleeding and improve function in experimental models of ICH (Peeling et al., 1998). Many studies have been carried out to assess treatment of ICH. Two recent large clinical trials of surgical removal of the deep and lobar hematomas (STICH I) and of lobar hematomas only (ISTITCH II) failed to show a beneficial effect from surgery (Mendelow et al., 2013). A minimally invasive procedure to remove the blood via a catheter with the aid of thrombolysis is under evaluation but has not been proven to be effective (Hanley et al., 2017).

High-Altitude Cerebral Edema High-altitude cerebral edema (HACE) occurs when the concentration of oxygen, which is normally maintained at 21%, is markedly reduced. As the altitude increases and the atmospheric pressure is reduced, the amount of oxygen is also reduced, reaching dangerously low levels when climbing the highest mountains. Acute reductions in oxygen cause a constellation of cerebral symptoms that includes, initially, headache, ataxia, and short-term memory impairment, and can progress to life-threatening cerebral edema with papilledema, coma, and death. Two major mechanisms are thought to be involved in HACE: (1) hypoxia may increase cerebral blood flow, leading to an increase in intravascular pressure and vasogenic edema; and (2) disruption of the Na+/K+-ATPase pump due to the hypoxic conditions could lead to cytotoxic edema (Wilson et al., 2009). Both the vasogenic and the cytotoxic edema raise the intracranial pressure and impede venous outflow, adding another possible factor. Reduced oxygen content of the air leads to a compensatory hyperventilation, lowering the partial pressures of both oxygen and carbon dioxide. Since hypoxia causes vasodilatation and hypocapnia vasoconstriction, the combined effects initially

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Treatment of brain edema has lagged behind the advances in understanding the mechanisms producing the edema. Reduction of volume in one of the three compartments may be helpful. Blood volume can be reduced with hyperventilation, which lowers carbon dioxide. However, excessive hyperventilation can cause vasoconstriction and ischemia. Reduction of CSF volume can be done mechanically by placing a drainage catheter into one of the ventricles. This can be difficult when cerebral edema has compressed the ventricular system. Intraventricular drainage is mainly used in patients with head injuries or acute hydrocephalus or is done post-surgically. Agents that reduce the production of CSF (e.g., acetazolamide, diuretics) may be used but are of marginal benefit. For many years, osmotic therapy has been the treatment of choice for temporarily lowering ICP. Initially, urea was used, but the small molecule entered the brain, causing rebound edema. Current osmotic treatment is done primarily with mannitol, which reduces brain volume, lowers CSF production, and improves cerebral blood flow. Osmotherapy with low-dose mannitol infused over several days lowers ICP. Earlier studies employed 3 g/kg of mannitol, which had a drastic effect on the serum electrolytes and permitted only one or two doses to be given. More recently, it was found that low doses of mannitol (0.25–1 g/kg) are as effective as higher doses, without less effect on electrolytes. Lower doses raise serum osmolality only slightly, suggesting that mannitol has several mechanisms of action. The effect of the small change in osmolality is to reduce brain tissue volume; this effect is more prominent in the noninfarcted than the infarcted hemisphere. Other effects are that mannitol reduces CSF and ISF secretion by 50%, which may contribute to its action. Some investigators have proposed that mannitol hyperosmolality alters the rheological properties of blood, whereas others have noted an antioxidant effect. Prolonged administration of mannitol results in an electrolyte imbalance that may override its benefit and that must be carefully monitored. Although mannitol has been used to treat edema in acute stroke, its efficacy has not been proven. More recently, hypertonic saline has been advocated for use in treatment of cerebral edema (Fink, 2012). Corticosteroids lower ICP primarily in vasogenic edema because of their beneficial effect on blood vessel permeability. However, they have been less effective in cytotoxic edema, and are contraindicated in the treatment of edema secondary to stroke or hemorrhage. In fact, systemic complications of corticosteroids can worsen the patient’s condition when used to treat ICH. Edema surrounding brain tumors, particularly metastatic brain tumors, responds dramatically

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to treatment with high doses of dexamethasone; this corticosteroid rapidly closes the BBB. Hence, it is important to obtain contrast-enhanced MRI or CT scans before treatment with corticosteroids. Otherwise, enhancement of the lesion may be missed. High doses of corticosteroids have been shown to be effective in brain edema secondary to inflammation in MS; the steroids act by closing the BBB, which can be seen on contrast-enhanced MRI (Rosenberg et al., 1996). Inflammatory lesions such as those that occur in acute attacks of MS respond well to high-dose methylprednisolone. Treatment with 1 g/day of methylprednisolone for 3–5 days reduces the inflammatory changes in the blood vessels during an acute exacerbation. Dramatic reduction in enhancement on MRI may be seen after treatment. However, the effect is lost after several months.

IDIOPATHIC INTRACRANIAL HYPERTENSION Before the advent of CT or MRI scanners, the complaint of headache and the finding of papilledema raised the suspicion of hydrocephalus or tumor. When tests were negative for either of these conditions, confusing names for the syndrome were invented, which have led to the use of inappropriate terms for this syndrome. It was first noted that otitis media was at times associated with papilledema that was suspected to be due to hydrocephalus, leading to the pre-imaging term otitic hydrocephalus. During the era of pneumoencephalography, which was done to show distortion of the ventricles to diagnose hydrocephalus or tumors, the term pseudotumor cerebri was invented to describe patients with papilledema who had neither. More recently, the syndrome has been called benign intracranial hypertension, but when blindness occurs it cannot be considered benign. None of these terms are satisfactory, and the descriptive term IIH is preferred, although, through common usage, pseudotumor cerebri has persisted in the literature.

Clinical Features Patients with IIH have a constellation of symptoms that includes headaches, transient visual obscurations, pulsatile tinnitus, diplopia, and sustained visual loss. Headache is the most frequent symptom; it is the presenting symptom in most patients and is an important reason for searching for papilledema in all headache patients. The pain characteristically wakes the patient from sleep in the early morning hours. Sudden movements such as coughing aggravate the headache. Headaches may be present for months before a diagnosis is made. Some patients complain of dizziness. Transient obscuration of vision occurs when changing position from sitting to standing. Visual fields show an enlarged blind spot due to the encroachment of the swollen optic nerve head. Prolonged papilledema may lead to sector scotomas and, rarely, vision loss when the swollen disc encroaches on the region of the macula. It is important to differentiate papillitis due to inflammation from papilledema due to increased CSF pressure. In the former, vision loss is prominent early in the course and the pupillary response is abnormal, whereas with papilledema, the vision is preserved until the late stages when the swollen disc encroaches on the macula. Dysfunction of one or both sixth cranial nerves may occur as an effect of shifts of cerebral tissue. Because the sixth cranial nerve is remote from the site of the process producing intracranial hypertension, the cranial neuropathy is a false localizing sign. The sixth nerve has a long course as it travels to the eye. Before entering the eye socket, it makes a 90-degree turn and goes through the canal of Dorello at the tip of the temporal bone. It is possibly at this site that compression of the abducens nerve could occur (Nathan et al., 1974). Diagnosis requires ruling out other causes of increased ICP. All patients require a CT or MRI scan to look for hydrocephalus and mass lesions. After a mass lesion is ruled out, LP is needed, with careful

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Drugs Frequently Associated with Idiopathic Intracranial Hypertension

BOX 88.2

Minocycline Isotretinoin Nalidixic acid Tetracycline Trimethoprim-sulfamethoxazole Cimetidine Prednisolone Methylprednisolone Tamoxifen Beclomethasone From Schutta, H.S., Corbett, J.J., 1997. Intracranial hypertension syndromes. In: Joynt, R.J., Griggs, R.C. (Eds.), Clinical Neurology, twelfth edition. Lippincott, Philadelphia, pp. 1–57.

attention to accurately measuring the CSF pressure, which must be elevated by definition. Characteristic CSF findings include normal or low protein, normal glucose, no cells, and elevated CSF pressure. The upper limit for normal CSF pressure is 180 mm H2O. Most IIH patients will have readings above 200 mm H2O, with pressures at times exceeding 500 mm H2O. Measurement of CSF pressure should be done with the patient’s legs extended and neck straight. As noted earlier, pressures taken with the patient in the sitting position are inaccurate. Movements of the fluid column with respiration should be seen to confirm proper placement of the needle. It is important to obtain an accurate pressure reading at the time of the initial LP, since measurements of pressure in subsequent LPs may be falsely reduced by damage to the dura and the loss of fluid during the initial puncture. Occasionally, CSF leaks into the epidural space and forms a false pocket; subsequent attempts at LP may sample this space rather than the actual CSF space. IIH occurs more frequently in women than in men. Obesity and menstrual irregularities, with excessive premenstrual weight gain, are often present. Because many illnesses may be associated with increased ICP, a search for an underlying cause is essential before the diagnosis of IIH is made by exclusion of other causes. MRI has rekindled interest in conditions that cause occlusions of the venous sinuses. When the sinuses draining blood from the brain are obstructed, absorption of CSF is reduced, causing the pressure of the CSF to increase. MR venography (MRV) is better for showing thrombosis of the sinuses than conventional MRI. The role of venous sinus obstruction in raising ICP, although important to rule out, is uncommon. When venous sinus obstruction is found as the cause, a hypercoagulable work-up is important. Obesity is often found in women with IIH. Endocrine abnormalities have been extensively investigated in both obese and nonobese subjects, but none have been identified. Drugs associated with the syndrome include tetracycline-type antibiotics, nalidixic acid, nitrofurantoin, sulfonamides, and trimethoprim-sulfamethoxazole (Box 88.2). Paradoxically, the withdrawal of corticosteroids used to treat increased ICP can cause an increase in ICP. Large doses of vitamin A, which are used in the treatment of various skin conditions, may cause the syndrome. Hypercapnia leads to retention of carbon dioxide and increase in blood volume. Sleep apnea and lung diseases may cause headaches and papilledema due to this mechanism. Less frequent causes include Guillain–Barré syndrome, in which increased CSF protein clogs the arachnoid villa, leading to an increase in ICP. Similarly, a cellular response in meningitis may increase CSF pressure by blocking outflow pathways. Uremic patients have an increased incidence of papilledema with IIH. Renal failure patients have increased levels of vitamin A, use

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corticosteroids, and take cyclosporine, which have all been linked to IIH. Other less well-substantiated causes of elevated CSF pressure include obstruction to venous outflow. Venous pressure measurement has shown high pressure in the superior sagittal sinus and proximal transverse sinuses, with a drop in venous pressure distal to the transverse sinus. In patients without a documented structural defect in the venous sinuses, increased right atrial filling pressure that was transmitted to the venous sinuses has been shown (Karahalios et al., 1996). Whether the high venous pressure and imaging evidence of venous narrowing is the cause or the result of the increased ICP is controversial.

Treatment Treatment involves reducing ICP. Acetazolamide is an inhibitor of carbonic anhydrase that lowers CSF production and pressure. It is given in a dose of 1–2 g/day. Electrolytes must be monitored to look for metabolic acidosis. Distal paresthesias are reported to occur in up to 25% of patients. The hyperosmolar agent glycerol (0.25–1 g/kg, two or three times daily) was advocated at one time but is no longer indicated; the increased blood sugar caused weight gain in a group of patients that are often obese. Corticosteroids reduce increased ICP, but the pressure may increase when they are tapered. In patients with rapidly progressive visual loss, corticosteroids can be given in high doses for several days before a more definitive treatment is started. Drug effects are often transient, and when the syndrome does not resolve spontaneously, other treatments are needed. Although the relationship of obesity to IIH is uncertain, loss of weight can lead to resolution of the syndrome, and some patients have undergone bariatric surgery to control the obesity, but controlled studies of this procedure are lacking. Visual fields should be measured and the size of the blind spot plotted. Swelling of the optic disc causes the enlarged blind spot. When papilledema spreads into the region of the macula, visual acuity falls, and, in extreme cases, blindness may occur. Although most patients with IIH retain normal vision, a small percentage of patients develop impairment of vision. When vision is threatened and drugs and LPs fail to lower CSF pressure, surgical intervention is necessary. Lumboperitoneal shunting has a high initial success rate, but subsequent shunt failure is common. Fenestration of the optic nerve sheath to drain CSF into the orbital region reduces the ICP, and some consider it the treatment method of choice in medically refractory patients. Stereotactic insertion of ventriculoperitoneal shunts is now possible and provides better long-term patency than lumboperitoneal shunts. In obese patients with IIH, weight loss is an important adjunct treatment, and some authors argue that it is as important as acetazolamide. Patients with fulminant IIH are rare but require urgent treatment with acetazolamide, high-dose steroids, and optic nerve fenestration or ventriculoperitoneal shunting. In one study from two institutions, a total of 16 patients were studied, all of who were women between the ages of 14 and 39 years. All were obese with mean CSF pressures of 541 mm H2O. All had surgical treatment, which reduced headaches and vomiting, but 50% remained legally blind, showing the serious nature of this form of the illness (Thambisetty et al., 2007). Patients with venous sinus occlusion as the suspected cause of increased ICP have had intravascular stents placed to improve flow. In a series of 12 patients with refractory IIH who had venous pressure gradients, stenting the transverse sinus stenosis improved 7, but the natural history of the illness is that most improve over time (Higgins et al., 2002). Although placement of a stent is less invasive than placement of an intraventriculoperitoneal shunt, there are sparse data on which to base a treatment strategy. There are no controlled studies of the efficacy and long-term consequences of placing venous stents in

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this population of younger patients. Most reports of stenting are anecdotal and endovascular procedure should be considered experimental until controlled studies are done (Mollan et al., 2018).

Brain Edema in Idiopathic Intracranial Hypertension Two MRI studies showed edema in the white matter in patients with IIH; there was an increase in white-matter water signal of a heavily T2-weighted imaging sequence obtained at 1.5 T (Gideon et al., 1995). Another study compared diffusion maps of the ADC in 12 patients fulfilling conventional diagnostic criteria for IIH and in 12 healthy volunteers. They reported a significantly larger ADC within subcortical white matter in the patient group than in the control group, without significant differences within cortical gray matter, the basal nuclei, the internal capsule, or the corpus callosum. In addition, four of seven patients with increased ADC in subcortical white matter also had increased ADC within gray matter (Moser et al., 1988). Another group measured mean diffusivity of water and the proton longitudinal relaxation time in 10 patients with IIH and 10 age-, sex-, and weightmatched controls. They failed to find significant differences in DWI and T1 values between patient and control groups in any of the brain regions investigated, concluding that IIH is not associated with abnormalities of convective transependymal water flow leading to diffuse brain edema (Bastin et al., 2003). Thus, based on the results of MRI studies, there is no consensus as to the presence of brain edema.

HYDROCEPHALUS Hydrocephalus is a pressure-dependent enlargement of the cerebral ventricles due to obstruction of drainage of the CSF. Mainly occurring in infants and the elderly, ventricular enlargement rarely causes diagnostic problems, because detection of enlarged ventricles has been greatly aided by CT and MRI. However, determining the underlying cause is still difficult, particularly in the elderly where separation of ventricular enlargement due to hydrocephalus from that due to loss of brain tissue can be challenging. In early life, obstruction of ventricular outflow often occurs in the cerebral aqueduct that opens into the fourth ventricle, leading to noncommunicating hydrocephalus. In the elderly, the site of obstruction is drainage from the subarachnoid space; when resistance to drainage of the CSF occurs outside the ventricles, it is referred to as communicating hydrocephalus. Hydrocephalus in the adult may be acute and life threatening, as when a cerebellar infarct or hemorrhage obstructs CSF outflow from the ventricles, and ventricular enlargement is rapid. Or it may be insidious and slowly produce symptoms, with normal pressure measured at the lumbar sac when the symptoms are finally diagnosed. Although CSF pressure may be normal at the time of discovery, most likely there was a period of increased pressure when ventricular enlargement initially began.

Hydrocephalus in Children In children younger than 2 years of age, enlargement of the ventricles produces an increase in head circumference because the skull sutures are still open. Children with head growth that is more rapid than expected for their age are suspected of having hydrocephalus and are imaged early in the course, preventing the large heads and lower-extremity spasticity that once occurred as part of the childhood form of hydrocephalus. The cause of hydrocephalus in newborns is often an infection in utero that causes scarring and closure of the cerebral aqueduct, with subsequent obstruction to the outflow of CSF. Infection in the meninges can cause scarring over the channels connecting the CSF in the ventricles with that in the subarachnoid space. Closure of the foramina

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Fig. 88.11 Transependymal Flow. Computed tomography scan performed several hours after a small amount of contrast material was infused through a ventricular shunt catheter to evaluate communication shows that dependent contrast in the lateral ventricles has diffused into the surrounding brain through the ependyma.

of Magendie and Luschka leads to noncommunicating hydrocephalus. Obstruction of CSF circulation may result in increased CSF pressure as the cerebral ventricles enlarge, but once that has occurred compensatory drainage mechanisms may lower the CSF pressure, as is often the case in the adult with idiopathic normal-pressure hydrocephalus (NPH). Acute noncommunicating hydrocephalus develops rapidly, reaching 80% of maximal ventricular enlargement within 6 hours owing to the continued production of CSF despite the increased pressure. A slower phase of enlargement follows the initial rapid expansion, and ventricular enlargement plus continual production of CSF causes fluid accumulation in the periventricular white-matter interstitial space, producing interstitial brain edema. When the hydrocephalus stabilizes and enters a chronic phase, CSF pressure may decrease, resulting in normal-pressure recordings on random measurements, although long-term monitoring reveals intermittent increases in ICP. Long-standing hydrocephalus may cause atrophy in the white matter surrounding the ventricles but rarely affects the gray matter. When the rate of ventricular enlargement stabilizes in patients with incomplete ventricular obstruction, CSF production is balanced by transependymal absorption (Fig. 88.11). Occasionally a patient escapes detection of hydrocephalus in early life, and an enlarged head is the only sign of an underlying problem. Many years may elapse before the hydrocephalus manifests symptoms, and they may decompensate after many years of stability. Hydrocephalus in children is often due to a structural abnormality such as a Chiari I or II malformation, aqueductal stenosis due to intrauterine infection, or other congenital causes such as anoxic injury, intraventricular hemorrhage, and bacterial meningitis. When the sutures are open and some expansion of the skull may be possible, the only sign of increased ICP may be bulging of the anterior fontanelle along with thinning of the skull and separation of the sutures. If the diagnosis is delayed, abnormal eye movements and optic atrophy may develop. Spasticity of the lower limbs may be observed at any

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stage. Acute enlargement of the ventricles is associated with nausea and vomiting. During the neonatal and early childhood period, irritability is a common symptom of hydrocephalus. The child feeds poorly, appears fretful, and may be lethargic. In the older child, headache may be a complaint. Vomiting due to increased ICP may be present in the morning. Remote effects of the increased pressure may affect the sixth cranial nerves on one or both sides, leading to the complaint of diplopia in the older child. The enlarged ventricles affect gait. A wide-based ataxic gait due to the stretching of the white-matter tracts from the frontal leg regions around the ventricles may be present. Premature infants weighing less than 1500 g at birth have a high risk of intraventricular hemorrhage, and approximately 25% of these infants develop progressive ventricular enlargement, as shown by CT, MRI, or ultrasound (Mazzola et al., 2014). Ventricular size in the neonate may be followed at the bedside with B-mode ultrasound through the open fontanelle. Long-term, follow-up studies of children with intraventricular hemorrhage due to prematurity show that 5% require shunting for hydrocephalus. The survivors of a large germinal plate hemorrhage often have multiple disabilities. Angiogenic factors play a role in the development of the hemorrhages (Ballabh et al., 2007). Once the sutures are closed, which generally occurs by the age of 3, hydrocephalus causes signs of increased ICP rather than head enlargement. Meningitis, aqueductal stenosis, Chiari malformations, and mass lesions may be the cause of hydrocephalus in these young children. Tumors originating from the cerebellum and brainstem produce acute symptomatology, including headaches, vomiting, diplopia, visual blurring, and ataxia. Symptoms are due to the acute hydrocephalus secondary to obstruction of the cerebral aqueduct and to pressure on brainstem structures. Examination shows papilledema, possible sixth cranial nerve palsy, and spasticity of the lower limbs. When the hydrocephalus is more long-standing, endocrine dysfunction may occur, involving short stature, menstrual irregularities, and diabetes insipidus. Excessively rapid growth of the head is the hallmark of hydrocephalus in the child before closure of the sutures. Charts are available to plot head growth and compare it with standardized curves for normal children. Bulging of the anterior fontanelle is found even with the child relaxed and upright. After 1 year, the firmness of the fontanelle cannot be used, because the sutures have closed. Other findings include the “crackedpot” sound on percussion of the skull (McEwen sign), engorged scalp veins, and abnormalities of eye movements. As spasticity develops, the deep tendon reflexes are increased. Treatment involves shunting CSF from the ventricles to drain fluid into another body cavity. The shunted CSF is generally drained into the peritoneal cavity. Complications of shunt placement include malfunction and shunt infection. Revisions of the shunt as the child grows are frequently necessary.

Adult-Onset Hydrocephalus In the adult, symptoms of acute hydrocephalus include headaches, papilledema, diplopia, and mental status changes. Sudden death may occur with severe increases in pressure. Although rare, hydrocephalus can cause an akinetic mutism due to pressure on the structures around the third ventricle. Other symptoms include temporal lobe seizures, CSF rhinorrhea, endocrine dysfunction (e.g., amenorrhea, polydipsia, polyuria), and obesity, which suggest third ventricle dysfunction. Gait disturbances are reported in patients with aqueductal stenosis, but hyperreflexia with Babinski sign is infrequent. The causes of adult-onset hydrocephalus are similar to those in children, but the frequencies differ. As in children, acute obstruction of the ventricles in adults results in rapidly progressive hydrocephalus

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with symptoms of raised ICP. Adults are more likely than children to present with an acute blockage of CSF flow by intraventricular masses, such as a colloid cyst of the third ventricle, an ependymoma of the fourth ventricle, or the intraventricular racemose form of cysticercosis. Masses obstructing CSF outflow cause sudden headaches, ataxia, and loss of consciousness. Diagnosis may be difficult in patients with colloid cysts when the symptoms are intermittent because of the ballvalve effect of the mass. Cerebellar hemorrhage and cerebellar infarction with edema cause an acute hydrocephalus by compressing the brainstem, occluding the cerebral aqueduct and fourth ventricle outflow pathways, and causing noncommunicating hydrocephalus and acute elevation in intraventricular pressure. Patients with cerebellar hemorrhage usually have a history of hypertension. Increasing drowsiness and difficulty walking often follow the acute onset of headache. Hemiparesis and brainstem findings evolve after the ataxia, providing a clue that the origin of the problem is in the posterior fossa. The expanding hemorrhagic mass in the posterior fossa, if it is encroaching on the brainstem, requires urgent neurosurgical attention, with placement of a ventricular catheter to decompress the lateral and third ventricles, followed by posterior fossa craniectomy to remove the mass and reduce pressure on the brainstem (Adams et al., 1965). In patients with cerebellar infarction, the progression is generally slower, since the maximum swelling takes place in 24–48 hours, but the consequences of the enlarging posterior fossa mass are the same as with hemorrhage, and surgery may be necessary to remove the necrotic tissues and restore normal CSF flow. CT is helpful to show enlargement of the ventricle, but MRI is better for imaging the cerebellar infarction (Fig. 88.12). Treatment of adult hydrocephalus involves an operation to insert a tube to shunt CSF from the ventricles to the peritoneal cavity. These devices have one-way valves that respond to pressure. In an emergency, hydrocephalic ventricles can be assessed readily owing to the increase in their size. Shunt malfunction may cause abrupt decompensation. Symptoms of acute increased ICP from a shunt malfunction resemble those seen with onset of the hydrocephalic process. Adult-onset hydrocephalus that is communicating may be due to a tumor in the basal cisterns, subarachnoid bleeding, or infection or inflammation of the meninges. In the pre-antibiotic era, syphilis, tuberculosis, and fungal infections were a common cause of hydrocephalus due to chronic obstruction of subarachnoid pathways. CSF cultures are indicated in the elderly patient with enlarged ventricles, and searching for other sources of infection in lungs and other organs may be helpful in establishing the type of infection.

Normal-Pressure Hydrocephalus Chronic hydrocephalus in the adult can produce symptoms of gait disturbance, incontinence, and memory loss, with or without symptoms and signs of raised ICP including headache, papilledema, and false localizing signs. Causes of chronic hydrocephalus include post–subarachnoid hemorrhage, chronic meningeal infections (e.g., fungal, tuberculosis, syphilis), and slow-growing tumors blocking the CSF pathways. Normal-pressure hydrocephalus is a term commonly used to describe chronic communicating adult-onset hydrocephalus. Typically, patients with NPH have the triad of mental impairment, gait disturbance, and incontinence. NPH can develop secondary to trauma, infection, or subarachnoid hemorrhage, but in about one-third of patients no etiology is found. Enlarged ventricles are seen on CT, and MRI shows both the enlarged ventricles and the transependymal CSF absorption. By definition, LP generally reveals a normal or minimally elevated CSF pressure. Normal pressure is an unfortunate term, because patients who have undergone long-term monitoring with this syndrome have intermittently elevated pressures, often during the night.

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Fig. 88.12 Cerebellar Infarct with Secondary Hydrocephalus. A, Initial diffusion-weighted image with cerebellar infarct in the territory of the left posterior inferior cerebellar artery. B, Initial axial T2-weighted magnetic resonance imaging shows normal ventricular size. C, Diffusion-weighted image 3 days later, showing swelling of the infarction in the cerebellum. D, Echo-planar T2 axial image shows enlargement of the ventricles prior to surgery for hydrocephalus.

The presenting symptoms may be related to gait or mental function. When gait is the presenting factor, the prognosis for treatment is better. NPH causes an apraxic gait, which is an inability to lift the legs, as if they were stuck to the floor. Motor strength is intact, reflexes are usually normal or slightly increased, and Babinski signs are absent. In some patients, attempts to elicit a Babinski sign will result in a grasp response of the toes, suggestive of frontal lobe damage. Patients may be misdiagnosed as having Parkinson disease, because the gait disorder is similar in the two syndromes, suggesting that the etiology of the problem in the hydrocephalic patient lies in the basal ganglia. Because many of these patients also have hypertension, and some have small or large strokes, such patients may have other neurological findings including spasticity and hyperreflexia with Babinski signs. NPH leads to a reduction in intellect, which at times may be subtle. The dementia is of the subcortical type and involves slowing of verbal and motor responses, with preservation of cortical functions such as language and spatial resolution. Neuropsychological testing quantifies the decline in intellect and the degree of dementia. Patients are apathetic and appear depressed. Incontinence of urine may occur, particularly in patients with prominent gait disturbance. In the early stages of the illness, presumably as the ventricles are undergoing enlargement, patients can experience drop attacks or brief loss of consciousness. Headache and papilledema are generally not part of the syndrome. Diagnosis of adult-onset hydrocephalus and selection of patients for placement of a ventriculoperitoneal shunt has been difficult. Many of these patients have hypertensive vascular disease with lacunar infarcts. Features of Parkinson disease were noted in earlier reports of the

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Clinical suspicion of NPH

(Cognitive decline, gait apraxia, incontinence)

MRI

Enlarged ventricles Transependymal flow

Gait improved

Large-volume LP

No change in gait

VP shunt Fig. 88.13 Magnetic Resonance Imaging of a Patient with Possible Normal-Pressure Hydrocephalus Who Had Extensive Vascular Disease with White-Matter Changes and Suspected Transependymal Absorption of Cerebrospinal Fluid (CSF). He had a large-volume lumbar puncture to remove CSF, but failed to show improvement, and did not have a shunt placed. There is evidence of a stroke in the basal ganglia (arrow), and of transependymal flow of CSF (arrowhead). He had features of Parkinson disease and responded to treatment with Sinemet. This patient illustrates the overlap of normal-pressure hydrocephalus with chronic microvascular disease, lacunar strokes, and Parkinson disease. Such patients may not benefit from shunting.

syndrome, and it is now recommended that all patients with Parkinson disease have scans to rule out hydrocephalus. CT and MRI have aided in separating Parkinson disease, lacunar state, and NPH, although NPH may occasionally coexist with these diseases (Fig. 88.13). Patients diagnosed with vascular diseases, such as lacunar state or subcortical arteriosclerotic encephalopathy (Binswanger disease) along with the hydrocephalus, respond poorly to shunting, and, if there is a positive response, it may be transient as the underlying disease progresses (Tullberg et al., 2002). LP with 20–40 mL removed often improves the gait, leading some investigators to use response to the removal of CSF as a diagnostic test for placement of a lumbar peritoneal shunt. Placing a lumbar catheter for continuous drainage improves diagnostic accuracy. Finally, although not used routinely, radionuclide cisternography may be helpful. The selection of patients for shunting requires a combination of clinical findings and diagnostic test results; no test can predict whether a patient should undergo an operation (Fig. 88.14). Drainage of CSF may involve the lymphatics of the brain, which are also called the glymphatics. Intrathecal injection of gadobutrol, a gadolinium contrast agent that can be imaged with T1-weighted MRI, can aid in visualizing pathways of CSF removal. There was reduced clearance of the contrast agent from the subarachnoid space and accumulation in the Sylvian fissure (Ringstad et al., 2017). A high incidence of vascular risk factors was found in patients with NPH, suggesting that it is a form of vascular dementia (Israelsson et al., 2017).

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WMHs

Lacunar state/ parkinsonism Fig. 88.14 An Algorithm for Selection of Patients for Ventriculoperitoneal (VP) Shunt. Patients with the clinical triad undergo FLAIR MRI. If communicating hydrocephalus is found without excessive atrophy and with transependymal absorption, then a large volume of cerebrospinal fluid is removed and the changes in the gait observed over several days. In those with improvement in gait, a VP shunt is done. Patients with white-matter changes in the deep white matter probably have lacunar state. Those with white matter changes compatible with microvascular disease most likely have lacunar state or parkinsonism. FLAIR, Fluid-attenuated inversion recovery; LP, lumbar puncture; MRI, magnetic resonance imaging; NPH, normal-pressure hydrocephalus; WMHs, white matter hyperintensities.

Neuroimaging in patients with NPH has shown an enlargement of the temporal horns of the lateral ventricle, with a disproportionate amount of cortical atrophy to that anticipated for the age of the patient. This is in contrast to patients with hydrocephalus ex vacuo due to a degenerative disease, such as Alzheimer disease, in which there is atrophy of the cerebral gyri and enlargement of both the sulci and ventricles. Another useful finding on proton-density MRI is the presence of presumed transependymal fluid in the frontal and occipital periventricular regions. Quantitative cisternography with single-photon emission CT has been successfully used to predict the results of a shunt. Other proposed diagnostic methods, including measuring the rate of absorption of CSF by infusion of saline or artificial CSF into the thecal sac, clinical improvement after CSF removal, or the prolonged monitoring of ICP, have been used with some success to select patients for surgery. Decreased cerebral blood flow has been reported in NPH; regional cerebral blood flow is reduced in both cortical and subcortical regions. Patients who show clinical improvement with shunting have a concomitant increase in cerebral blood flow. Removal of CSF may result in an increase in cerebral blood flow in patients in whom NPH is likely to respond to shunt therapy.

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After the initial report and the hope of curing many people of dementia, a large number of patients underwent placement of ventriculoperitoneal shunts. As the number of patients who showed no improvement with shunts grew and the complication rates of placing a shunt in an elderly patient became evident, the rate of diagnosis and number of shunts placed at most centers has dramatically declined. However, none of the currently available tests by themselves identify the patients who will benefit from shunting. Most helpful is a combination of clinical signs and judiciously chosen laboratory tests. Various success rates for shunt placement have been reported; some reports describe improvement in approximately 80% of treated patients, while others report lower rates. In the early days of treatment of NPH patients with shunts, a high rate of shunt failure occurred, with complications of shunting being a major problem. Serious complications

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occurred in as many as one-fourth of the patients, including infection and subdural hematomas. More recently, the rates of correct diagnosis and complication-free treatments have improved, but the definitive diagnostic test and complication-free treatment remain elusive goals. Clearly, more information is needed to aid in the diagnosis and management of patients with this potentially treatable syndrome.

Acknowledgments The neuroradiological illustrations were generously provided by Blaine Hart, MD, Department of Radiology (Neuroradiology), University of New Mexico Health Sciences Center. The complete reference list is available online at https://expertconsult. inkling.com.

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89 Developmental Disorders of the Nervous System Harvey B. Sarnat, Laura Flores-Sarnat

OUTLINE Embryological and Fetal Development of the Nervous System, 1345 Neurulation, 1347 Disorders of Neurulation (1–4 Weeks’ Gestation), 1348 Mitotic Proliferation of Neuroblasts (Neuronogenesis), 1348 Disorders of Neuronogenesis, 1349 Programmed Cell Death (Apoptosis), 1349 Disorders of Programmed Cell Death, 1349 Neuroblast Migration, 1349 Major Mechanisms of Neuroblast Migration: Radial Glial Fiber Guides and Tangential Migration along Axons, 1350 Disorders of Neuroblast Migration, 1351 Architecture of the Cortical Plate, 1353 Fissures and Sulci of Cortical Structures, 1353 Disorders of Fissures and Sulci, 1354 Growth of Axons and Dendrites, 1354 Disorders of Neurite Growth, 1355 Electrical Polarity of the Cell Membrane, 1355 Disorders of Membrane Polarity, 1355 Synaptogenesis, 1355 Disorders of Synaptogenesis, 1355 Biosynthesis of Neurotransmitters, 1356

Disorders of Neurotransmitter Synthesis, 1356 Myelination, 1356 Disorders of Myelination, 1356 Cajal-Retzius Neurons and Subplate Neurons of the Fetal Brain, 1357 Etiology of Central Nervous System Malformations, 1357 Ischemic Encephalopathy in the Fetus, 1358 Molecular Genetic Classification of Malformations of the Nervous System, 1358 Clinical Expression of Selected Malformations of the Nervous System, 1359 Disorders of Symmetry and Cellular Lineage, 1359 Disorders of Neurulation (1–4 Weeks’ Gestation), 1359 Midline Malformations of the Forebrain (4–8 Weeks’ Gestation), 1362 Disorders of Early Neuroblast Migration (8–20 Weeks’ Gestation), 1365 Disturbances of Late Neuroblast Migration (after 20 Weeks’ Gestation), 1365 Disorders of Cerebellar Development (32 Days’ Gestation to 1 Year Postnatally), 1365

EMBRYOLOGICAL AND FETAL DEVELOPMENT OF THE NERVOUS SYSTEM

Membrane receptors respond to various transmitters at synapses, to a variety of trophic and adhesion molecules, and during development to substances that attract or repel growing axons in their intermediate and final trajectories. Molecular biology is the basis of linking a DNA sequence to a specific gene and a particular locus on a specific chromosome, and ultimately making a correlation with normal function and a particular disease. Table 89.1 shows known genetic loci and mutations in human central nervous system (CNS) malformations. In most cases, mutations affect the genetic programming of the spatial and temporal sequences of developmental processes. Molecular genetic data are rapidly becoming available because of intense interest in this key to understanding neuroembryology in general and neural induction in particular. Other aspects of current investigative interest include the roles of neurotropic factors, hormones, ion channels, and neurotransmitter systems in fetal brain development. Genetic manipulation in animals has created many genetic models of human cerebral malformations. These contribute greatly to our understanding of human dysgeneses and provide insights into the pathogenesis of epilepsy and other functional results of dysgeneses. Maturation progresses in a predictable sequence with precise timing. Insults that adversely affect maturation influence events occurring at a particular time. Some are brief (e.g., a single exposure to a toxin),

Neuroembryology integrated with molecular genetics provides the key to understanding congenital malformations of the nervous system. Modern neuroembryology or ontogenesis encompasses not only classical descriptive morphogenesis but also the molecular genetic programming of development and the immunocytochemical demonstration of maturation of neuronal and glial proteins in individual cells and sequences of neurotransmitter biosynthesis, synapse formation, and myelination. Neuroimaging and electrocerebral maturation, as determined by electroencephalogram (EEG) in preterm infants, contribute other aspects of ontogenesis of normal and abnormal brain formation that are particularly relevant to clinical neurology. Maturation refers to both growth, a measure of physical characteristics over time, and development, the acquisition of metabolic functions, reflexes, sensory awareness, motor skills, language, and intellect. Molecular development, by contrast with molecular biology, refers to the maturation of cellular function by changes in molecular structures such as the phosphorylation of neurofilaments. In neurons, it also includes the development of an energy production system that actively maintains a resting membrane potential, the synthesis of secretory molecules as neurotransmitters, and the formation of membrane receptors.

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TABLE 89.1

Malformations

Neurological Diseases and Their Treatment

Genetic Loci of Known Human Mutations in Central Nervous System

Malformation

Inheritance

Agenesis anterior commissure; hypoplasia corpus callosum Agenesis corpus callosum with neuropathy Aicardi-Goutières syndrome Cerebellar hypoplasia Cerebellar hypoplasia, Hutterite dysequilibrium Cerebrohepatorenal syndrome (Zellweger)* Coffin-Lowry syndrome Congenital muscular dystrophy with cerebral/cerebellar dysplasia Dandy-Walker malformation Hemimegalencephaly† Hemimegalencephaly, isolated (sporadic) Hemimegalencephaly associated with epildermal nevus or especially proteus syndrome Holoprosencephaly‡ Holoprosencephaly Holoprosencephaly Holoprosencephaly Holoprosencephaly Holoprosencephaly Holoprosencephaly Joubert syndrome (JBTS1) Joubert syndrome (JBTS2) Joubert syndrome (JBTS3) Joubert syndrome with nephronophthisis Kallmann syndrome* Lissencephaly I (isolated and Miller-Dieker syndrome) Lissencephaly II with cerebellar hypoplasia Lissencephaly II, muscle-eye-brain disease Lissencephaly II, Walker-Warburg syndrome Lissencephaly II, Fukuyama muscular dystrophy Lissencephaly with genital anomalies Meckel-Grüber syndrome Microcephaly, primary Midbrain agenesis and cerebellar hypoplasia Periventricular nodular heterotopia Periventricular nodular heterotopia Periventricular nodular heterotopia and posterior pituitary ectopia Pituitary aplasia, ectopia (neurohypophysis) Pituitary aplasia (adenohypophysis) Pontocerebellar hypoplasia, nondyskinetic Rett syndrome Sacral agenesis§

Symbol: Gene or Transcription Product

Locus

AR AR XR AR AR XR AR AD AR

PAX6 SLC12A6 for transporter protein CC3 ribonuclease H2 subunits OPHN1 VLDLR DCX RSK2 FKRP (fukutin)

Xq12 Xq22.3-q23 Xp22.2 2q36.1 Xq28

L1-CAM AKT3; somatic mutation AKT1; somatic mutation

AD, AR AR; sporadic AR; sporadic AD, sporadic AR; sporadic AR; sporadic AR; sporadic AR AR AR AR XR AR AR AR AR AR XR AR AR ?AR; sporadic XD AD AR AR

7q36-qter 13q32 2q21 18p11.3 q22.3 10q11.2 9q34.3 11p11.2-q12.3 6q23 ? Xp22.3 17p13.3 7q22 1p32

1pq25-q32 7q36 Xq28 ?

AR XD AD

Schizencephaly Septo-optic-pituitary dysplasia Sotos syndrome (megalencephaly) Subcortical laminar heterotopia (band heterotopia) Tuberous sclerosis

AR AR; sporadic AD, AR, sporadic XD AD

X-linked hydrocephalus (X-linked aqueductal stenosis and pachygyria)

XR

7q11-21 Xq28 7q36.1-qter 1q41-q42.1 Unknown 3p21.1-p21.2 5q35 Xq22.3-q23 9q34.3, 16p13.3 Xq28

SHH ZIC2 SIX3 TGIF PTCH (SHH receptor) DKK (head inducer) Dhcr7 (SHH-related) ? ? AHI1; jouberin NPHP1 KAL1;EMX2 LIS1 RELN POMGnT1 POMGnT1 fukutin ARX MKS3; meckelin MCPH5 EN2 FLN-A ? HESX1 HESX1 Pitx2 ? MECP2 SHH HLXB9 HESX1, PAX3 NSD1 DCX TSC1; hamartin TSC2; tuberin L1-CAM

*The DCX (doublecortin) mutation is primary in subcortical laminar heterotopia but also is described in Zellweger syndrome, though it is likely only a secondary defect in this lysosomal disease associated with major neuroblast migratory defects; DCX is localized on the X chromosome, and Zellweger syndrome is an autosomal recessive trait. DCX also is a secondary genetic defect in Kallmann syndrome (anosmia due to agenesis or defective migration of olfactory bulb neurons and hypogonadotropic hypogonadism, the hypothalamic secretory cells having the same origin as the olfactory neurons).

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TABLE 89.1 Genetic Loci of Known Human Mutations in Central Nervous System Malformations—cont’d †The

role of L1-CAM in hemimegalencephaly is not certain and is more likely a secondary defect and not the primary genetic mutation. is associated with many chromosomal defects in addition to those listed here, but the gene products associated with the others have not yet been identified. Only 20% of genetically studied cases have one of the six genetic mutations demonstrated. §Sacral agenesis (AD form) maps to the same locus at 7q36 as one form of holoprosencephaly and also is associated with defective SHH expression, the same genetic defect expressed at opposite ends of the neural tube. Both sacral agenesis and holoprosencephaly also occur with a high incidence in infants born to mothers with diabetes mellitus. Agenesis of more than two vertebral bodies is generally associated with dysplasia of the spinal cord in that region during fetal development: fusion of ventral horns; deformed central canal with heterotopic ependyma, consistent with defective neural induction. A second gene with a locus at 1q41-q42.1 is also identified as another cause of autosomal dominantly transmitted sacral agenesis. AD, Autosomal dominant; AR, autosomal recessive; CAM, cell adhesion molecule; OPHN1, oligophrenin-1; RELN, Reelin; SHH, Sonic hedgehog; TGIF, TG-interacting factor; XD, X-linked dominant; XR, X-linked recessive. ‡Holoprosencephaly

whereas others act over many weeks or throughout gestation (e.g., congenital infections, maternal diabetes mellitus, and genetic or chromosomal defects). Even brief insults may have profound influences on later development by interfering with processes essential to initiate the next stage of development. Often this makes the timing of an adverse event difficult. Timing of onset of mutated genetic expression or of embryonic or fetal exposure to a teratogenic exogenous toxin is one of the most important determinants of the nature and extent of cerebral malformations (Sarnat, 2018a; Sarnat and Flores-Sarnat, 2017). The anatomical and physiological correlates of neurological maturation reflect the growth and development of the individual neuron and its synaptic relations with other neurons. The mature neuron is a secretory cell with an electrically polarized membrane. Though endocrine and exocrine cells are secretory and muscle cells possess excitable membranes, only neurons embrace both functions. Some epithelial cells are adherent to neighboring cells forming a sheet of epithelium or glandular villi, and have weakly polarized membranes, but they are not excitable. The precursors of neurons are neither secretory nor excitable. The cytological maturation of neurons is an aspect of ontogenesis that is as important as is their spatial relations with other cells, both for future function and for the pathogenesis of some functional neurological disorders of infancy such as neonatal seizures (Sarnat, 2013, 2015; Sarnat and Flores-Sarnat, 2014). Neuroblasts are postmitotic neuroepithelial cells committed to neuronal lineage. These cells have not yet achieved all functions of mature neurons such as membrane polarity, secretion, and synaptic relations with other neurons, and often they are still migratory. Use of the term blast is different for neural development than for hematopoieses, in which blast cells are still in the mitotic cycle or may even be neoplastic. The events of neural maturation after initial induction and formation of the neural tube are each predictive of specific types of malformation of the brain and of later abnormal neurological function. These are (1) neurulation or formation of the neural tube, (2) mitotic proliferation of neuroblasts, (3) programmed death of excess neuroblasts, (4) neuroblast migration, (5) growth of axons and dendrites, (6) electrical polarity of the cell membrane and the energy pump to maintain a resting membrane potential, (7) synaptogenesis, (8) biosynthesis of neurotransmitters, and (9) myelination of axons. Malformations of the nervous system are unique. No two individual cases are identical, even when categorized as the same anatomical malformation, such as alobar holoprosencephaly (HPE), syndromic or isolated agenesis of the corpus callosum, and types 1 and 2 lissencephaly. Functional expression of anatomically similar cases also may vary widely. For example, two cases of HPE with nearly identical imaging findings and similar histological patterns of cortical architecture and subcortical heterotopia at autopsy may differ in that one infant may have epilepsy refractory to pharmacological control, whereas the other may have no clinical seizures at all. The difference may be at the level of synaptic organization

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and the relative maturation of afferent input and neuronal maturation (Sarnat and Born, 1999; Sarnat et al., 2010). A discussion of the critical sequence of events in neural maturation follows.

NEURULATION Neurulation refers to the formation and closure of the neural tube. The formation of the neural tube from the neural plate starts with the establishment of the axis in the neural plate. The three early axes—longitudinal, horizontal, and vertical—persist during life and correspond to the basic body plan of all vertebrates (Sarnat and Flores-Sarnat, 2001b). Gastrulation occurs at 16 days’ gestation in the human; the Henson node and primitive streak establish bilateral symmetry as the basic body plan and the three axes of the body, as well as of the future neural tube. A flat neural plate is formed around the primitive streak and is the earliest differentiation of a neuroepithelium. The lateral margins of this neuroepithelial neural plate contain the precursors of neural crest cells. Shortly thereafter, grooving and bending of the neural plate occurs in the rostrocaudal axis. Subsequent closure of the lateral margins of the folding neural placode ensues in the dorsal midline to form the neural tube. To accomplish closure, intercellular filaments interdigit cells of the two sides to form a veil at midline closure points and the neuropores. At this time, the neural crest separates bilaterally at the two fusing lips of the closing neural tube, and its cells migrate along predetermined pathways to form the peripheral nervous system including autonomic ganglion cells and their axons and Schwann cells, chromaffin tissue, melanocytes, adipocytes, blood vessels, and various other cells derived from all three of the traditional germ layers: ectoderm, mesoderm, and endoderm. Because of the pervasiveness of neural crest derivatives and the expression of the same genes in all germ layers, Hall has proposed that the neural crest be regarded as a fourth germ layer with status equal to the other three (Hall, 2009). Neural crest cells terminally differentiate only after reaching their final destination. The inhibitory function of versican, a chondroitin sulfate proteoglycan, is an important factor of the extracellular matrix for neural crest cell migration (Dutt et al., 2006). The process just described is primary neurulation. Another process, secondary neurulation, occurs in the most caudal regions of the spinal cord and is limited to the lower sacral region, the part of the incipient spinal cord that formed caudal to the posterior neuropore, which is not at the extreme posterior end of the neural placode. During secondary neurulation, rather than the ependyma forming from the dorsal surface of the placode, which then becomes folded, a central canal grows rostrally from the posterior end of the solid cylinder of neural tissue within its core. It may or may not reach the central canal of primary neurulation more rostrally, and often in the midgestational or earlier fetus in particular, a transverse section through the lower sacral spinal cord reveals two ependymal-lined central canals, both in the vertical

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axis and one above the other. This is a normal condition, by contrast with two central canals side-by-side in the horizontal axis, at any level of the spinal cord, which represents duplication from the overexpression of a dorsalizing gene in the vertical axis of the neural tube and is found in some malformations. Following neurulation, an associated process begins: segmentation of the neural tube and its compartmental division into neuromeres (called rhombomeres in the hindbrain). Segmentation of the neural tube is one of three independent segmentation processes in the vertebrate body, the others being the branchial arches and the somites (Graham et al., 2014).

Disorders of Neurulation (1–4 Weeks’ Gestation) Incomplete or defective formation of the neural tube from the neural placode is the most common type of CNS malformation in the human. Anencephaly and meningomyelocele are the most frequent forms. Anencephaly (aprosencephaly with open cranium) is a failure of the anterior neuropore to close at 24 days’ gestation, or perhaps to remain closed. The lamina terminalis and its derivatives fail to form, and most forebrain structures do not develop. Structures derived from the ventral part of the lamina terminalis, the basal telencephalic nuclei, may form imperfectly. Because the deficient forebrain neuroectoderm does not induce development of the overlying mesoderm, the cranium, meninges, and scalp do not close in the sagittal midline, exposing the remaining brain tissue to the surrounding amniotic fluid throughout gestation. The original induction failure, however, is probably that of mesodermal tissue on neuroectoderm, and is due to a defective rostral end of the notochord. Failure of craniofacial induction by the neural tube, mediated through the prosencephalic and mesencephalic neural crest, is another major pathogenetic factor (Sarnat and Flores-Sarnat, 2005). The small nodule of residual telencephalic tissue called the area cerebrovasculosa consists of haphazardly oriented mature and immature neurons, glial cells, and nerve fibers. Perfusing this neural matrix is an extensive proliferation of small, thin-walled vascular channels, so concentrated in places as to resemble a cavernous hemangioma. This abnormal vasculature, particularly prominent at the surface of the telencephalic nodule, is probably the result of a necrotizing and resorptive process. Cephaloceles (encephalocele, exencephaly) are less serious defects than those found in anencephaly. A cephalocele is a mass of neural tissue protruded through a developmental defect in the cranium. The cerebral tissue in the cephalocele sac is usually extremely hamartomatous without recognized architecture. It may include heterotopia from an unexpected site. Zones of infarction, hemorrhage, calcifications, and extensive proliferations of thin-walled vascular channels are common, approaching the disorganized tissue of the area cerebrovasculosa of anencephaly. The remaining intracranial brain is often dysplastic as well. The ventricular system may be partially incorporated into the cephalocele sac. Meningomyelocele (spinal dysraphism, rachischisis, spina bifida cystica) involves the caudal end of the neural tube and results from the posterior neuropore not closing at 28 days prenatally. The hypothesis that meningomyelocele and atelencephaly are due to increased pressure and volume of fluid within the primordial ventricular system of the developing neural tube, which causes rupture at one end and prevents reclosure, has not been widely embraced. Formation of the choroid plexuses has not yet occurred at the time of neural tube closure, and embryological evidence of hydrocephalus at that stage in experimental animals is lacking. Although many mechanical theories have been proposed and several teratogenic drugs, hypervitaminosis A, and genetic models are able to produce neural tube defects and hydrocephalus in experimental animals, none explains the pathogenesis of faulty neurulation in humans. F ECF

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MITOTIC PROLIFERATION OF NEUROBLASTS (NEURONOGENESIS) After formation of the neural tube, proliferation of neuroepithelial cells in the ventricular zone associated with mitoses at the ventricular surface generates neurons and glial cells. The rate of division is greatest during the early first trimester in the spinal cord and brainstem and during the late first and early second trimester in the forebrain. Within the ventricular zone of the human fetal telencephalon, only 33 mitotic cycles provide the total number of neurons required for the mature human cerebral cortex (10 cycles in rodents), because of an exponential increase (Caviness et al., 1981). Most mitotic activity in the neuroepithelium occurs at the ventricular surface, and the orientation of the mitotic spindle determines the subsequent immediate fate of the daughter cells. If the cleavage plane is perpendicular to the ventricular surface, the two daughter cells become equal neuroepithelial cells preparing for further mitosis. If, however, the cleavage is parallel to the ventricular surface, the two daughter cells are unequal (asymmetrical cleavage). In that case, the one at the ventricular surface becomes another neuroepithelial cell, whereas the one away from the ventricular surface separates from its ventricular attachment and becomes a postmitotic neuroblast ready to migrate to the cortical plate. Furthermore, the products of two genes that determine cell fate, called numb and notch, are on different sides of the neuroepithelial cell. Therefore, with symmetrical cleavages, both daughter cells receive the same amount of each, but. With asymmetrical cleavage, the cells receive unequal ratios of each, which also influences their subsequent development (Mione et al., 1997). The orientation of the mitotic spindle requires centractin. The mitotic spindle, the strands of which are microtubules, is linked to the plasma membrane during the splitting of the cytoplasm (cytokinesis) by a protein complex called centralspindlin (Lekomtsev et al., 2012). Active mitoses cease well before the time of birth in most parts of the human nervous system, but a few sites retain a potential for postnatal mitoses of neuroblasts. One recognized site is the periventricular region of the cerebral hemispheres (Kendler and Golden, 1996). Another is the external granular layer of the cerebellar cortex, where occasional mitoses persist until 1 year of age. Postnatal regeneration of these neurons after destruction of most by irradiation or cytotoxic drugs occurs in animals and may occur in humans as well. Primary olfactory receptor neurons also retain a potential for regeneration. In fact, if a constant turnover of these neurons in the olfactory epithelium did not occur throughout life, the individual would become anosmic after a few upper respiratory infections, which transiently denude the intranasal epithelium. Neuronogenesis also involves the biosynthesis of cell-specific proteins. Many of these are detectable in the germinal matrix as evidence of early commitment of cells not only to a neuronal lineage but also to a fate as a specific type of neuron. The previously held concept that germinal matrix cells were uniformly undifferentiated postmitotic neuroepithelial cells was incorrect. But a population of “stem cells” with mitotic potential also is present in the subventricular zone and just beneath the hippocampal dentate gyrus (Johansson et al., 1999). These have generated considerable interest because of a potential for regeneration of the damaged adult brain and because they may be induced to mature as neurons (Schuldiner et al., 2001). Transplanted stem cells have an increased risk of neoplastic transformation, however (Dlouhy et al., 2014). Cultures of stem cells not only can generate neurons but also may even generate a poorly formed miniature cortex or whole brain (Lancaster et al., 2013; van den Ameele et al., 2014). 02 .4.(1( 4 (

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e

c sp

Fig. 89.1 Severe Cerebral Hypoplasia. The brain of this full-term neonate weighed only 12.6 g (normal mean is 350 g), although the cranium was closed and mainly filled with fluid. The dysplastic architecture of the telencephalon, including dysplastic cerebellar tissue, extended into a frontal encephalocele (e) and was not that of a neural tube defect or fetal infarction. The spinal cord (sp) is well formed except for the absence of descending tracts. The cerebellum (c) is small but normally laminated. This brain probably represents lack of neuronal proliferation. Note the well-formed fossae at the base of the skull, despite the absence of cerebral development. (Reproduced with permission from Sarnat, H.B., de Mello, D.E., Blair, J.D., et al., 1982. Heterotopic growth of dysplastic cerebellum in frontal encephalocele in an infant of a diabetic mother. Can J Neurol Sci. 9, 31–35.)

Disorders of Neuronogenesis Destructive processes may destroy so many neuroblasts that regeneration of the full complement of cells is impossible. This happens when the insult persists for a long time or is repetitive, destroying each subsequent generation of dividing cells. Inadequate mitotic proliferation of neuroblasts results in hypoplasia of the brain (Fig. 89.1). Such brains are small and grossly malformed, either because of a direct effect on neuroblast migration or by destruction of the glial cells with radial processes that guide migrating nerve cells. The entire brain may be affected, or portions may be selectively involved. Cerebellar hypoplasia often is a selective interference with proliferation of the external granular layer. In some cases, cerebral hypoplasia and microcephaly are the result of precocious development of the ependyma before all mitotic cycles of the neuroepithelium are complete, because ependymal differentiation arrests mitotic activity at the ventricular surface. The mutation of a gene that programs neuronogenesis may be another explanation for generating insufficient neuroepithelial cells. In somatic mutations that give rise to hamartomatous malformations of the brain, such as hemimegalencephaly and tuberous sclerosis, the genetic program for neuronal lineage, differentiation, and cellular growth is altered such that proliferation may be deficient and those neuroblasts that do form are dysmorphic, often megalocytic, and do not function normally, including becoming epileptogenic.

PROGRAMMED CELL DEATH (APOPTOSIS) Normal mitotic proliferation produces excessive neuroblasts in every part of the nervous system. Reduction of this abundance by 30%–50% is by a programmed process of cell death, or apoptosis, until achieving the definitive number of immature neurons. The factors that arrest the process of apoptosis in the fetus are multiple and are in part genetically determined. Cells that do not match with targets are more vulnerable to degeneration than those that achieve synaptic contact with other cells. Endocrine hormones and neuropeptides modulate apoptosis.

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Some homeotic genes such as c-fos are important in the regulation of apoptosis in the nervous system, and other suppressor genes stop the expression of apoptotic genes. Caspase-3 is a key mediator of apoptosis, a protease activated as early as neural tube formation; it also is active in many neurodegenerative diseases (D’Amelio et al., 2012). During apoptosis, cells break up into membrane-bound fragments, a process regulated by the protein pannexin-1, which has its own membrane channels; it can be deregulated by quinolone antibiotics (Poon et al., 2014). Two phases of apoptosis are distinguished. One involves as-yet undifferentiated neuroepithelial cells or neuroblasts with incomplete differentiation; the other phase involves fully differentiated neurons of the fetal brain. The first phase begins during embryonic life and may extend to midgestation in some parts of the brain (e.g., periventricular telencephalic neuroepithelium) until ependyma differentiates at the ventricular surface. The second phase may be ongoing throughout life, as occurs in primary olfactory neurons of the nasal mucosa, and in the olfactory bulb and hippocampus, closely associated with a reservoir of stem cell progenitors. In addition to cellular apoptosis, mitochondria within cells also undergo a similar autophagy (mitophagy), largely mediated by the genes Parkin and PINK1, mutations of which explain some hereditary neurodegenerative diseases (Scarffe et al., 2014).

Disorders of Programmed Cell Death Spinal muscular atrophy (see Chapter 98) is an example of a human disease caused by apoptosis not stopping at the proper time. In this disorder, continued loss of spinal motor neurons (SMNs) after the normal deletion of surplus embryonic neuroblasts expresses itself as a progressive denervating process. Genetic factors are crucial in determining the arrest of cell death, which accounts for the hereditary character of spinal muscular atrophy. The SMN defective gene at the chromosome 5q13.1 locus has now been isolated and is normally responsible for arresting apoptosis in motor neuroblasts (Roy et al., 1995). Other neurodegenerative diseases of fetal life and infancy are more widespread within the CNS, rather than limited to one type of neuron such as the motor neuron. The characteristic feature is also progressive neuronal loss that is apoptotic rather than necrotic in character: No inflammatory or glial reaction occurs, and the features of the DNA degradation differ from ischemic necrosis. An example is pontocerebellar hypoplasia, a group of progressive degenerative diseases that begin prenatally and continue postnatally (Barth et al., 1995). Despite the name, they involve much more than the cerebellar system. These diseases are associated with extensive cerebral cortical and basal ganglionic abnormalities even in motor neurons, which cause a clinical presentation at birth resembling spinal muscular atrophy. This autosomal recessive group of diseases, all genetically distinct from olivopontocerebellar atrophy, exemplifies a semantic difficulty. If an atrophic process begins before development is complete, it results in both hypoplasia and superimposed atrophy. In the CNS, glial cells also undergo apoptosis. Glial necrosis intimately links to the interhemispheric passage of commissural fibers in the corpus callosum. In a murine model of callosal agenesis, glial cells that do not degenerate act as a barrier to crossing axons and prevent the corpus callosum from forming.

NEUROBLAST MIGRATION No neurons of the mature human brain occupy their site of generation from the neuroepithelium. They migrate to their mature site to establish the proper synaptic connections with appropriate neighboring neurons and send their axons in short or long trajectories to targets. The subependymal germinal matrix (Fig. 89.2) is the subventricular

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zone of the embryonic concentric layers and consists of postmitotic premigratory neuroblasts and glioblasts. In general, the movement of maturing nerve cells is centrifugal, radiating toward the surface of the brain. The cerebellar cortex is exceptional in that external granule cells first spread over the surface of the cerebellum and then migrate into the folia. Migration of neuroblasts begins at about 6 weeks’ gestation in the human cerebrum and is not completed until at least 34 weeks of fetal life, although the majority of germinal matrix cells after midgestation are glioblasts. Glioblasts continue to migrate until early in the postnatal period. Within the brainstem, neuroblast migration is complete by 2 months’ gestation. Cerebellar external granule cells continue migrating throughout the first year of life. Neuroblast migration permits a three-dimensional spatial relationship to develop between neurons, which facilitates the formation of complex synaptic circuits. The timing and sequence of successive waves of migrating neuroblasts are precise. In the cerebral cortex, immature nerve cells reach the pial surface and then form deeper layers

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Fig. 89.2 Coronal section of forebrain of 16-week normal fetus, showing extensive subependymal germinal matrix (g) of neuroblasts and glial precursors that have not yet migrated. The surface of the brain is just beginning to develop sulci (arrowheads). Migrating neuroblasts (m) are seen in the subcortical white matter. The corpus callosum (cc) is artifactually ruptured, and the two hemispheres should be closely approximated. (Hematoxylin-eosin stain.) cn, Caudate nucleus; ic, anterior limb of internal capsule.

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as more recent arrivals replace their position at the surface. Neurons forming the most superficial layers of neocortex are thus the last to have migrated, although in the three-layered hippocampus, the most superficial neurons represent the earliest migratory wave. Three major groups of molecules control neuroblast migration (Gressens, 2006): (1) molecules of the cytoskeleton that determine the initiation (filamin-A and ADP-ribosylation factor GEF2) and ongoing progression (doublecortin and LIS1) of neuroblast movement; (2) signaling molecules involved in lamination, including reelin and other proteins not yet associated with human diseases; and (3) molecules modulating glycosylation that provide stop signals to migrating neuroblasts (e.g., POMT1 [protein O-mannosyl-transferase], involved in WalkerWarburg syndrome; POMGnT1 [protein O-mannose β-1,2-N-acetylglucosaminyltransferase], involved in muscle-eye-brain disease; and fukutin, involved in Fukuyama muscular dystrophy). The laminated arrangement of the mammalian cerebral cortex requires a large cortical surface area to accommodate increasing numbers of migrating neuroblasts and glioblasts. Initially the cortical plate shows no histological layering, a process beginning at about midgestation, but rather has an immature columnar architecture. The lamination is superimposed upon this columnar pattern, but columnar architecture is still seen postnatally, particularly at the crowns of gyri and the depths of sulci. Even before histological lamination is evident, ribonucleic acid (RNA) probes for specific neuronal identities can already detect future organization of the cortical plate (Hevner, 2007). Convolutions provide this large surface area without incurring a concomitant increase in cerebral volume. The formation of gyri and sulci is thus a direct result of migration (Fig. 89.3). Most gyri form in the second half of gestation, which is a period of predominant gliogenesis and glial cell migration. Therefore, the proliferation of glia in the cortex and subcortical white matter may be more important than neuroblast migrations in the formation of convolutions, but the growth of dendrites and synaptogenesis also may influence gyration by contributing mass to the neuropil.

Major Mechanisms of Neuroblast Migration: Radial Glial Fiber Guides and Tangential Migration along Axons The majority of neuroblasts arriving at the cortical plate do so by means of radial glial guides from the subventricular zone. A second route, tangential migration, uses axons as the guides for the migratory

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Fig. 89.3 Lateral (A) and ventral (B) views of a normal brain of a 16-week fetus. Primary fissures (e.g., sylvian, calcarine) are formed early in gestation, but primary sulci, such as the central and parieto-occipital, form at midgestation, and secondary and tertiary sulci and gyri develop after 22 weeks. At midgestation the surface of the cortex is essentially smooth.

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Fig. 89.4 Radial glial fibers extending from subependymal region (right) toward cerebral cortex (left), guiding migrating neuroblasts in a 16-week fetus. (Glial fibrillary acidic protein reaction. Bar = 10 µm.)

neuroblasts. The genetically determined programming of neuroblast migration begins when cells are still undifferentiated neuroepithelial cells and even before all their mitotic cycles are complete. Neuroepithelial cells express the gene products of the lissencephaly gene (LIS1), as do ependymal cells and Cajal-Retzius cells of the molecular layer of cerebral cortex. The expression of this gene is defective in type 1 lissencephaly (Miller-Dieker syndrome), a severe disorder of neuroblast migration (Clark et al., 1997). An understanding of its function in migration is incomplete. The guidance of most neurons of the forebrain to their predetermined site from the germinal matrix (embryonic subventricular zone) is by long radiating fibers of specialized fetal astrocytes (Fig. 89.4). The elongated processes of these glial cells span the entire wall of the fetal cerebral hemisphere; their cell bodies are in the periventricular region, and their terminal endfeet are on the limiting pial membrane at the surface of the brain (see Fig. 89.4). Radial glial cells are the first astroglial cells of the human nervous system converted into a mature fibrillary astrocyte of the subcortical white matter; some are still present at birth. Mature astrocytes are present throughout the CNS by 15 weeks’ gestation, and gliogenesis continues throughout fetal and postnatal life. Several types of glial cells are recognizable between 20 and 36 weeks’ gestation. Facilitating the mechanical process of neuroblasts gliding along a radial glial fiber are several specialized proteins at the radial glial fiber surface membrane or extracellular space. An example is astrotactin, secreted by the neuroblast (Zheng et al., 1996). Glial cells and neural cell adhesion molecules also facilitate gliding (Jouet and Kenwrick, 1995). These adhesion molecules must be deactivated when the migratory neuroblast reaches the neural plate so that the next arriving neuroblast on the same radial glial fiber can bypass the first to establish the inside-out arrangement of the cortical plate, with the earliest migratory waves forming the deep layers and the last arrivals forming the superficial layers. Fetal ependymal cells have radiating processes that resemble those of the radial glial cell but do not extend beyond the germinal matrix and secrete molecules in the extracellular matrix. Some adhesion molecules are present in the extracellular matrix (Thomas et al., 1996). These molecules serve as lubricants, as adhesion molecules between the membranes of the neuroblast and the radial glial fiber, and as nutritive and growth factors. They stimulate cell movement. Deficient molecules lead to defective migration. For example, the abnormality of the L1 adhesion molecule is the defective genetic program in X-linked hydrocephalus accompanied by polymicrogyria and pachygyria. Other inhibitory cell adhesion molecules also are essential for detachment of neuroblasts from radial glia (Anton et al., 1996).

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The process of transformation of radial glial cells into astrocytes and ependymal cells begins during the first half of gestation and completes postnatally. During midgestation when neuronal migration is at a peak, many radial glial cells remain attached to the ventricular and pial surfaces, increasing in length and curving with the expansion and convolution of the cerebral wall. From 28 weeks’ gestation to 6 years of age, astrocytes of the frontal lobe shift from the periventricular to the subcortical region. The centrifugal movement of this band of normal gliosis marks the end of neuronal migration in the cerebral mantle. Ependyma does not completely line the lateral ventricles until 22 weeks’ gestation. Studies of messenger RNA (mRNA) in individual glioblasts indicate that these immature glial precursors already exhibit differences related to their final differentiation (Rao et al., 2016). Radial glial cells also act as resident stem cells in the fetal brain. In the presence of injury, such as a cortical microinfarct, radial glia are capable of differentiating as neurons to replace those that were lost. Radial glia express nestin and other primitive proteins found only in cells of multipotential lineage or that participate in early developmental processes, such as floor-plate ependymal cells. In addition to the radial migration to the cerebral cortex, tangential migration also occurs, but the number of neuroblasts is far smaller (Rakic, 1995; Takano et al., 2004). These migrations perpendicular to the radial fibers probably use axons rather than glial processes as guides for migratory neuroblasts. This explains why not all cells in a given region of cortex are from the same clone or vertical column. Most of the tangentially migrating neuroblasts in the cerebral cortical plate are generated in the fetal ganglionic eminence, a deep telencephalic structure of the germinal matrix that gives origin to basal ganglionic neurons and to the γ-aminobutyric acid (GABA)-ergic inhibitory interneurons of the cerebral cortex. These neurons in the cortex from tangential migration have some unique metabolic features and distinctive immunoreactivities in tissue section for antibodies against soluble calcium-binding molecules, such as calretinin and parvalbumin (Sarnat, 2013; Takano et al., 2004; Ulfig, 2002). Calretinin-reactive inhibitory interneurons in the cerebral cortex comprise about 12% of total neurons and are a subset of total neurons arriving at the cortical plate by tangential migration, which represent about 20% of total cortical neurons. These also include a population of disinhibitory interneurons that suppress the activity of inhibitory interneurons (Pi et al., 2013). Tangential migrations occur in the brainstem and olfactory bulb as well as in the cerebrum. The subpial region is another site of neuroblast migration that does not use radial glial cells. Calretinin-reactive neurons are in the cerebellum as well as the cerebral cortex (Yew et al., 1997), particularly Purkinje cells, basket cells, and neurons of the dentate and inferior olivary nuclei of the cerebellar system, but not those of the pontine nuclei, which similarly originated in the rhombic lip of His.

Disorders of Neuroblast Migration Nearly all malformations of the brain are a direct result of faulty neuroblast migration, or at least involve a secondary impairment of migration. Imperfect cortical lamination, abnormal gyral development, subcortical heterotopia, and other focal dysplasias relate to some factor that interferes with neuronal migration, whether vascular, traumatic, metabolic, or infectious. The most severe migratory defects occur in early gestation (8–15 weeks), often associated with even earlier events in the gross formation of the neural tube and cerebral vesicles. Heterotopia of brainstem nuclei also occurs. Later defects of migration are expressed as disorders of cortical lamination or gyration such as lissencephaly, pachygyria, and cerebellar dysplasias. Insults during the third trimester cause subtle or focal abnormalities of cerebral architecture that may express in infancy or childhood as epilepsy.

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Most disturbances of neuroblast migration involve arrested migration before the journey is complete. These disorders are divisible into three anatomical phases, depending on where the migratory arrest occurred. An example of neuroblasts never having begun migration from the periventricular region is periventricular nodular heterotopia, an X-linked genetic disorder due to defective expression of the gene, filamin-A (FLNA). Subcortical laminar heterotopia results when neuroblasts begin migration but arrest in the subcortical white matter before reaching the cortical plate. This is another X-linked recessive trait but is due to a different gene called doublecortin (DCX). The term double cortex is sometimes used, but this name is incorrect because unlike a true cortex, the subcortical heterotopia lacks lamination. If the neuroblasts reach the cortical plate but lack correct lamination, accompanying this abnormal architecture of the cortical plate are abnormalities of gyration such as lissencephaly or pachygyria. Several different genes, including LIS1 and reelin (RLN), are important in cortical plate organization (Curran and D’Arcangelo, 1998) and mutated in malformations of the terminal phase of neuroblast migration. Lissencephaly is a condition of a smooth cerebral cortex without convolutions. Normally at midgestation, the brain is essentially smooth; the interhemispheric, sylvian, and calcarine fissures are the only ones formed. Gyri and sulci develop between 20 and 36 weeks’ gestation, and the mature pattern of gyration is evident at term, although some parts of the cerebral cortex (e.g., frontal lobes) are still relatively small. In lissencephaly type 1 (Miller-Dieker syndrome), the cerebral cortex remains smooth. Lesser degrees of this gross morphological defect exist, with a few excessively wide gyri (pachygyria) or multiple excessively small gyri (polymicrogyria). The histopathological pattern is that of a four-layer cortex in which the outermost layer (1) is the molecular layer, as in normal six-layered neocortex. Layer 2 corresponds to layers 2 through 6 of normal neocortex, layer 3 is cell-sparse as a persistent fetal subplate zone, and layer 4 consists of incompletely migrated neurons in the subcortical intermediate zone. In lissencephaly type 2 (Walker-Warburg syndrome), poorly laminated cortex with disorganized and disoriented neurons is seen histologically, and the gross appearance of the cerebrum is one of a smooth brain or a few poorly formed sulci (Fig. 89.5). The term cobblestone refers to the aspect of the surface, with multiple shallow furrows not corresponding to normal sulci. The cerebral mantle may be thin, suggesting a disturbance of cell proliferation as well as of neuroblast migration. Malformations of the brainstem and cerebellum often are present as well (see Fig. 89.5). Lissencephaly type 1 and type 2 (Walker-Warburg syndrome, Fukuyama muscular dystrophy, muscle-eye-brain disease of Santavuori) are genetic diseases. LIS1 was the first gene discovered in the lissencephalies, but many more have now been identified (Fry et al. 2014). Lissencephaly also results from nongenetic disturbances of neuroepithelial proliferation or neuroblast migration, including destructive encephaloclastic processes such as congenital infections during fetal life. More recently it has been recognized that the lissencephalies, including those resulting from mutations in LIS1, DCX, and ARX genes, are disturbances not only in radial migration but also involve tangentially migrating neuroblasts (Marcorelles et al., 2010). Other abnormal patterns of gross gyration of the cerebral cortex occur secondary to neuroblast migratory disorders. Pachygyria signifies abnormally large, poorly formed gyri and may be present in some regions of cerebral cortex, with lissencephaly in other regions. Polymicrogyria refers to excessively numerous and abnormally small gyri that similarly may coexist with pachygyria. The small gyri often show fusion of adjacent molecular zones and other gaps in the pial membrane and leptomeninges that also result in overmigration (Squier and Jansen, 2014). However, polymicrogyria does not necessarily always denote a primary migratory disorder of genetic origin.

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Fig. 89.5 Sagittal T1-weighted magnetic resonance image of a 10-month-old girl with lissencephaly type 2 and Dandy-Walker malformation. The cerebral mantle is thin, and the lateral ventricles are greatly enlarged. A few abnormal shallow fissures at the cerebral surface may indicate abortive gyration or pachygyria. The cerebellum is severely hypoplastic (arrow indicates anterior vermis), and the posterior fossa contains a large fluid-filled cyst. The brainstem also is hypoplastic, and the basis pontis is nearly absent. A differential diagnosis of this image is pontocerebellar hypoplasia, but the high position of the torcula indicates a Dandy-Walker malformation.

Small, poorly formed gyri may occur in zones of fetal ischemia, and they regularly surround porencephalic cysts due to middle cerebral artery occlusion in fetal life. In the cerebral hemisphere, most germinal matrix cells become neurons during the first half of gestation, and most form glia during the second half of gestation. Nonetheless, a small number of germinal matrix cells are neuronal precursors, migrating into the cerebral cortex in late gestation. Because the migration of the external granular layer in the cerebellar cortex is incomplete until 1 year of age, a potential for acquired insults to interfere with late migrations persists throughout the perinatal period. Anatomical lesions such as periventricular leukomalacia, intracerebral hemorrhages and abscesses, hydrocephalus, and traumatic injuries may disrupt the delicate radial glial guide fibers and prevent normal migration even though the migrating cell itself may escape the focal destructive lesion. Damaged radial glial cells tend to retract their processes from the pial surface. The migrating neuron travels only as far as its retracted glial fibers carry it. If this fiber retracts into the subcortical white matter, the neuroblast stops there and matures, becoming an isolated heterotopic nodule composed of several nerve cells that were migrating at the same time in the same place. In these nodules, neurons of various cortical types differentiate without laminar organization and with haphazard orientations of their processes, but a few extrinsic axons may prevent total synaptic isolation of the nodule. Interference with the glial guide fibers in the cerebral cortex itself results in neurons either not reaching the pial surface or not being able to reverse direction and then descending to a deeper layer. The consequence is imperfect cortical lamination, which interferes with the development of synaptic circuits. These disturbances of late neuroblast migration do not produce the gross malformations of early gestation and may be undetectable by imaging techniques. They may account for many neurological sequelae after the perinatal period,

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CHAPTER 89 Developmental Disorders of the Nervous System including seizures, perceptual disorders, impairment of gross or fine motor function, learning disabilities, and intellectual disability. In sum, either defective genetic programming or acquired lesions in the fetal brain that destroy or interrupt radial glial fibers may cause disorders of neuroblast migration. Cells may not migrate at all and become mature neurons in the periventricular region, as occurs in X-linked periventricular nodular heterotopia (Eksioglu et al., 1996) and in some cases of congenital cytomegalovirus infection. Cells may become arrested along their course as heterotopic neurons in deep subcortical white matter, as occurs in many genetic syndromes of lissencephaly-pachygyria and in many metabolic diseases including cerebrohepatorenal (Zellweger) syndrome and many aminoacidurias and organic acidurias. The same aberration may occur in acquired insults to the radial glial cell during ontogenesis. Cells may overmigrate beyond the limits of the pial membrane into the meninges as ectopic neurons, either singly or in clusters known as marginal glioneuronal heterotopia, or brain warts. Rarely, herniation of the germinal matrix into the lateral ventricle may occur through gaps in the ependyma; those cells mature as neurons, forming a non-neoplastic intraventricular mass that may or may not obstruct cerebrospinal fluid (CSF) flow. Whether disoriented radial glial fibers actually guide neuroblasts to an intraventricular site or neuroblasts are physically pushed in a direction of less resistance is uncertain.

BOX 89.1

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Fissures of the Developing Brain

Forebrain Fissures Interhemispheric (4.5 weeks) Choroidal (5 weeks) Optic/ocular (5 weeks) Hippocampal (6 weeks) Sylvian (8–9 weeks) Calcarine (10–12 weeks) There also are more than 30 sulci in the mature cerebral cortex Hindbrain and Cerebellar Fissures Sagittal intercollicular (10 weeks) Transverse intercollicular (10–11 weeks) Longitudinal paravermal Transverse cerebellar fissures: Primary (anterior/posterior lobes) Posterolateral (flocculonodular lobe) Posterior superior Horizontal Prepyramidal Sagittal basilar pontine Sagittal interpyramidal

Architecture of the Cortical Plate The first wave of radial migration brings subventricular neuroblasts to the middle of the marginal zone at 7 weeks’ gestation. These initial cells forming the cortical plate separate the marginal zone into a superficial molecular layer that includes the Cajal-Retzius neurons, and the deeper subplate zone, a transitory lamina that has disappeared by about 34 weeks. More than 90% of radial migration of neuroblasts is complete by 16 weeks’ gestation, and most of the remaining immature cells of the periventricular germinal matrix yet to migrate will become glioblasts. After reaching the cortical plate, migratory neuroblasts must detach from their radial glial fiber by losing the adhesion molecule that has held it in place, so that the next migratory neuroblast may pass to a more superficial position in the mature cortex, an inside-out arrangement described by Rakic (1972, 2002) so that the deepest cortical layers are from the earliest migratory waves and layer 2 neurons are the last wave. The histological architecture of the cortical plate in the first half of gestation is radial microcolumnar. Synaptic layers between neurons also are initially radial. Horizontal lamination is superimposed, beginning at about 22 weeks’ gestation, and becomes the dominant architecture of the mature cortex. If neuroblasts cannot detach from their radial glial fiber, a disorganized cortical plate results (Anton et al., 1996). Another mechanism of cortical dysplasia is a maturational arrest with persistence of radial architecture. This pattern is seen in some metabolic diseases such as methylmalonic acidemia, in some chromosomopathies such as DiGeorge syndrome (22q11.1 deletion), and in focal cortical dysplasias type 1 (Sarnat and Flores-Sarnat, 2013a). Such maturational arrest is epileptogenic, but fetuses of less than 26 weeks cannot have seizures generated in the cortex because cortical synapses are too few. Despite the change from radial to horizontal histological layering, metabolic cell markers show specific neuronal types already positioned before this transition (Hevner, 2007). Genetic patterning of specific areas is programmed in part by the thalamocortical projections (O’Leary et al., 2007). The U-fiber layer beneath the cortex and following the gyral contours consists of short association axons of layer 6 neurons that connect different parts of the same gyrus and immediately adjacent gyri, but do not provide commissural fibers or descending projections to

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subcortical structures. U-fibers generally myelinate later than the deep white matter, except those lining primary fissures and major sulci such as the Rolandic and parieto-occipital. The U-fiber layer does not begin to form until midgestation, when gyration and sulcation of the cortex is initiated. The U-fiber layer beneath focal cortical dysplasias contains excessive neuronal dispersion from layer 6 and elaborate synaptic plexi formed from and between these displaced neurons (Sarnat et al., 2018).

FISSURES AND SULCI OF CORTICAL STRUCTURES Fissures and sulci are grooves that form in laminated cortices, principally cerebral and cerebellar. Such folding accomplishes a need for an enlarging surface area without a concomitant increase in tissue volume as development proceeds. Without gyration of the cerebral cortex and foliation of the cerebellar cortex, the brain would be so large and voluminous at birth that neither the neonate nor the mother would survive delivery. Fissures and sulci both result from mechanical forces during fetal growth, but they differ in that fissures form from external forces and sulci form from internal forces imposed by the increased volume of neuronal cytoplasm and the formation of neuropil, the processes of neurons and glial cells (Sarnat and Flores-Sarnat, 2013c). The ventricular system acts as another external force, surrounded by but outside of the brain parenchyma. Whereas fissures generally form earlier and often are deeper than sulci, these are not the most important differences. Box 89.1 lists the various fissures of the brain, and Fig. 89.6 is a drawing of the development of the human telencephalic flexure, which becomes, after closure of the operculum, the sylvian fissure. It should be noted that the ventral bending of the primitive oval-shaped telencephalic hemisphere results in the original posterior pole becoming the temporal—not the occipital—lobe, and that the lateral ventricle bends with the brain. The occipital horn of the lateral ventricle is a more recent diverticulum of the original simple ventricle and, as such, remains the most variable part of the ventricular system, symmetrical in only 25% of normal individuals. Cerebellar folia are the equivalent of cerebral cortical gyri. A temporally and spatially precise sequence of the development of fissures, sulci, and cerebellar folia is genetically programmed and enables the neuroradiologist and neuropathologist

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The proteoglycan keratan sulfate has been known since 1990 to be an important molecule in the dorsal median septum of the spinal cord that prevents rostrally growing dorsal column axons from crossing the midline before their intended destinations in the nuclei gracilis 6 wk/semester and cuneatus at the caudal medulla oblongata; aberrant decussation would confuse the brain about laterality of sensory stimuli (Snow et al., 1990). Keratan sulfate is selective, however, repelling excitatory glutamatergic axons while facilitating inhibitory GABAergic axons. The 9 wk/semester great majority of dorsal root ganglion neurons that project axons into the dorsal columns are glutamatergic, by contrast with spinothalamic fibers that mainly are GABAergic; ascending axons of the nuclei gracilis 12 wk/semester and cuneatus to the thalamus also are GABAergic. Another repulsive factor for guidance of olfactory axons away from septal receptors is a 3.5 wk/semester 4.5 wk/semester 6 wk/semester secreted protein called Slit, which is the ligand for the Slit receptor Robo (Brose et al., 1999; Li et al., 1999; Rothberg et al., 1990). Commissural axons also are enabled to cross the ventral median septum of the spi15 wk/semester nal cord that repulses longitudinal axons growing rostrally or caudally Fig. 89.6 The Telencephalic Flexure that Forms the Sylvian Fissure. in the longitudinal axis of the neural tube and early fetal spinal cord (Bovolenta and Dodd, 1990) Keratan sulfate also occurs in the forebrain and is strongly to also assess maturational delay of this aspect of ontogenesis. The expressed in early fetal life in the thalamus and globus pallidus, later gestational age of a premature infant may be determined to within a appearing in the molecular zone and later diffusely in the cortical 2-week period or less from the convolutional pattern of the brain. plate, finally becoming more localized in the deep cortical laminae and the U-fiber layer, where it impedes the penetration of axons Disorders of Fissures and Sulci from deep white-matter heterotopia so that they cannot integrate The telencephalic sylvian fissures fail to form in HPE and form abnorinto cortical synaptic circuitry and epileptic networks (Sarnat, 2019). mally in many major malformations of the brain, including lissenGranulofilamentous keratan sulfate also binds to neuronal somatic cephalies, schizencephaly, and severe cerebral hypoplasias. Abnormal membranes, but not to dendritic spines, explaining why axosomatic gyration is a regular feature of many neuroblast migratory disorders, synapses are inhibitory and axodendritic synapses are excitatory including lissencephaly, pachygyria, and polymicrogyria, and also in (Sarnat, 2019). An additional function of keratan sulfate in the brain, alobar and semilobar HPE (Sarnat et al., 2013c). Accurate diagnosis by where is it secreted by astrocytes into the intercellular matrix, is to neuroimaging thus not only is available postnatally but also by prenasurround axonal fascicles so that axons can neither enter nor exit the tal fetal magnetic resonance imaging (MRI), even though microscopic fascicles except at programmed places. Both large and long fascicles, details of cortical lamination and organization are below the resolution such as the corticospinal tract, and short fascicles, such as the coarse of these techniques. local axonal bundles within the globus pallidus and similar but smaller “pencil fibers of Wilson” within the corpus striatum, are insulated (Sarnat, 2019). Keratan sulfate also has a wider distribution in the body GROWTH OF AXONS AND DENDRITES in organs other than the CNS. It is strongly expressed in cornea, cartiDuring the course of neuroblast migration, neurons remain largely lage, bone, synovium, connective tissues, and other sites (Caterson and undifferentiated cells, and the embryonic cerebral cortex at midgestaMelrose, 2018; Pomin, 2015, 2018). It may explain why cartilage is not tion consists of vertical columns of tightly packed cells between radial penetrated by nerves except at designated foramina. blood vessels and extensive extracellular spaces. Cytodifferentiation Matrix proteins such as laminin and fibronectin also provide a begins with a proliferation of organelles, mainly endoplasmic reticusubstrate for axonal guidance. Cell-to-cell attractions operate as the lum and mitochondria in the cytoplasm, and clumping of condensed axon approaches its final target. Despite the long delay between the nuclear chromatin at the inner margin of the nuclear membrane. migration of an immature nerve cell and the beginning of dendritic Rough endoplasmic reticulum becomes swollen, and ribosomes growth, the branching of dendrites eventually accounts for more proliferate. than 90% of the synaptic surface of the mature neuron. The pattern The outgrowth of the axon always precedes the development of of dendritic ramification is specific for each type of neuron. Spines dendrites, and the axon forms connections before the differentiaform on the dendrites as short protrusions with expanded tips, protion of dendrites begins. Ramón y Cajal first noted the projection of viding sites of synaptic membrane differentiation. The Golgi method the axon toward its destination and named this growing process the of impregnation of neurons and their processes with heavy metals cone d’accroissement (growth cone). The tropic factors that guide the such as silver or mercury, used for more than a century, continues growth cone to its specific terminal synapse, whether chemical, endoto be one of the most useful methods for demonstrating dendritic crine, or electrotaxic, have been a focus of controversy for many years. arborizations. Among the many contributions of this technique to However, we now know that diffusible molecules secreted along their the study of the nervous system, beginning with the elegant piopathway by the processes of fetal ependymal cells and perhaps some neering work of Ramón y Cajal, none has surpassed its demonstraglial cells guide growth cones during their long trajectories. Some moltion of the sequence of normal dendritic branching in the human ecules (e.g., brain-derived neurotropic growth factor, netrin, S-100β fetus. Newer immunocytochemical techniques for demonstrating protein) attract growing axons, whereas others (e.g., the glycosaminodendrites also are now available, such as microtubule-associated glycan keratan sulfate—not to be confused with another very different protein 2. These techniques are applicable to human tissue resected protein, keratin) strongly repel them and thus prevent aberrant decussurgically, as in the surgical treatment of epilepsy, and to the tissue sations and other deviations. secured at autopsy. Dorsal

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Disorders of Neurite Growth If a neuron disorients during migration and faces the wrong direction in its final site, its axon is capable of reorienting itself as much as 180 degrees after emerging from the neuronal cell body. Dendrites, by contrast, conform strictly to the orientation of the cell body and do not change their axis. The dendritic tree growth stunts if axodendritic synapses are not established. Because so much dendritic differentiation and growth occurs during the last third of gestation and the first months of the postnatal period, the preterm infant is particularly vulnerable to noxious influences that interfere with maturation of dendrites. Extraordinarily long dendrites of dentate granule cells and prominent basal dendrites of pyramidal cells occur in full-term infants on life-support systems. Retardation of neuronal maturation in terms of dendrite development and spine morphology occurs more frequently in premature infants, compared with term infants of the same conceptional age, possibly as a result of asphyxia. Infants with fetal alcohol syndrome also have a reduced number and abnormal geometry of dendritic spines of cortical neurons. Traditional histological examination of the brains of intellectually disabled children often shows remarkably few alterations to account for their profound intellectual deficit. The study of dendritic morphology by the Golgi technique has revealed striking abnormalities in some of these cases. The best documentation of these alterations occurs in chromosomal diseases such as trisomy 13 and Down syndrome. Long, thin, tortuous dendritic spines and the absence of small stubby spines are a common finding. Children with unclassified intellectual disability but normal chromosomal numbers and morphology also show defects in the number, length, and spatial arrangement of dendrites and synapses. Abnormalities of cerebellar Purkinje cell dendrites occur in cerebellar dysplasias and hypoplasias. They consist of cactus-like thickenings and loss of branchlet spines. Abnormal development of the dendritic tree is also a common finding in many metabolic encephalopathies, including Krabbe disease and other leukodystrophies, Menkes kinky hair disease, gangliosidoses, ceroid lipofuscinosis, and Sanfilippo syndrome. Among genetically determined cerebral dysgeneses, reports of aberrations in the structure and number of dendrites and spines exist in cerebrohepatorenal (Zellweger) syndrome and in tuberous sclerosis.

ELECTRICAL POLARITY OF THE CELL MEMBRANE The development of membrane excitability is one of the important markers of neuronal maturation, but knowledge is incomplete about the exact timing and duration of this development. Membrane polarity establishes before synaptogenesis and before the synthesis of neurotransmitters begins. Because the maintenance of a resting membrane potential requires considerable energy expenditure to fuel the sodium-potassium pump, the undifferentiated neuroblast would be incapable of maintaining such a dynamic condition as a resting membrane potential. The development of ion channels within the neural membrane is another important factor in the maturation of excitable membranes and the maintenance of resting membrane potentials.

Disorders of Membrane Polarity Epileptic phenomena are largely due to inappropriate membrane depolarizations. They represent a complex interaction of excitatory and inhibitory synapses that modulate the resting membrane potential, metabolic alterations, and many unknown factors that also contribute to the discharge threshold of neural membranes. Cerebral malformations are often associated with seizures because of abnormal synaptic circuitry, and the role of abnormal resting membrane potentials in development is largely speculative at this time. Electrolyte imbalances

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in the serum certainly influence the depolarization threshold, and hypothalamic disturbances may alter endocrine function and electrolyte balance. Finally, abnormal membrane receptors and ion channels in the neuronal plasma membrane are the result of many recently discovered genes associated with specific types of epilepsy and may or may not have a histopathologically abnormal phenotype.

SYNAPTOGENESIS Synapse formation follows the development of dendritic spines and polarization of the cell membrane. The relation of synaptogenesis to neuroblast migration differs in different parts of the nervous system. In the cerebral cortex, synaptogenesis always follows neuroblast migration. In the cerebellar cortex, however, the external granule cells develop axonal processes that become the long parallel fibers of the molecular layer and make synaptic contact with Purkinje cell dendrites before migrating through the molecular and Purkinje cell layer to their mature internal position within the folium. Synaptophysin immunoreactivity is a useful marker for studying normal and abnormal synaptogenesis in the fetus and newborn. Throughout the brain, the precisely programmed sequence of synaptogenesis can be identified in sections of fetal brain of various gestational ages (Sarnat et al., 2010, 2013a, 2013b, 2013c). Afferent nerve fibers reach the neocortex early, before lamination occurs in the cortical plate. The first synapses are axodendritic and occur both external to and beneath the cortical plate in the future layers I and VI, which contain the first neurons that have migrated. An excessive number of synapses form on each neuron, with subsequent elimination of those that are not required. Outside the CNS, muscle fibers also begin their relation with the nervous system by receiving multiple sources of innervation from multiple motor neurons, later retaining only one. Transitory synapses also form at sites on neurons where they no longer exist in the mature condition. The SMNs of newborn kittens display prominent synapses on their initial axonal segment, where they never occur in adult cats. Somatic spines are an important synaptic site on the embryonic Purkinje cell, but these spines and their synapses disappear as the dendritic tree develops. A structure/function correlation is possible in the developing visual cortex. In preterm infants of 24 to 25 weeks’ gestation, the visual evoked potentials (VEPs) recorded at the occiput exhibit initial long-latency negativity, but by 28 weeks’ gestation, a small positive wave precedes this negativity. The change in this initial component of the VEP corresponds to dendritic arborization and the formation of dendritic spines that occurs at that time. The EEG of the premature infant follows a predictable and timelinked progression in maturation. The EEG reflects synaptogenesis more closely than any other feature of cerebral maturation and thereby provides a noninvasive and clinically useful measure of neurological maturation in the preterm infant. Fetal EEG may even detect neurological disease and seizures in utero.

Disorders of Synaptogenesis Because the formation of dendritic spines and the formation of synapses are so closely related, the same spectrum of diseases already discussed is equally appropriate for consideration in this section. In preterm infants, who are generally unwell even if they do not have specific neurological disease, the rate of maturation of the EEG is often slow, which may reflect an impairment of synapse formation. Chronic hypoxemia particularly delays neurological maturation, including synapse formation. Deletions of δ-catenin, a neuron-specific catenin implicated in adhesion and dendritic branching, lead to severe synaptic dysfunction and correlate with the severity of intellectual disability

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in cri du chat syndrome (Israely et al., 2004). Delayed synaptogenesis occurs in many chromosomopathies and genetic diseases involving the fetal brain, as well as in many inborn metabolic diseases. Precocious synaptogenesis also can occur, as demonstrated in fetal HPE in the cerebral cortex and the retina of the cyclopean eye (Sarnat and FloresSarnat, 2013b; Sarnat et al., 2014). Precocious synapse formation is not advantageous because it is out of synchrony with other simultaneous processes of neuronal maturation and may lead to early development of epileptic circuitry and severe infantile epilepsies.

diplegia, and other chronic neurological handicaps. Phenylketonuria (a disorder of phenylalanine metabolism) and maple syrup urine disease (a disorder of the metabolism of the branched-chain amino acids leucine, isoleucine, and valine) are well-documented examples. However, it is not certain whether absence of the product of the deficient enzyme, or toxicity of high levels of precursors upstream from the enzyme deficiency, is the principal insult to the nervous system.

BIOSYNTHESIS OF NEUROTRANSMITTERS

Myelin insulates individual axons and provides greatly increased speed of conduction. It is not essential in all nerves, and many autonomic fibers of the peripheral nervous system remain unmyelinated throughout life. Conduction velocity in central pathways is important in coordinating time-related impulses from different centers that converge on a distant target and in ensuring that action potentials are not lost by synaptic block. The basis of nervous system functions is the temporal summation of impulses to relay messages across synapses. Myelination of pathways in the CNS occurs in a predictable spatial and temporal sequence. Some tracts myelinate as early as 14 weeks’ gestation and complete their myelination cycle in a few weeks. Examples include the spinal roots, medial longitudinal fasciculus, dorsal columns of the spinal cord, and most cranial nerves. Between 22 and 24 weeks’ gestation, myelination progresses in the olivary and cerebellar connections, the ansa lenticularis of the globus pallidus, the sensory trigeminal nerve, the auditory pathways, and the acoustic nerve, as well as the trapezoid body, lateral lemniscus, and brachium of the inferior colliculus. By contrast, the optic nerve and the geniculocalcarine tract (i.e., optic radiations) do not begin to acquire myelin until near term. Some pathways are late in myelinating and have myelination cycles measured in years. The corpus callosum begins myelinating at 4 months postnatally and is not complete until mid-adolescence. Some ipsilateral association fibers connecting the frontal with the temporal and parietal lobes do not achieve full myelination until about 32 years of age. Myelination can now be accurately measured in specific central pathways by using T2-weighted MRI sequences, but the time at which myelination can be detected is somewhat later than with traditional myelin stains of brain tissue sections, such as Luxol fast blue. Newer neuropathological methods using gallocyanin and immunoreactivity to myelin basic protein may detect myelination even earlier than the traditional stains. Electron microscopy remains the most sensitive method of demonstrating the earliest myelination in tissue sections.

The basis for synthesis of neurotransmitters and neuromodulating chemicals is the secretory character of the neuron, without which synaptic transmission is impossible. Several types of substances serve as transmitters: (1) acetylcholine (ACh); (2) monoamines, including dopamine, norepinephrine, epinephrine, and serotonin; (3) neuropeptides, including substance P, somatostatin, and opioid-containing peptide chains such as the enkephalins; and (4) simple amino acids, including glutamic acid, aspartic acid, GABA, and glycine. Some transmitters are characteristically inhibitory (e.g., glycine, GABA, and ACh in the CNS). Each neuronal type produces a characteristic transmitter—motor neurons produce ACh, cerebellar Purkinje cells produce GABA, and granule cells produce glutamic acid in the adult. Neuropeptides may coexist with other types of transmitters in some neurons. In some parts of the brain, transitory fetal transmitters may appear during development and then disappear. Substance P and somatostatin are present in the fetal cerebellum at midgestation, but these neuropeptides are never found in the mature cerebellum. In the cerebral cortex of the frontal lobe, the pattern of laminar distribution of cholinergic muscarinic receptors in the mature brain is the inverse of that in the fetus. The functions of these transitory transmitter systems are unknown. Some serve as tropic molecules rather than transmitters in early development. Even amino acid transmitters such as GABA may serve mainly a tropic function at an early stage in development. In situ hybridization and immunocytochemical techniques demonstrate neurotransmitters in neurons of the developing brain of experimental animals and may be applicable to human tissue under some circumstances (Dupuy and Houser, 1997). The ontogeny of neurotransmitter systems depends not only on the mechanisms of synthesis of chemical transmitters but also on the development of highly specific receptors of these chemical signals and their ability to modify excitability of neuronal membranes and trigger action potentials after the recognition of specific molecules (Rho and Storey, 2001; Simeone et al., 2003).

Disorders of Neurotransmitter Synthesis Ischemic and hypoxic insults impair RNA transcription and result in arrest of the synthesis of secretory products. Many of the clinical neurological deficits observed in asphyxiated neonates are probably the result of neurotransmitter depletion and functional synaptic block. Some amino acid neurotransmitters, by contrast, are neurotoxic when released in large quantities. The excitatory amino acids glutamic acid and aspartic acid induce transsynaptic degeneration when released in this way (as might occur with hypoxic stresses) and may be a major source of irreversible brain damage in asphyxiated neonates. Developmental disorders due to inborn errors of metabolism that block the chemical pathway of transmitter synthesis may occur, but they are probably incompatible with survival if they interfere with synthesis of a major transmitter such as ACh, monoamines, or an essential peptide. Many defects in the metabolic pathways of particular amino acids are associated with intellectual disability, epilepsy, spastic

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MYELINATION

Disorders of Myelination Many metabolic diseases impede the rate of myelination. Hypothyroidism is a classic example. Menkes kinky hair disease, a disorder of copper absorption and metabolism, is another example. Many aminoacidurias, including phenylketonuria, are also associated with delayed myelination. The neuropathological findings in cerebrohepatorenal (Zellweger) syndrome include disorders of neuroblast migration and myelination. Some leukodystrophies (e.g., Krabbe disease, perinatal sudanophilic leukodystrophy) express defective myelination in fetal life. Chronic hypoxia in premature infants is probably the most common cause of delayed myelination and contributes to the delay found in clinical neurological maturation. Myelination depends on fatty acids supplied by the maternal and infant diet; nutritional deficiencies during gestation or in postnatal life may result in delayed myelination and be clinically expressed as developmental delay. Unlike disorders of neuronal migration, delay in myelination is reversible. Removing the insult may allow myelination to catch up to reach the appropriate level of maturity.

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Fig. 89.7 Silver stain of molecular layer of motor cortex in a 20-week fetus. The long fibers (arrowheads) extending parallel to the surface of the brain are axons of Cajal-Retzius neurons. (Bielschowsky stain. Bar = 10 µm.)

CAJAL-RETZIUS NEURONS AND SUBPLATE NEURONS OF THE FETAL BRAIN Cajal-Retzius cells are large, mature, stellate neurons in the marginal (outermost) zone of the fetal cerebral cortex. They are the first cells to appear at the surface of the embryonic cerebrum, preceding the first wave of radial migration from the subventricular zone and forming a plexus in the marginal (later the molecular) zone. They migrate to the surface from the ganglionic eminence, the source of GABAergic inhibitory interneurons that will later arrive at the cortical plate by tangential migration (Sarnat and Flores-Sarnat, 2002). The first afferent processes to enter the marginal layer are dendrites of pyramidal cells of layer VI; synapses between Cajal-Retzius and pyramidal neurons of layer VI form the first intrinsic cortical circuits (Marín-Padilla, 1998). They eventually have synaptic contacts with cortical neurons in all layers. Cajal-Retzius cells contain acetylcholinesterase and oxidative enzymes and secrete GABA and probably ACh as neurotransmitters. Their long axons extend parallel to the surface of the brain, plunging short branches into layer II (Fig. 89.7). Cajal-Retzius neurons are sparse by term but persist even in the adult, though their function after maturity is uncertain. They strongly express the transcription product of the LIS1 gene, which is defective in X-linked hydrocephalus associated with polymicrogyria and defective neuroblast migration. CajalRetzius neurons also strongly express spastic diplegia, RLN, another gene essential for radial neuroblast migration and organization of the cortical plate (Clark et al., 1997; Sarnat and Flores-Sarnat, 2002). This is the only specific disease involving Cajal-Retzius neurons. The subplate zone is a transitory layer of neurons in early development that will regress at midgestation and eventually disappear, its neurons being incorporated into the deep layers of the cortical plate. The subplate zone also is essential for organization of the cortical plate and, in preterm infants, can contribute to subcortical white-matter injury (Pogledic et al., 2014).

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The fetal cerebral cortex has a subpial or external granular layer that histologically resembles that of the cerebellum but is of quite a different character. Cells of the cerebral cortex rise in columns from the germinal matrix of the hippocampus to form a thin layer on the surface of the archicortex at 12 weeks’ gestation. They rapidly spread over the neocortex in a predictable sequence to cover the entire convexity by the 16th to 18th week, with the layer reaching the greatest thickness by 22 weeks’ gestation. Subsequent involution of the external granular layer results from migration of these cells into the cerebral cortex, where they can no longer be distinguished. Only remnants of this once prominent layer persist at term, confined to the inferior temporal and orbital surfaces. These surfaces are the last sites from which they finally disappear from the neocortex, although a few may persist over the paleocortex even into adult life. Their fate within the cerebral cortex is unknown, but speculation is that they mature into glial cells, because they lack ultrastructural features of neurons, and they stain immunocytochemically for glial fibrillary acidic protein but not for vimentin. The subpial granular layer of the cerebral hemispheres is partially or totally absent in most cases of HPE, even at the gestational period when it is normally most prominent; this absence may contribute to the marginal glioneural heterotopia found in the meningeal spaces and superficial cortical layers. The layer of the subpial granule cells may serve as a barrier to reverse the direction of migration in neuroblasts reaching the surface. In the Fukuyama type of congenital muscular dystrophy associated with cerebral cortical dysplasia, a heterotopic layer of stellate glial cells forms at the surface of the cerebral cortex, into which migrating neurons accumulate as they reach the surface, rather than reversing direction and entering deeper layers of the cortex.

ETIOLOGY OF CENTRAL NERVOUS SYSTEM MALFORMATIONS The causes of cerebral malformations generally fall into one of two categories. The first category is genetic and chromosomal disease in which programming of cerebral development is defective. This genetic category also includes many inborn metabolic diseases in which cerebral dysgenesis may be due to biochemical insults during development, rather than (or in addition to) primary errors in molecular genetic codes for neural programming. The second category is epigenetic and includes all induced malformations in which a teratogenic influence acts at a particular time in ontogenesis; the malformation depends on the timing of the insult in relation to brain development at that moment. The timing may be brief, as with a single exposure to a toxic drug, a dose of radiation, or a traumatic injury of the fetal brain. It may be repeated two or more times or may be prolonged and involve the fetus at several stages of development. Examples of the latter include certain congenital infections such as toxoplasmosis and cytomegalovirus infection, which may be active throughout most of gestation, even into the postnatal period. Genetic factors are the most frequent causes of malformations during the first half of gestation. Environmental factors are more important in late gestation and may cause disturbances of late neuroblast migrations, particularly in premature infants. In some cases, no definite inductive factor is identifiable despite intensive clinical investigations during life and meticulous postmortem studies. Fetal alcohol syndrome in which the fetus is exposed to maternal alcohol intake results in a small brain with delayed synaptogenesis and other maturational features. The vascular development of the fetal and neonatal brain is impaired by alcohol and contributes to deficient growth and chronic ischemia (Jégou et al., 2012).

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Ischemic Encephalopathy in the Fetus Among the environmental factors that may interfere with the developmental process in utero or postnatally, either briefly or more chronically, none is more important as a cause of morbidity than ischemic encephalopathy. Circulatory insufficiency or, less often, hypoxemia may interfere with migrations by causing infarction, which interrupts glial guide fibers. After birth, hypoxia is more frequent than pure ischemia as a cause of encephalopathy. Ischemia also affects the fetal cerebrum by producing watershed infarcts between zones of arterial supply because of the fetus’s poorer collateral circulation compared with that of the mature brain. Thinwalled vessels radiate perpendicular to the surface of the brain. The precursors of these radial vessels originate from leptomeningeal arteries and are evident at 15 weeks’ gestation in the human embryo; horizontal branches appear in deep cortical layers at 20 weeks’ gestation and increase to supply the superficial cortex by 27 weeks’ gestation. The capillary network of the cortex proliferates mainly in the postnatal period as radial arterioles decrease in number. Severe ischemia of the immature brain may result in cuffs of surviving nerve cells surrounding the radial arterioles, with vertical columns of necrotic tissue between these zones related to immaturity of the vascular bed. Alternating radial zones of viable cerebral tissue and infarcted tissue thus occur in the cerebral cortex. Infarcts not only destroy maturing nerve cells that have already completed their migration but also interfere with continuing and future migrations into those regions. The zones of infarction eventually become gliotic and disrupt the geometric architecture of the cortex. The existence of fetal watershed zones of the cortical vascular bed is important in the pathogenesis of ulegyria, an atrophy of gyri that grossly resembles polymicrogyria. Focal areas of cortical atrophy and gliotic scarring occur after perinatal ischemic or hypoxic encephalopathy. The four-layered cortex of polymicrogyria is quite a different lesion from ulegyria, resulting from a primary disturbance of neuroblast migration. Some authors question this interpretation, however, and provide evidence of postmigratory laminar necrosis of the cortex. The distribution of polymicrogyria is frequently in vascular territories of fetal brain and often forms a rim surrounding a porencephalic cyst in the territory of the middle cerebral artery. Multicystic encephalomalacia and hydranencephaly are end-stage sequelae of massive cerebral infarction in the developing brain. Watershed zones also exist in the brainstem between the territories supplied by paramedian penetrating short and long circumferential arteries, which originate from the basilar artery. Transitory hypoperfusion in the basilar artery in fetal life may produce watershed infarcts in the tegmentum of the pons and medulla oblongata. This is a probable pathogenesis of Möbius syndrome and probably also of “failure of central respiratory drive” in neonates with hypoventilation not due to pulmonary or neuromuscular disorders (Sarnat, 2004b). The cause is involvement of the tractus solitarius, which receives afferents from chemoreceptors such as the carotid body and provides efferent axons to motor neurons that innervate the diaphragm and intercostal muscles. Mitochondria are the energy-generating organelles of all cells (except mature erythrocytes) and produce enzymes essential for cellular respiration. In mitochondrial diseases of early infancy, mitochondria of endothelial cells are more severely altered in muscle and brain than surrounding myofibers and neural cells, unlike the reverse involvement in adults (Sarnat et al., 2012a). In infants suffering hypoxic/ischemic insults, who do not have primary mitochondrial disease, their endothelial mitochondria may also be impaired and contribute to ischemic lesions of the brain.

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MOLECULAR GENETIC CLASSIFICATION OF MALFORMATIONS OF THE NERVOUS SYSTEM Classification is a fundamental human thought process, allowing us to organize data in a systematic manner and understand relations. The traditional basis for classification of CNS malformations is descriptive morphogenesis. New insights into the molecular genetic programming of neural development require the integrations of this information with the anatomical criteria (Sarnat and Flores-Sarnat, 2001b, 2004; Simeone, 2002). For example, lissencephaly and HPE are two important malformations, each formerly thought to be distinctive. It is now recognized that many different genetic defects cause each; hence they are end stages of ontogenetic errors with diverse causes (see following discussion). A pure genetic classification to replace anatomical criteria, by contrast, would not be useful to clinicians, radiologists, or pathologists, and would be incomplete because many genetic mutations remain unknown. A compromise that addresses the deficiencies of both pure anatomical and pure genetic schemes of classification is one based on patterns of genetic expression in which the precise genetic mutation may or may not be known but is stated while preserving anatomical criteria (Sarnat and Flores-Sarnat, 2001b; Sarnat and Menkes, 2000). The upregulation or downregulation of a dorsalizing or ventralizing gene may be recognizable by its anatomical effect on neural tube development, even if the precise gene is unknown. The traditional categories of CNS development that allow categories of ontogenetic processes, such as neuronogenesis, neuroblast migration, and synaptogenesis, and their disturbances in malformations, may be preserved in the proposed new scheme of classification. They are supplemented by new categories such as “disturbances of cellular lineage” (e.g., tuberous sclerosis; hemimegalencephaly) and disorders of embryonic neuromeric segmentation (e.g., absence of the midbrain and upper pons; absence of the basal ganglia; Chiari malformations). Some genes specify particular types of cellular differentiation and may change the cell type at different stages of development (Marquardt and Pfaff, 2001). One of the most important concepts in the integrated morphological-molecular-genetic scheme is the gradients of genetic expression (Sarnat and Flores-Sarnat, 2001b). The gradients are those of the axes of the neural tube: dorsoventral and ventrodorsal, rostrocaudal and sometimes caudorostral, and mediolateral. Nearly all genes have gradients of expression, with stronger expression in some regions and gradually lesser influence more distally. For example, if the rostrocaudal gradient in HPE extends as far as the midbrain, mesencephalic neural crest migration is impaired, and midfacial hypoplasia results, regardless of the severity of the forebrain malformation (see following discussion). Some authors attempt to develop schemes of regional classification for malformations (e.g., limited to the cerebral cortex for use in genetic epilepsies). All classifications should consider the entire CNS, however, because the rostrocaudal gradients of genetic expression may cause important subcortical defects, and indeed some seizure disorders may even originate in subcortical structures. The upregulation and downregulation of genes also is sometimes easier to understand in the anatomically simpler structures of the brainstem and spinal cord, allowing extrapolation to more complex forebrain structures. A simple chronological listing of genes in the order from those that are initially expressed in the embryo is not feasible because most genes express at several different stages of development. Genes subserve different functions at each stage, initially as organizer genes for the basic architecture of the neural tube such as axes, cephalization, dorsal and ventral surfaces, and segmentation. These same genes later express as regulator genes for the differentiation and maintenance of particular cellular identities and functions.

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CHAPTER 89 Developmental Disorders of the Nervous System Focal cortical dysplasias are a special group because in general they are highly epileptogenic and often refractory to medical treatment, requiring surgical excision. An international consortium of neuropathologists established by the International League Against Epilepsy (ILAE) defined and standardized diagnostic criteria and terminology for the focal cortical dysplasias. A scheme was thus published and is widely accepted, yet still has the flexibility to undergo present and future modifications as more data and new concepts emerge (Blümcke et al., 2011). After years of additional experience by the ILAE Consortium on Neuropathology, recommendations for revision of the original 2011 scheme were published (Najm et al. 2018). One major distinction is altered cortical architecture with disoriented and displaced but normal neurons, and those dysplasias that additionally involve cytological abnormalities of the neurons themselves. These abnormalities of growth and morphogenesis of some clones of neurons and glial cells in postzygotic somatic mutations are related to the mammalian target of rapamycin (mTOR) signaling pathway (Lindhurst et al. 2011; Mühlebner et al. 2019; Xu et al. 2019). Other pathways integrating with mTOR include the PI3K and AKT gene families that are the genetic etiology of many neurocutaneous syndromes, particularly epidermal nevus syndrome, including Proteus and CLOVES that also involves progressive overgrowth in the extremities, viscera and in the brain as hemimegalencephaly (Flores-Sarnat, 2013, 2016). An additional factor in the pathogenesis of mTOR pathway disorders, particularly in tuberous sclerosis complex, is the expression of inflammatory markers in fetal brain (Prabowo et al., 2013; Sarnat and Scantlebury, 2017). The role of inflammation since fetal life in such genetic diseases has been little studied and much new data are anticipated.

CLINICAL EXPRESSION OF SELECTED MALFORMATIONS OF THE NERVOUS SYSTEM Table 89.2 summarizes the clinical features of major malformations of the brain.

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as severe forms occur. Associated forms additionally include the features of the particular syndrome, such as lipomatosis of the ipsilateral face in epidermal nevus syndrome and Proteus syndrome (Flores-Sarnat, 2013). Hamartomatous brain malformations, such as tuberous sclerosis and hemimegalencephaly as isolated or neurocutaneous-associated forms, are now known to be somatic mutations, which explains patchy involvement of skin and brain and multisystemic involvement in many cases (Lee et al., 2012; Poduri et al., 2012). Hemimegalencephaly is a mutation in the AKT3 gene, and the mTOR pathway is activated as it is in tuberous sclerosis. In addition, abnormal phosphorylated tau is upregulated in both disorders. Tau is a microtubule-associated protein and microtubules in early development are essential in establishing neuronal polarity, growth, differentiation, synapse formation and other cytological features (Sarnat et al., 2012b; Sarnat and Flores-Sarnat, 2015). Hemimegalencephaly and focal cortical dysplasia type 2 are a spectrum of the same disorder. The difference between the extent of the focal malformation with dysplastic neurons is the timing of onset of mutated genetic expression in the 33 mitotic cycles of periventricular primitive neuroepithelium (Sarnat, 2018; Sarnat and Flores-Sarnat, 2017a,b). This neuroembryological evidence is confirmed by genetic evidence with the same conclusion (D’Gama et al., 2015, 2017; Lee et al., 2012).

Disorders of Neurulation (1–4 Weeks’ Gestation) Incomplete or defective formation of the neural tube from the neural placode is the most common type of malformation of the human CNS. Anencephaly has an incidence of 1 per 1000 live births; meningomyelocele is almost as frequent. Geographical and ethnic differences occur among various populations in the world. Nonetheless, it is a medical problem and human tragedy of much greater proportions because the majority of infants affected with defects of the posterior neural tube survive with major neurological handicaps. The causes of these disorders in the first month of gestation are usually not evident, despite intensive epidemiological, genetic, dietary, and toxicological surveys.

Hemimegalencephaly

Anencephaly (Aprosencephaly With Open Cranium)

Hemimegalencephaly is one of the most enigmatic cerebral malformations, because it is a severe dysgenesis limited to one cerebral hemisphere or, less commonly, includes the ipsilateral cerebellar hemisphere and brainstem (total hemimegalencephaly). Though traditionally regarded as another disorder of neuroblast migration, this feature is probably only secondary to involvement of radial glial cells and perhaps the neuroblasts themselves, and the primary process is a disturbance of cellular lineage and also involvement of genes of symmetry expressed as early as gastrulation (FloresSarnat, 2002a, 2003, 2008). Individual neural cells exhibit both glial and neuronal proteins and have abnormal growth and morphology. Some cases of hemimegalencephaly are isolated, but others are particularly associated with neurocutaneous syndromes: epidermal nevus syndrome and Klippel-Trénaunay syndrome (Flores-Sarnat, 2006). Neurological clinical features and neuropathological findings are virtually identical in isolated and associated forms. Partial epilepsy is the principal clinical feature in severe and moderate forms, often refractory to medical treatment and abolished only by hemispherectomy or other surgical resections. In epidermal nevus syndrome, 38% of patients have hemimegalencephaly and 77% have epilepsy, infantile spasms being the most frequent form (Flores-Sarnat, 2016). Other less constant features include variable intellectual disability and contralateral motor deficit. Mild as well

Anencephaly is a failure of the closing of the anterior neuropore at 24 days’ gestation. Death in utero occurs in approximately 7% of anencephalic pregnancies, 34% of such babies are premature, and 53% at term. Stillbirth, presumably resulting from intrapartum death, occurs in 20% of these deliveries. In one study of 211 pregnancies, 72% (153) of anencephalic offspring were liveborn; of those, 67% (103) died within 24 hours, but six survived 6 or more days (maximum 28 days) (Jaquier et al., 2006). The prenatal diagnosis of anencephaly is by examination of amniotic fluid for elevation of α-fetoprotein, and confirmation is by sonographic imaging as early as 12 weeks’ gestation. The face may show a midline hypoplasia, similar to HPE (see following section on HPE), probably because the rostrocaudal gradient of a defective genetic expression extends to the midbrain and interferes with mesencephalic neural crest migration (Sarnat and Flores-Sarnat, 2001a).

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Cephalocele (Encephalocele; Exencephaly) Most encephaloceles are parietal or occipital (Fig. 89.8) and contain supratentorial tissue, cerebellar tissue, or both. Frontal encephaloceles are less common in North America and Europe but are the most frequent variety in Thailand, Vietnam, and surrounding countries. They usually include olfactory tissue. Cases of encephaloceles related to Agent Orange (containing the herbicides 2,4-dichlorophenoxyacetic

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0, 75% of patients involved. *In holoprosencephaly, anatomical varieties do not correspond to genetic defect and correlate poorly with midfacial hypoplasia. †Normal face in isolated form, cutaneous or subcutaneous signs in associated forms. Most are unilateral findings.

Neurological Diseases and Their Treatment

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Holoprosencephaly, lobar, semilobar* Holoprosencephaly, lobar, middle interhemispheric variant* Septo-optic-pituitary dysplasia Callosal agenesis, complete or partial Callosal agenesis, Aicardi syndrome Callosal agenesis lipoma Colpocephaly, primary Lissencephaly type 1 (Miller-Dieker syndrome) Lissencephaly type 2 (Walker-Warburg syndrome) Pachygyria (Fukuyama muscular dystrophy) Cerebrohepatorenal disease (Zellweger syndrome) Tuberous sclerosis Hemimegalencephaly† Chiari malformations Dandy-Walker malformation Aqueductal stenosis/ atresia Cerebellar hypoplasias

Cephalo- Dysmorphic Visual Intellectual facies Microcephaly cele Hydrocephalus Epilepsy Impairment Disability Hypotonia Spasticity

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TABLE 89.2

CHAPTER 89 Developmental Disorders of the Nervous System

BOX 89.2

Stenosis

Causes of Congenital Aqueductal

Genetic or Presumed Genetic Causes Holoprosencephaly Chiari II malformation X-linked hydrocephalus with aqueductal stenosis and pachygyria Autosomal recessive hydrocephalus with aqueductal stenosis Mutation of dorsalizing gene in vertical axis of neural tube Agenesis of mesencephalic and metencephalic neuromeres Primary defective ependymal and choroid plexus epithelia (?)

e

Fig. 89.8 Lateral view of the brain of a term neonate with Meckel-Grüber syndrome. This dysplasia is a large occipital encephalocele (e) and lissencephaly. The brain is smooth and shows only a sylvian fissure and a few shallow abnormal sulci near the vertex. The encephalocele contains disorganized neural tissue, angiomatous malformations, focal hemorrhages, and zones of infarction.

acid [2,4-D] and 2,4,5-trichlorophenoxyacetic acid [2,4,5-T]), which was used in the Vietnam War, are still reportedly observed in Cambodia. Skin may completely cover the encephalocele, or thin, distorted meningeal membranes may be exposed. When the ventricular system also is herniated into the encephalocele sac, hydrocephalus develops. Leaking CSF rapidly leads to infection. Some encephaloceles, particularly those of the occipital midline, may become so large that they exceed the size of the infant’s head. Nasopharyngeal encephaloceles are rare but may be a source of meningitis from CSF leak through the nose. Malformations of the visceral organs often coexist with encephaloceles, and other congenital anomalies of the eyes and face, cleft palate, and polydactyly are also common. The entire brain may be severely hypoplastic (see Fig. 89.1). Frontal and nasal encephaloceles protrude though bony foramina that normally close in the fetus: the fonticulus frontalis in the case of frontal (forehead midline) encephaloceles and the foramen cecum in the case of intranasal encephaloceles. Nasal encephaloceles might be confused clinically with nasal polyps, and CSF leak in the nose may be confused with benign nasal secretions. Both of these foramina fail to close because of defective prosencephalic neural crest tissue, which migrates from the dorsal part of the lamina terminalis as a vertical sheet of cells in the frontal midline. Neurological handicaps may be severe because even if the herniated tissue within the encephalocele is small and easily excised, concomitant intracranial malformations of the brain often result in epilepsy, intellectual disability, and motor impairment. Cortical blindness often occurs in the case of occipital encephaloceles. The treatment of choice of small encephaloceles is surgical excision and closure of overlying cutaneous defects. Seizures and hydrocephalus are common but treatable complications.

Meningomyelocele (Spinal Dysraphism, Spina Bifida Cystica) The basis of classification of spina bifida syndromes is on either the bony vertebral deformity or the neurological lesion and associated clinical deficit. No deficits are associated with spina bifida occulta without herniation of tissue or mild spina bifida cystica with herniation of meninges alone. Deficits from herniation of nerve roots include motor, sensory, and autonomic neuropathy (meningomyelocele). Extensive defects occur with herniation of the parenchyma of the spinal cord (myelodysplasia). Most lesions are lumbosacral in location, but meningomyelocele

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Acquired Causes in Utero Intraventricular hemorrhage with thrombus in aqueduct Congenital infections (e.g., cytomegalovirus infection, mumps) Ependymitis/ventriculitis with gliosis around and within aqueduct Chronic arachnoiditis Hydranencephaly Aqueductal membrane across lumen Amnion rupture sequence Aneurysms, venous angiomas, and other vascular malformations Cystic dilatation of perivascular Virchow-Robin spaces in midbrain Tumors of aqueduct (e.g., ependymoma, astrocytoma, glioneuronal hamartoma, neuroepithelial tumor of subcommissural organ) Tumors that compress the midbrain tectum from above (e.g., pineal tumors and cysts, arachnoidal cysts, lipomas)

also may occur in the thoracic or even the cervical region, usually as an extension rostrally of lumbosacral lesions. The level of involvement determines much of the clinical deficit. Type II Chiari malformation is consistently present, and aqueductal stenosis coexists in 50% of cases. Hydrocephalus is a common complication involving most patients with meningomyelocele; it causes neurological deficit. The treatment of meningomyelocele is controversial and enters the arena of medical ethics. Surgical closure of small defects in the neonatal period is the rule. Large defects associated with complete paraplegia and flaccid neurogenic bladder, often accompanied by hydronephrosis, severe hydrocephalus, and other cerebral malformations, are associated with poor quality of life. A decision not to treat such infants or not to prolong survival poses a moral question addressed by the physicians in consultation with parents, hospital ethics committees, and other individuals the parents may identify. The most important immediate complications of large meningomyeloceles are hydrocephalus and infection from leaking CSF. Long-term complications include chronic urinary tract infections, decubiti, hydrocephalus, paraplegia, and other neurological deficits. Intellectual disability is common but may be mild.

Congenital Aqueductal Stenosis Another aspect for consideration in the category of disorders of neurulation is the downregulation of genes in the vertical axis of the neural tube. In the case of the ventrodorsal gradient due to defective sonic hedgehog (SHH) expression, sacral agenesis with dysplastic spinal cord at the levels of the deficient vertebrae (and notochord) is the best example. Downregulation in the dorsoventral gradient of several genes or gene families, including ZIC2, SHH in the forebrain, BMP, and PAX, may result in HPE (see following section on HPE) or may cause defective development of the dorsomedial septum of the midbrain with aqueductal stenosis (Sarnat and Flores-Sarnat, 2001a). Box 89.2 lists the various causes of congenital aqueductal stenosis (Sarnat and Flores-Sarnat, 2001a).

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Neurological Diseases and Their Treatment

Best Documented Genetic Mutations in Holoprosencephaly

Chromosomal Locus

Defective Gene

Vertical Gradient Effect

2p21 7q36 13q32 18q11.3 9q22.3 10q11.2

SIX3 SHH ZIC2 TGIF PTCH DKK

Dorsoventral Ventrodorsal (spinal cord, hindbrain), dorsoventral (midbrain, forebrain)* Dorsoventral Ventrodorsal Ventrodorsal Ventrodorsal

*Although SHH is a powerful ventralizing gene in the embryonic spinal cord and hindbrain, recent evidence indicates that at the level of the midbrain and most rostral regions of the neural tube, it changes its gradient and becomes dorsalizing in the vertical axis. Data from Blaess, S., Corrales, J.D., Joyner, A.L., 2006. Sonic hedgehog regulates Gli activator and repressor functions with spatial and temporal precision in the mid/hindbrain region. Development 133, 1799–1809.

Midline Malformations of the Forebrain (4–8 Weeks’ Gestation) Several developmental malformations of the prosencephalon relate embryologically to failure of the lamina terminalis to differentiate into telencephalic structures. The lamina terminalis is the rostral membrane of the primitive neural tube that forms with closure of the anterior neuropore. The expression of such disorders is mainly as midline defects, not only because of its location in the midline but also because of impaired lateral growth of the cerebral hemispheres due to deficient or abnormal cellular migration centrifugally to form the cerebral cortex. The series of midline prosencephalic malformations relates to the embryological time of the beginning of each and includes alobar, semilobar, and lobar HPE, arhinencephaly, septo-optic dysplasia, colpocephaly, and agenesis of the corpus callosum. The lamina terminalis, after differentiating the forebrain structures, becomes the anterior wall of the third ventricle in the mature brain. It extends between the optic chiasm ventrally and the rostrum of the corpus callosum dorsally. Some authors contend that a defective cephalic notochord induces midline forebrain defects. Understanding of the complex embryological relationship of neuroectoderm and mesoderm in early ontogenesis is incomplete.

Holoprosencephaly HPE is a malformation in which the two cerebral hemispheres appear fused in the midline but is really a failure of cleavage in the midsagittal plane of the embryonic cerebral vesicle at 33 days’ gestation and thus a paramedian hypoplasia of the forebrain (Fallet-Bianco, 2018). HPE has a frequency of one in 16,000 live births but one in 250 spontaneously aborted fetuses in the first trimester; hence it is among the most common of the major cerebral malformations. Traditionally, HPE was a single malformation with three variants: alobar, semilobar, lobar. A fourth was added later: the middle interhemispheric variant (Hahn and Pinter, 2002; Simon et al., 2002). Another variant recently described is septopreoptic HPE, demonstrated as noncleavage restricted to the preoptic and septal region by MRI in seven patients (Hahn et al., 2010); we have now recognized two additional cases (unpublished). Recent molecular genetic data redefine HPE as a common end-stage malformation with six known different genetic mutations demonstrated in various cases (Golden, 1998; Table 89.3). Other chromosomal defects (in loci 3p26, 4,5, 6, 14q13, 14q21.1-q21.2, 20, 21q22.3) are known in which the specific genetic mutation is not yet identified. All six known defective genes together account for only about 20% of cases, so many more gene defects remain undiscovered. Furthermore, each of the traditional anatomical variants of HPE is demonstrable in each of the six known genetic forms, signifying that these merely represent degrees of severity

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without etiological implication. A defect in the ZIC2 gene is associated with chromosome 13q deletions, and HPE is frequent in infants with trisomy 13 (Brown et al., 1998). One of the most studied of the genetic mutations is the strong ventralizing gene, SHH; lack of expression of this gene in the prechordal mesoderm ventral to the rostral end of the neural tube results in no neural induction (Roessler et al., 1996). Abnormal SHH expression also may be altered in metabolic diseases with impaired cholesterol synthesis and high serum levels of the cholesterol precursor molecule7-dehydrocholesterol, as in the SmithLemli-Opitz syndrome associated with HPE (Kelley et al., 1996). After chromosomal defects, the most common association of HPE is maternal diabetes mellitus; sacral agenesis is another common malformation in infants of diabetic mothers. Both involve downregulation of SHH. A defect at the same chromosome 7p36.2 locus associated with an autosomal dominant form of HPE also affects SHH at the posterior, rather than the anterior, end of the neural tube and results in sacral agenesis (Lynch et al., 1995). Disturbed insulin metabolism may affect SHH in programming the neural tube. Olfactory bulbs and tubercles differentiate at 41 days, a few days after forebrain cleavage, but olfactory agenesis usually accompanies all but the mildest forms of HPE; therefore, the term arhinencephaly, often used interchangeably, is incorrect. Callosal agenesis also is a uniform feature except in the mildest forms, and the cerebral mantle shows gross disorganization with multiple heterotopia, poorly laminated cortical gray matter, and heterotopic neurons and glial cells in the overlying meninges. Extensions of germinal matrix into the lateral ventricles through gaps in the ependyma are common. Thus, although HPE can be dated to about 33 days’ gestation at onset, the pathological process extends throughout most of fetal life. Five different anatomical variants of HPE reflect different degrees of abnormal cerebral architecture. Characteristic of alobar HPE is a brain with a single midline telencephalic ventricle rather than paired lateral ventricles and continuity of the cerebral cortex across the midline frontally. The roof of the monoventricle balloons into a dorsal cyst. The corpus striatum and thalamus of the two sides are uncleaved, and the third ventricle may obliterate with rudiments of ependymal rosettes in its place. In semilobar HPE, an incomplete interhemispheric fissure forms posteriorly, and the occipital lobes, including the occipital horns of the ventricular system, may approach a normal configuration despite noncleavage of the frontal lobes across the midline. Lobar HPE is a less severe dysgenesis; the hemispheres form well but are in continuity through a band of cortex at the frontal pole or the orbital surface, and the indusium griseum and cingulate gyri overlying the corpus callosum are in continuity. The corpus callosum incompletely forms but is not totally absent, as in alobar and semilobar HPE. The middle interhemispheric variant consists of hypoplasia of the middle part of

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CHAPTER 89 Developmental Disorders of the Nervous System the corpus callosum and associated structures of the medial side of the hemispheres. The most recently recognized and rarest form of HPE, demonstrated by MRI, is the septo-preoptic, which seems transitional between this malformation and septo-optic-pituitary dysplasia (Hahn et al. 2010). In the more severe forms of HPE, the optic nerves are hypoplastic or fused to enter a single median eye. Midline cerebellar defects, absent pyramidal tracts, and malformed brainstem structures accompany the more severe forms of this malformation. Meningeal heterotopia or marginal glioneuronal nodules commonly result from overmigration, perhaps associated with hypoplasia or absence of the transitory external granular glial layer of Brun of the fetal brain in HPE. The diagnosis of HPE often occurs at the time of delivery, because 93% of patients exhibit midline facial dysplasias. Midfacial hypoplasia is present in most patients with HPE, but others have a normal face. The facial dysmorphism ranges from mild hypotelorism and vomer bones to severe forms including cebocephaly with a single naris, severe hypotelorism and absence of the premaxilla and vomer bones to produce a midline cleft lip and palate, or cyclopia with a midline proboscis dorsal to the single median eye. This eye, resulting from fusion of the two lateral halves of the incipient globes, is associated with a persistent long hyaloids canal containing a hyaloids artery that normally regresses at 7 weeks’ gestation; precocious synapse formation is seen around ganglion cells of the retina (Sarnat et al., 2014). The severity of the facial dysmorphism does not correlate as well with the anatomical variant as originally expressed in the often-cited statement “the face predicts the brain.” Midfacial hypoplasia does correlate, however, with the rostrocaudal extent of the defective genetic expression. If the gradient extends to the embryonic mesencephalic neuromere and causes hypoplasia of the midbrain, neural crest formation and migration are affected (Sarnat and Flores-Sarnat, 2001a). The mesencephalic neural crest is the most rostral origin of neural crest, and this tissue forms not only peripheral neural structures such as the ciliary ganglion but also most of the membranous bones of the face, globe of the eye (except the retina and choroid), and much of the facial connective tissue. The various forms of HPE are well demonstrated by most imaging techniques (Fig. 89.9), including prenatal ultrasound. The imaging features of each anatomical variant are distinctive (Hahn and Pinter, 2002) and correspond well to the gross neuropathological findings (Golden, 1998). The anterior cerebral artery is usually a single azygous vessel coursing just beneath the inner table of the skull, a pathognomonic finding. The sagittal sinuses, deformed or replaced by a network of large abnormal veins, resemble the early embryonic pattern of venous drainage. The EEG in HPE shows multifocal spikes that often evolve into hypsarrhythmia. In the neonatal period, the characteristic feature of the waking EEG is almost continuous high-voltage alpha-theta monorhythmic activity, becoming discontinuous in sleep. VEPs also are abnormal or altogether absent. The characteristic clinical course of HPE is severe developmental delay and a mixed pattern of seizures that often are refractory to antiepileptic drugs. The presence or absence of seizures does not correlate with the anatomical severity or variant of the defective forebrain and correlates poorly with the genetic mutation (Hahn and Pinter, 2002). A better correlation may be with the degree of mediolateral extension of genetic expression in disrupting the histological architecture of the cortex, or it may relate to an abnormal sequence of maturation of axosomatic (inhibitory) and axodendritic (excitatory) synapses in relation to the maturation of the neuron innervated by these axonal terminations (Sarnat and Flores-Sarnat, 2001a). Some patients develop hydrocephalus that requires a ventriculoperitoneal shunt. This condition is paradoxically more common in the less severe anatomical forms of the malformation. In the severe

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Fig. 89.9 (A-D) Unenhanced computed tomographic scan of a 6-year-old boy with semilobar holoprosencephaly. The lateral ventricles are fused, particularly frontally, but show some division into two occipital horns. A deep abnormal sulcus is seen across the fused frontal lobes (arrowheads). This is one of several radiological variants of holoprosencephaly.

alobar form, a “dorsal cyst” occupies the entire posterior one-half to two-thirds of the intracranial space and, occasionally, even protrudes through the anterior fontanelle as a unique encephalocele that may be larger than the rest of the head. No other type of encephalocele occurs at the anterior fontanelle. The dorsal cyst seems to originate from a dilated suprapineal recess of the third ventricle and later is a dorsal membrane that includes the roof of the forebrain, extending from the hippocampi (Sarnat and Flores-Sarnat, 2001a). Endocrine dysfunction may be present, associated with hypothalamic or pituitary involvement, and vasopressin-sensitive diabetes insipidus occurs in about 86% of cases, other hypothalamic–pituitary dysfunction being much less frequent (Plawner et al., 2002). The basis of this specific involvement of the paraventricular and supraoptic hypothalamic nuclei may be hypoplasia in some cases in which the midline hypoplasia involves the diencephalon as well as the forebrain (most patients), but it also occurs in some children without hypothalamic noncleavage. One hypothesis is that the primary gene defect suppresses expression of the gene orthopedia (OTP). OTP and downstream genes such as SIM1 and BRN2 are essential for terminal differentiation of neuroendocrine cells of these hypothalamic nuclei (Sarnat and Flores-Sarnat, 2001a). The treatment of HPE symptoms entails treating the complications (e.g., seizures, hydrocephalus, endocrine disturbances). Educational potential and needs depend on the degree of intellectual, speech, and visual impairments.

Isolated Arhinencephaly and Kallmann Syndrome Absence of olfactory bulbs, tracts, and tubercles commonly accompanies extensive malformations such as HPE and septo-optic dysplasia but may occur with callosal agenesis or as an isolated cerebral anomaly. Kallmann syndrome is an X-linked autosomal dominant condition limited to males, in which anosmia secondary to arhinencephaly without other forebrain malformations is associated with lack of secretion of gonadotropic hormones. The defective gene is KAL1 at the

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chromosome Xp22.3 locus. Also implicated is the EMX2 gene, though schizencephaly does not occur with Kallmann syndrome (Taylor et al., 1999). Olfactory reflexes may be elicited in the neonate consistently after 32 weeks’ gestation and provide a useful supplement to the neurological examination of newborns suspected of cerebral dysgenesis. The olfactory bulb develops in a unique manner and also is unique in being the only special sensory system to not project efferent axons to the thalamus, because the deep granular cell core of the olfactory bulb that extends into the olfactory tract is its own thalamic equivalent (Sarnat and Flores-Sarnat, 2017b). Many abnormalities of olfactory bulb development are known in addition to agenesis. Some are abnormal lamination and fusion of the bulbs of the two sides (Sarnat and Flores-Sarnat, 2017a, 2017b).

Septo-Optic-Pituitary Dysplasia De Mosier first recognized the association of a rudimentary or absent septum pellucidum with hypoplasia of the optic nerves and chiasm in 1956. Underdevelopment of the corpus callosum and anterior commissure and detachment of the fornix from the ventral surface of the corpus callosum are additional features. Patients with this combination of anomalies overlap others with semilobar HPE, and some many children with septo-optic-pitutary dysplasia have hypoplasia of the olfactory bulbs arhinencephaly as well, though olfactory perception is not totally abolished (Sarnat and FloresSarnat, 2017a, 2017b). Disturbances of the hypothalamic–pituitary axis often occur in septo-optic dysplasia, ranging from isolated growth hormone deficiency to panhypopituitarism and deficient secretion of antidiuretic hormone. Hypothalamic hamartomas, gliosis, and the absence of some hypothalamic nuclei may be associated with a histologically normal pituitary. Absence of the neurohypophysis is demonstrable postmortem in some cases. Midline cerebellar defects and hydrocephalus occur inconsistently in septo-optic dysplasia. One cerebellar lesion, called rhombencephalosynapsis is aplasia of the vermis and midline fusion of the cerebellar hemispheres and of the dentate nuclei, probably the downregulation of a dorsalizing gene at the level of rhombomere 1 (Sarnat, 2000). Clinical manifestations relate mainly to the endocrine deficiencies and vision impairment. Ataxia may be compensable if the cerebellar vermis is mildly involved. Seizures are uncommon. Intellectual development usually is normal. Hypertelorism is not a constant finding. Chromosome analysis is invariably normal. The gene HEXS1 is is defective in at least some cases (Dattani et al., 1998). No reports of familial cases exist. However, a high incidence of teenage pregnancy and drug abuse in early gestation occurs in mothers of affected infants. Septooptic-pituitary dysplasia has occurred in an infant of a diabetic mother.

Rhombomeric Deletions and Ectopic Genetic Expression Rare patients with absence of certain parts of the brain appear in the literature. Only recently, by understanding the families of genes responsible for neural tube segmentation (e.g., HOX, WNT, PAX), have these conditions been understood at the level of molecular embryology. Agenesis of the midbrain and upper pons (metencephalon) with cerebellar hypoplasia are attributable to the EN2 gene, which produces an almost identical malformation in the knockout mouse model (Sarnat et al., 2002). EN1 and WNT1 genes also are essential for development of the mesencephalic and rhombomere 1, but the animal models of these genetic defects produce total agenesis of the cerebellum. SHH also regulates the temporal and spatial precision of the midbrain–hindbrain junction, mediated through Gli activator (Blaess et al., 2006). Absence of the corpus striatum might be due to mutation of the EMX1 gene, which is essential in

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the programming of the basal telencephalon but not the cerebral cortex (Sarnat and Flores-Sarnat, 2001a). The Chiari malformations, particularly type II, were incompletely explained by mechanical theories of pathogenesis, but a molecular genetic hypothesis of ectopic expression provides a more complete and reasonable explanation (see the online section Chiari Malformation at http://expertconsult.inkling.com) (Sarnat and Flores-Sarnat, 2001b, 2004). Despite documentation of many of these genetic malformations in experimental animal models, definitive confirmation in humans has not occurred.

Agenesis of the Corpus Callosum A commissural plate differentiates within the lamina terminalis at day 39 of embryonic life. The plate acts as a bridge for axonal passage and provides a preformed glial pathway to guide decussating growth cones of commissural axons. Microcystic degeneration in the commissural plate and physiological death of astrocytes precedes the interhemispheric projection of the first axons. The earliest callosal axons appear at 74 days in the human embryo, the genu and the splenium are recognizable at 84 days, and the adult morphology is achieved by 115 days. The pathogenesis of callosal agenesis relates to the commissural plate; if this plate is not available to guide axons across, the corpus callosum does not develop. Failure of physiological degeneration of a portion of the plate results in a glial barrier to axonal passage and the disappearance or deflection of primordial callosal fibers posteriorly to another destination within their hemisphere of origin (bundle of Probst). Other destinations of callosal axons that are unable to cross the midline at their expected site include passage into the anterior commissure, which can become enlarged as much as four times its normal volume by the addition of these axons; aberrant sites of crossing of individual fibers not forming large bundles; and, occasionally, callosal axons descending within the internal capsule with the corticospinal tract as far as the spinal cord, where their termination and function remain unknown (Sarnat, 2008). The anterior commissure also passes through the embryonic lamina terminalis, more ventrally than the corpus callosum; its earliest pioneer axons traverse the midline 3 weeks earlier than those of the corpus callosum, at about 7–8 weeks’ gestation (Cho et al., 2013). Tridimensional diffusion tensor imaging (tractography) now enables assessment of white-matter connectivity prenatally, including corpus callosal fibers that are unable to cross the midline normally at the commissural plate, in second and third trimester fetuses (Kasprian et al., 2013). Agenesis of the corpus callosum is a common malformation, having a 2.3% prevalence in computed tomography (CT) scans in North America and 7%–9% prevalence in Japan. Most cases are isolated malformations, but callosal agenesis is an additional feature of many other prosencephalic dysplasias; it also occurs with aplasia of the cerebellar vermis and anomalous pyramidal tract. Simple callosal agenesis may involve the entire commissure or may be partial, usually affecting only the posterior fibers. Hypoplasia or partial agenesis of the commissure is much more common than total agenesis. In callosal agenesis, the anterior and hippocampal commissures are always well formed or large. A rare genetic form of callosal agenesis is associated with defective neural crest migration causing aganglionic megacolon (Hirschsprung disease). The cause is a defective human gene, Smad-interacting protein 1 (SMAD1), at the chromosome 2q22-q23 locus (Cacheux et al., 2001). In the absence of a corpus callosum, the lateral ventricles displace laterally, and the third ventricle rises between them (Fig. 89.10). Often the ventricles dilate mildly, but intraventricular pressure is normal. The anomaly may be demonstrable by most imaging techniques. The varying degrees of partial callosal agenesis produce several radiographic variants. Clinical symptoms of callosal agenesis may be minimal and unrecognized in children of normal intelligence. Detailed neurological

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1. It appears as a primary malformation, histologically associated with poorly laminated striate cortex, subcortical heterotopia, and defective ependymal lining of the occipital horns. 2. It is common in many cases of agenesis of the corpus callosum because of absence of the splenium and hypoplasia of white matter. 3. It may be the acquired result of periventricular leukomalacia, especially in premature infants, because of loss of periventricular white matter in the posterior half of the cerebral hemispheres. Clinical findings are usually those of intellectual disability, spastic diplegia, epilepsy, and vision loss, but it does not always cause complete blindness. CT in the neonatal period or early infancy demonstrates most cases. Isotope cisternography shows normal CSF dynamics in most. Colpocephaly is associated with several syndromes and systemic disorders including cerebrohepatorenal (Zellweger) disease, hemimegalencephaly, and several chromosomal disorders. The EEG in colpocephaly ranges from normal in mild cases to near-hypsarrhythmia in infants who develop myoclonic epilepsy. Bilateral posterior slowing of low voltage with occipital spikes is common. Colpocephaly also develops late in fetal life because of infarction and cystic degeneration of the deep white matter of the posterior third of the cerebral hemispheres, rather than as a developmental disorder of neuroblast migration. It is often confused with hydrocephalus. Fig. 89.10 Pneumoencephalogram (from the preimaging period) of an 18-month-old boy with agenesis of the corpus callosum associated with an interhemispheric arachnoidal cyst (arrowhead), a complication of some cases of callosal agenesis. The lateral ventricles are widely separated from the medial side of each hemisphere by the bundle of Probst; the third ventricle rises between them. The brainstem, cerebellum, and cerebral cortical convolutions appear normal. The patient has intellectual disability and epilepsy.

examination discloses deficits in the interhemispheric transfer of perceptual information for verbal expression. Intellectual disability or learning disabilities occur in some cases. Epilepsy is common, particularly in patients diagnosed early in life. Seizures may relate more to minor focal cortical dysplasias than to the callosal agenesis itself. Hypertelorism is present in many and often is associated with exotropia and inability to converge. The EEG characteristically shows interhemispheric asynchrony or poor organization, with or without multifocal spikes, but is not specific enough to establish the diagnosis. Asynchronous sleep spindles after 18 months of age are a good clue to the diagnosis. Several hereditary forms of callosal agenesis occur besides its occurrence as an additional anomaly in some cases of tuberous sclerosis and other genetic syndromes. Andermann syndrome is an autosomal recessive syndrome of callosal agenesis, mental deficiency, and peripheral neuropathy. Aicardi syndrome consists of agenesis of the corpus callosum, chorioretinal lacunae, vertebral anomalies, intellectual disability, and myoclonic epilepsy. This disorder is found almost exclusively in girls and is thought to be X-linked dominant (Xp22) and generally lethal in the male fetus. The EEG shows a typically asymmetrical asynchronous burst-suppression pattern. Neuropathological findings in Aicardi syndrome include a variety of minor dysplasias in addition to agenesis of the corpus callosum and anterior commissure, and nonlaminated polymicrogyric cortex with abnormally oriented neurons. Callosal agenesis is a common component in many chromosomal disorders, particularly trisomies 8, 11, and 13. Interhemispheric lipoma replacing part of the corpus callosum is associated with a high incidence of epilepsy.

Colpocephaly

Lissencephaly (Agyria, Sometimes With Pachygyria)

Lissencephaly is a failure of development of convolutions in the cerebral cortex because of defective neuroblast migration. The cortex remains smooth, as in the embryonic brain (see Fig. 89.8). The migrations of the cerebellum and the brainstem also usually are involved, but the thalamus and basal ganglia form properly. Structural and metabolic abnormalities of the fetal ependyma may be supplementary factors in disturbing the normal development of radial glial cells. The cytoarchitecture of the neocortex in lissencephaly takes one of two forms. In the first, a four-layered sequence develops. The outermost layer is a widened molecular zone; layer 2 contains neurons corresponding to those of normal laminae III, V, and VI; layer 3 is cell-sparse; and layer 4 contains heterotopic neurons that have migrated incompletely. Decreased brain size leads to microcephaly with widened ventricles, representing a fetal stage rather than pressure from hydrocephalus, and an uncovered sylvian fossa representing lack of operculation. The second form of cortical architectural abnormality in lissencephaly is disorganized clusters of neurons with haphazard orientation, forming no definite layers or predictable pattern. Type 2 lissencephaly is associated with several closely related genetic syndromes: Walker-Warburg syndrome, Fukuyama muscular dystrophy, muscle-eye-brain disease of Santavuori, and Meckel-Grüber syndrome, the latter often associated with posterior encephalocele (see Fig. 89.8). Additional text available at http://expertconsult.inkling.com.

Disturbances of Late Neuroblast Migration (after 20 Weeks’ Gestation) Additional text available at http://expertconsult.inkling.com.

Disorders of Cerebellar Development (32 Days’ Gestation to 1 Year Postnatally) Additional text available at http://expertconsult.inkling.com.

Colpocephaly is a selective dilatation of the occipital horns, not due to increased intraventricular pressure but rather due to loss of white matter. Colpocephaly occurs in three conditions:

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The complete reference list is available online at https://expertconsult. inkling.com.

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eFig. 89.11 (A) This 7-month-old boy has Miller-Dieker syndrome. He had severe developmental delay, tetraparesis, and epilepsy. Note he required a gastrostomy. (B) He has the typical facies of this genetic syndrome, with a high forehead with temporal hollowing, upturned nares, and long philtrum (upper lip). His gaze is dysconjugate, but there is no paresis of extraocular muscles. Sagittal (C) and parasagittal (D) views of T1-weighted magnetic resonance images show type 1 lissencephaly with very thick cortex and only mild ventriculomegaly. The cerebellum and brainstem, including the basis pontis, are grossly well formed. The corpus callosum is very thin. Extra-axial (i.e., subarachnoid) spaces are wide over the convexities of the cerebral hemispheres and in the cisterns surrounding the brainstem.

Miller-Dieker syndrome (type 1 lissencephaly). Miller-Dieker syndrome is a familial lissencephaly characterized clinically by microcephaly and a peculiar facies that includes micrognathia, high forehead, thin upper lip, short nose with anteverted nares, and lowset ears (eFig. 89.11). Neurologically, the children are developmentally delayed in infancy and intellectually disabled, lack normal responsiveness to stimuli, initially exhibit muscular hypotonia that later evolves into spasticity and opisthotonos, and develop intractable seizures. Death before 1 year of age is common. The EEG often shows focal or multifocal spike-wave discharges that later become bisynchronous bursts of diffuse paroxysmal activity, and extremely high-voltage diffuse rhythmic theta and beta activity. At autopsy, the original cases showed lack of gyral development in the cerebral cortex. Later patients with the typical craniofacial features and clinical course showed gyral development, although the convolutions were abnormal, and pachygyria predominated. The term Miller-Dieker syndrome as originally proposed was to distinguish this syndrome from other cases of lissencephaly without the clinical and dysmorphic facial features. A microdeletion at the chromosome 17p13.3 locus is demonstrable by high-resolution studies in most patients with Miller-Dieker syndrome, and family members of the original patients show the defect (Chong

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et al., 1997). The responsible gene is LIS1. Histological examination of the brain in Miller-Dieker syndrome confirms the presence of a severe disorder of neuroblast migration, as in other cases of lissencephaly.

Walker-Warburg and related syndromes (type 2 lissencephaly). Type 2 lissencephaly/pachygyria includes several distinctive

disorders of different genetic origin involving α-dystroglycan due to mutations in any of several genes: POMT1, POMT2, LARGE, FKTN, and FKRP (Devisme et al., 2012). All involve the terminal organization and architecture of the cortical plate and abnormal gyration or lack of gyration, sometimes termed cobblestone lissencephalies. Most also include a dystrophic myopathy. The eye is involved in some. In Fukuyama muscular dystrophy, a congenital muscular dystrophy is associated with cerebral dysgenesis of this type and due to mutation in the gene, fukutin (FKTN). Though common in Japan, where it is the second most common muscular dystrophy (after Duchennetype dystrophy), it is rare in other ethnic populations. The muscleeye-brain disease of Santavuori is most common in Finland but also exists in other northern European ethnic groups. Walker-Warburg syndrome is another congenital muscular dystrophy found in diverse ethnic groups. An autosomal recessive type 2 lissencephaly associated with cerebellar hypoplasia is due to defective expression of reelin, and

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PART III

Neurological Diseases and Their Treatment

X-linked congenital hydrocephalus (usually due to aqueductal atresia) is associated with pachygyria and mutation of the cell adhesion gene, L1CAM.

X-Linked recessive lissencephaly with abnormal genitalia.

The most recently defined genetic form of lissencephaly is due to a mutation in the ARX gene in both the mouse and human (Kitamura et al., 2002). It generally is associated with microencephaly and global cerebellar hypoplasia but also with abnormal genitalia. The brain malformation is the most severe of the lissencephalies, and affected children are profoundly intellectually disabled and have epilepsy.

Subcortical Laminar Heterotopia (Band Heterotopia) and Bilateral Periventricular Nodular Heterotopia Subcortical laminar heterotopia and bilateral periventricular nodular heterotopia both result from X-linked recessive traits occurring almost exclusively in females. Both disorders present clinically as severe seizure disorders in childhood, although they are often associated also with intellectual disability and other neurological deficits. In subcortical laminar heterotopia, a band of gray-matter heterotopia within the subcortical white matter lies parallel to the overlying cerebral cortex but separated from it by white matter. Histologically, it lacks lamination, as does the normal cortex, and consists of disoriented neurons and glial cells and fibers with poorly organized architecture. The few male fetuses that have not spontaneously aborted have been born with lissencephaly, in addition, and even more severe neurological deficits. The defective gene and its transcription product in subcortical laminar heterotopia are known; the latter is called doublecortin (Gleeson et al., 1999). In bilateral periventricular nodular heterotopia, islands of neurons and glial cells occur in the subependymal regions around the lateral ventricles; they are neuroepithelial cells that have matured in their site of origin without migrating (Eksioglu et al., 1996). The gene responsible is filamin-1. MRI best demonstrates both conditions, but they are also detectable by CT.

Schizencephaly Schizencephaly is a unilateral or bilateral deep cleft (usually in the general position of the sylvian fissure) but is not a sylvian fissure. This cleft is the full thickness of the hemispheric wall, and no cerebral tissue remains between the meninges and the lateral ventricle (the pial-ependymal seam). If the cerebral cortical walls on either side of the deep cleft are in contact, the condition is closed lip, and if a wide subarachnoid space separates the two walls, it is open lips, but these two variants do not provide a clue to pathogenesis. Schizencephaly is often classified as a neuroblast migratory disorder, but this mechanism is only partially true; it is primarily a disorder of development of the telencephalic flexure (see Fig. 89.6). It may occur either as a Mendelian or sporadic genetic trait or as a fetal deformation of the telencephalic hemisphere at the time of development of the telencephalic flexure (Sarnat and Flores-Sarnat, 2010); in some cases, it results from porencephaly due to fetal cerebral infarction. Schizencephaly was thought to be associated with defective expression of the gene EMX2 (Granata et al., 1997), but this is not the case (Tietjen et al., 2007), and the genetic basis remains unknown. It may be associated with a variable degree of lissencephaly/pachygyria, may be bilaterally symmetrical, or may be asymmetrical and more severe on one side. Schizencephaly is unilateral in half of cases.

Disturbances of Late Neuroblast Migration (after 20 Weeks’ Gestation) Although major neuronal migrations in the developing human brain occur in the first half of gestation, late migrations of immature nerve cells continue. A few neuronal precursors continue to migrate to the cerebral cortex after 20 weeks’ gestation. Perinatal disorders of cerebral F ECF

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perfusion, small intraparenchymal hemorrhages in premature infants, intracranial infections, and hydrocephalus are examples of common perinatal complications that may interfere with late neuronal migrations, either by destroying migrating neuroblasts or by disrupting their radial glial fiber guides. Reactive gliosis is detectable as early as 20 weeks’ gestation in the fetal brain, and proliferation of astrocytes is already evident 4 days after an insult. A gliotic plaque may block neuronal migration.

Disorders of Cerebellar Development (32 Days’ Gestation to 1 Year Postnatally) The cerebellum has the longest period of embryological development of any major structure of the brain. Neuroblast differentiation in the cerebellar plates (rhombic lips of His) of the dorsolateral future medulla oblongata and lateral recesses of the future fourth ventricle are recognizable at 32 days. Neuroblast migration from the external granular layer is not complete until 1 year postnatally. Because of this extended ontogenesis, the cerebellum is vulnerable to teratogenic insults longer than most parts of the nervous system. Malformations of the cerebellum may occur alone or be associated with other brainstem or cerebral dysplasias. The cerebellar cortex is especially susceptible to toxic effects of many drugs, chemicals, viral infections, and ischemic-hypoxic insults.

Selective Vermal Aplasia Selective hypoplasia or aplasia of the vermis, with intact lateral hemispheres, occurs in some genetic disorders in association with other midline defects involving the forebrain, as in some cases of HPE and callosal agenesis. Characteristic of Joubert syndrome, a specific autosomal recessive trait, is episodic hyperpnea, abnormal eye movements, ataxia, and intellectual disability. Joubert syndrome has a variable but often progressively worsening course, with improvement in some cases. Anomalies of visceral organs and polydactyly may be associated. Joubert syndrome is one of several disorders now recognized as “ciliopathies.”

Selective Cerebellar Hemispheric Aplasia Selective agenesis of the cerebellar hemispheres is much less common than aplasia of the vermis alone. Other components of the cerebellar system, such as the dentate and inferior olivary nuclei, may also be dysplastic. The lateral hemispheres and the inferior olivary and pontine nuclei more commonly are selectively involved in certain degenerative diseases of genetic origin, such as olivopontocerebellar atrophy and other spinocerebellar degenerations.

Dandy-Walker Malformation The Dandy-Walker malformation consists of a ballooning of the posterior half of the fourth ventricle, often but not always associated with lack of patency of the foramen of Magendie. In addition, the posterior cerebellar vermis is aplastic, and there may be heterotopia of the inferior olivary nuclei, pachygyria of the cerebral cortex, and other cerebral and sometimes visceral anomalies. Hydrocephalus from obstruction usually develops, but if treated promptly, the prognosis may be good. Neurological handicaps such as spastic diplegia and intellectual disability probably relate more to the associated malformations of the brain than to the hydrocephalus. Various incomplete forms are described as Dandy-Walker variants, particularly in MRI studies, but the classification of these is debated. Some authors regard the Blake pouch cyst as within the spectrum of Dandy-Walker malformations. Blake pouch cyst is derived from the posterior membranous area of the roof of the fourth ventricle; by 26 weeks’ gestation it normally communicates with the subarachnoid space, forming the foramen of Magendie (Azab et al., 2014). If the 02 .4.(1( 4 (

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foramen fails to perforate at the programmed time, the cyst remains attached to the roof of the fourth ventricle posteriorly and obstructive hydrocephalus may develop. The anterior membranous area usually remains normal so that the vermis and lateral hemispheres of the cerebellum develop appropriately. Blake pouch cyst is a phenotypic syndrome with multiple genotypes, including distal chromosome 13q deletion that causes haploinsufficiency of ZIC2 and ZIC5 genes and two adjacent zinc finger protein genes (Myers et al., 2017).

Chiari Malformation The Chiari malformation is a displacement of the tonsils and posterior vermis of the cerebellum through the foramen magnum, compressing the spinomedullary junction; this simple form is termed Chiari type I malformation. Type II involves an additional downward displacement of a distorted lower medulla and dysplasia of medullary nuclei and is a constant feature in lumbosacral meningomyelocele. Chiari type III malformation, a rare form, involves cervical spina bifida with cerebellar encephalocele. Chiari originally identified a type IV in 1896, but this type is actually cerebellar hypoplasia with no relation to the other types, and the term Chiari malformation type IV is now used only in its historical context. Hydrocephalus is commonly associated with Chiari malformations. The pathogenesis has been a matter of controversy for many years. Mechanical theories have dominated since the time of Chiari: (1) the traction theory, a result of a tethered spinal cord with traction as the vertebral column grows; (2) the pulsion theory of fetal hydrocephalus pushing the cerebellum and brainstem from above; and (3) the crowding theory in which a small posterior fossa provides insufficient room for the growth of neural structures and causes a “toothpaste tube effect.” The torcula is indeed too low and the volume of the posterior fossa too small, so that this latter explanation is probably a true contributory factor, but only in late gestation as a superimposed secondary influence. A molecular genetic hypothesis of ectopic expression of a segmentation gene in the rhombomeres explains not only the Chiari malformation but also the brainstem anomalies, the myelodysplasia, and the defective basioccipital and supraoccipital bone formation that results in a too-small posterior fossa (Sarnat, 2004a).

Global Cerebellar Hypoplasia Global cerebellar hypoplasia has diverse causes that include chromosomal and genetically determined diseases, Tay-Sachs disease, Menkes kinky hair disease, some cases of spinal muscular atrophy, and sporadic cases of unknown cause. Histologically, there may be a selective depletion of granule cells or a loss of Purkinje cells and other neuronal elements in addition to granule cells (eFig. 89.12). In selective granule cell depletion, the axons and dendrites of Purkinje cells are deformed. Clinically, the most constant features of cerebellar hypoplasia in infancy are developmental delay and generalized muscular hypotonia. Truncal titubation and ataxia become evident after several months, and nystagmus and intention tremor may appear in severe cases. Tendon stretch reflexes usually are hypoactive but may be hyperactive if corticospinal tract deficit is also present because of cerebral involvement.

Focal Cerebellar Dysplasia Focal dysplasias and hamartomas of the cerebellar cortex (eFig. 89.13) are often incidental findings at autopsy and are often clinically asymptomatic. More extensive lesions present abnormal cerebellar findings clinically. These small focal malformations are a disorder of neuronal migration

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eFig. 89.12 Cerebellar cortex of infant with cerebellar hypoplasia shows extensive gliosis and loss of all neuronal elements. This histological appearance resembles that of cerebellar sclerosis secondary to acquired injury, but in the latter condition there are usually a few neurons still surviving. Some cases of cerebellar hypoplasia show selective loss of granule cells and preservation of Purkinje cells. (Hematoxylineosin stain. Bar = 100 µm.)

eFig. 89.13 Focal Dysplasia of Cerebellar Cortex. The normal laminar architecture is disrupted, and granule and Purkinje cells show a haphazard orientation and array. Some granule cells are spindle shaped, resembling the shape assumed during transit from the external granular layer in normal development. This dysplasia is due to faulty neuronal migration and probably occurred at midgestation. (Hematoxylin-eosin stain. Bar = 15 µm.)

programmed as genetic defects or, more commonly, acquired from brief insults during the long period of cerebellar development. Focal ischemic insults and exposure to cytotoxic drugs or viruses are among the more common causes. The granule cells of the cerebellar cortex retain a regenerative capacity lost early in gestation by most other neurons, but the regenerative pattern of lamination in the cerebellar cortex may be imperfect. Displaced neurons in the cerebellar white matter, or in different laminae than they belong, such as Purkinje cells in the granule cell layer, may be disturbances of neuroblast migration (Laure-Kamionowsky et al., 2011; Sarnat, 2018). Displaced Purkinje cells are not really as “isolated” as they appear histologically because the Bergmann glial cells of the Purkinje cell layer dip down to include them, and they also are in synaptic contact, as are other Purkinje neurons (Sarnat, 2018b).

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90 Autism and Other Neurodevelopmental Disabilities Reet Sidhu, D. David O’Banion, Christine Hall OUTLINE Autism Spectrum Disorders, 1366 Diagnostic Criteria, 1366 Epidemiology, 1366 Clinical Features, 1368 Management, 1371 Prognosis, 1371 Intellectual Disability, 1371 Clinical Features, 1371 Diagnosis and Etiology, 1372 Management, 1375

Learning Disability, 1376 Dyslexia, 1376 Dyscalculia, 1377 Disorder of Written Communication, 1378 Developmental Coordination Disorder, 1378 Attention-Deficit/Hyperactivity Disorder, 1380 Clinical Features, 1380 Evaluation and Etiology, 1380 Management, 1383

AUTISM SPECTRUM DISORDERS

and/or gastrointestinal disorders. (See Box 90.1 and Table 90.1 for DSM-5 criteria for ASD.) The range of disabilities seen among children on the spectrum cannot be overemphasized.

Diagnostic Criteria Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairments in two areas: (1) deficits in social communication and social interactions; and (2) restricted and repetitive patterns of behavior, interests, and activities (APA, 2013a). With the revised Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5), ASD now subsumes what were previously separate diagnostic categories of autistic disorder (also referred to as classic autism or early infantile autism), pervasive developmental disorder– not otherwise specified (PDD-NOS), and Asperger syndrome. The changes are based on research results which, thus far, have failed to document either PDD-NOS or Asperger syndrome as separate biological entities. The prior diagnostic manual also included deficits in language expression as a criterion, but this is no longer the case as not all children with ASD have language disorders. However, pragmatic language skills are incorporated into the social domain as all individuals with ASD have deficits in this domain of language. Under the DSM5, diagnosis of ASD requires an individual to exhibit three deficits in social communication and at least two symptoms in the category of restricted range of activities/repetitive behaviors. Within the second category, a new symptom is included: hyper- or hyporeactivity to sensory input or unusual interests in sensory aspects of the environment. Deficits in social communication and interactions include those in social reciprocity, nonverbal communication, and skills in developing, maintaining, and understanding social relationships. Symptoms must be present in early development but need not be shown until social demands exceed the individual’s capacity. Furthermore, DSM-5 specifies three levels of severity (mild, moderate, severe) rated separately for social communication and restricted, repetitive behaviors, based on what level of support the individual requires. In addition to the diagnosis, individuals are also described in terms of any known genetic cause (e.g., fragile X syndrome [FXS], Rett syndrome), level of language and intellectual disability (ID), and presence of medical conditions such as seizures, psychiatric disorders (e.g., anxiety, depression),

Epidemiology There has been a significant increase in the prevalence of ASD in the United States, particularly since the late 1990s. In the 1990s, the estimated frequency was about 1 per 1000 for autism and 2 per 1000 for ASD (Williams et al., 2006), while, more recently, the estimated prevalence is much higher. The Autism and Developmental Disabilities Monitoring Network (2018), which identifies ASD through screening and review of health and education records that document behaviors associated with ASD in 11 sites in the United States, most recently reported a prevalence rate of 16.8 per 1000 (1 in 59) among 8 year olds, with prevalence estimates varying from 5.7 to 21.9 per 1000 in the different sites. Non-Hispanic White children were approximately 7% more likely to be identified with ASD than non-Hispanic Black children and 22% more than Hispanic children. ASDs are four times more likely in males than in females. Whether there has been an actual increase in ASD prevalence or if the apparent increase is due to other factors is still under investigation. Factors such as increased awareness among parents and professionals (Fombonne, 2009), broadening of the diagnosis with emphasis on the spectrum aspect of the disorder, including mildly affected individuals (Shattuck, 2006; Wing and Potter, 2002), change in referral patterns, and using the diagnosis as a basis for intervention services (Blumberg et al., 2013; Idring et al., 2014; Shieve et al., 2011) may account for an apparent increase in prevalence rates. Both advanced maternal and paternal age may play a role in increasing the frequency of autism (Durkin et al., 2008). The theory that the measles, mumps, rubella (MMR) vaccine plays any role in the increase has been completely discredited (Marshall et al., 2015, Maglione et al., 2014). The prevalence of ASD in siblings of children with ASD ranges from 2% to 18% (Lauritesen et al., 2005; Ozonoff et al., 2011; Schaefer and Mendelsohn, 2013). The high concordance in monozygotic twins (Rosenberg et al., 2009), the increased risk for recurrence in siblings (≈5%– 10%), a broader autistic phenotype in families with an autistic proband,

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BOX 90.1

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DSM-5 Criteria for an Autistic Spectrum Disorder

A. Persistent deficits in social communication and social interaction across multiple contexts, as manifested by the following, currently or by history (examples are illustrative, not exhaustive, see text): 1. Deficits in social-emotional reciprocity, ranging, for example, from abnormal social approach and failure of normal back-and-forth conversation; to reduced sharing of interests, emotions, or affect; to failure to initiate or respond to social interactions. 2. Deficits in nonverbal communicative behaviors used for social interaction, ranging, for example, from poorly integrated verbal and nonverbal communication; to abnormalities in eye contact and body language or deficits in understanding and use of gestures; to a total lack of facial expressions and nonverbal communication. 3. Deficits in developing, maintaining, and understanding relationships, ranging, for example, from difficulties adjusting behavior to suit various social contexts; to difficulties in sharing imaginative play or in making friends; to absence of interest in peers. Specify current severity: Severity is based on social communication impairments and restricted repetitive patterns of behavior (see Table 90.8). B. Restricted, repetitive patterns of behavior, interests, or activities, as manifested by at least two of the following, currently or by history (examples are illustrative, not exhaustive; see text): 1. Stereotyped or repetitive motor movements, use of objects, or speech (e.g., simple motor stereotypies, lining up toys or flipping objects, echolalia, idiosyncratic phrases). 2. Insistence on sameness, inflexible adherence to routines, or ritualized patterns or verbal nonverbal behavior (e.g., extreme distress at small changes, difficulties with transitions, rigid thinking patterns, greeting rituals, need to take same route or eat food every day). 3. Highly restricted, fixated interests that are abnormal in intensity or focus (e.g., strong attachment to or preoccupation with unusual objects, excessively circumscribed or perseverative interest).

4. Hyper- or hyporeactivity to sensory input or unusual interests in sensory aspects of the environment (e.g., apparent indifference to pain/ temperature, adverse response to specific sounds or textures, excessive smelling or touching of objects, visual fascination with lights or movement). Specify current severity: Severity is based on social communication impairments and restricted, repetitive patterns of behavior (see Table 90.8). C. Symptoms must be present in the early developmental period (but may not become fully manifest until social demands exceed limited capacities, or may be masked by learned strategies in later life). D. Symptoms cause clinically significant impairment in social, occupational, or other important areas of current functioning. E. These disturbances are not better explained by intellectual disability (intellectual developmental disorder) or global developmental delay. Intellectual disability and autism spectrum disorder frequently co-occur; to make comorbid diagnoses of autism spectrum disorder and intellectual disability, social communication should be below that expected for general developmental level. Note: Individuals with a well-established DSM-5 diagnosis of autistic disorder, Asperger disorder, or pervasive developmental disorder not otherwise specified should be given the diagnosis of autism spectrum disorder. Individuals who have marked deficits in social communication, but whose symptoms do not otherwise meet criteria for autism spectrum disorder, should be evaluated for social (pragmatic) communication disorder. Specify if: With or without accompanying intellectual impairment With or without accompanying language impairment Associated with a known medical or genetic condition or environmental factor Associated with another neurodevelopmental, mental, or behavioral disorder With catatonia

Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (© 2013). American Psychiatric Association.

TABLE 90.1 Severity Level

Severity Levels for Autism Spectrum Disorder Social Communication

Restricted, Repetitive Behaviors

Level 3 Severe deficits in verbal and nonverbal social communication skills cause severe impair“Requiring very subments in functioning, very limited initiation of social interactions, and minimal response stantial support” to social overtures from others. For example, a person with few words of intelligible speech who rarely initiates interaction and, when he or she does, makes unusual approaches to meet needs only and responds to only very direct social approaches Level 2 Marked deficits in verbal and nonverbal social communication skills; social impairments “Requiring substanapparent even with supports in place; limited initiation of social interactions; and tial support” reduced or abnormal responses to social overtures from others. For example, a person who speaks simple sentences, whose interaction is limited to narrow special interests, and who has markedly odd nonverbal communication

Inflexibility of behavior, extreme difficulty coping with change, or other restricted/repetitive behaviors markedly interfere with functioning in all spheres. Great distress/difficulty changing focus or action Inflexibility of behavior, difficulty coping with change, or other restricted/repetitive behaviors appear frequently enough to be obvious to the casual observer and interfere with functioning in a variety of contexts. Distress and/or difficulty changing focus or action Level 1 Without supports in place, deficits in social communication cause noticeable impairments. Inflexibility of behavior causes significant interference with functioning in one or more con“Requiring support” Difficulty initiating social interactions, and clear examples of atypical or unsuccessful texts. Difficulty switching between activities. response to social overtures of others. May appear to have decreased interest in social Problems of organization and planning hamper interactions. For example, a person who is able to speak in full sentences and engages in independence communication but whose to-and-fro conversation with others fails, and whose attempts to make friends are odd and typically unsuccessful

Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (© 2013). American Psychiatric Association.

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which includes anxiety and mood as well as social style and obsessive characteristics (Daniels et al., 2008), and the association with a number of genetic disorders support a hereditary basis in many cases (Gillberg, 2010). Developmental regression or loss of previously established skills during the first 1–3 years of life has been estimated as occurring in approximately one-third of children with ASD at an average age of 1.78 years (Barger et al., 2013). A meta-analysis of studies on the prevalence of developmental regression in children with ASD found that rates differed based on type of regression measured. Studies focusing on language regression (e.g., loss of words) were estimated as occurring in 25%; those on both language and social regression (e.g., play skills, joint attention, response to name) in 38%; mixed regression (including cognitive and/or motor skills) in 33%; and unspecified regression in 39%. Similarly, regression prevalence differed based on sampling methods, with population-based studies showing a prevalence rate of 22%; clinic-based prevalence at 34%; and parent survey-based prevalence as 41% (Barger et al., 2013). While most studies on regression in autism have relied on retrospective parent reports, recently there has been a shift towards prospective studies that focus on infants who are at genetically high risk for autism. These studies have tracked early-appearing social behaviors such as shared affect, social interest, gaze to face and eyes, and response to name. In a review of these prospective studies, Ozonoff and Iosif (2019) found evidence that most children with autism had a period of relatively typical development followed by decline in social behaviors starting at about 9 months. In some studies, as many as 80% of infants with ASD demonstrated this early regression in social behaviors (Jones et al., 2014; Ozonoff et al., 2018b; Pearson et al., 2018). While ASD cannot be reliably diagnosed until 18 months of age, there is evidence that ASD can be detected as early as 12 months old based on early social behaviors, including looking at people, use of gestures, response to name, and repetitive motor actions (Osterling et al., 2002). An eye-tracking study found that typical eye gaze is present but declines in 2- to 6-month-old children who are later diagnosed with ASD (Johnson and Klin, 2013).

Clinical Features The intelligence quotient (IQ) is not one of the defining criteria for an ASD diagnosis (Matson and Shoemaker, 2009). The Autism and Developmental Disabilities Monitoring Network (2018) found that 31% of children with ASD have an ID (IQ < 70), 25% are in the borderline range (IQ 71–85), and 44% have IQ scores in the average to above average range (i.e., IQ > 85). Normal range IQ is a positive prognostic sign. Having a higher verbal IQ at 2–3 years of age appears to predict better outcome, particularly if intervention is delivered early (Anderson et al., 2014) Long-term prognosis also correlates with acquisition of language skills. An estimated one-third of people with autism are nonverbal, and those with verbal language often demonstrate significant difficulties with prosody and pragmatic language (Rapin and Tuchman, 2006; Tager-Flusberg et al., 2009). Individuals with conversational language by age 5–6 do significantly better than children with little or no language. Early joint attention (the ability to draw another person’s attention to an object of interest through the use of eye gaze and gestures, such as pointing), as well as vocal and motor imitation skills, was more impaired in children who did not develop language by age 5 (but had relatively strong nonverbal cognitive skills) than in children who did develop language by 5 years (Thurm et al., 2007). The dominant feature of ASD is a difference in a child’s social communication and interaction. Typically developing children show a natural proclivity to learn from the social world, and they seek out social input spontaneously and frequently starting in the first weeks of life. By contrast, children with ASD tend to be more drawn to interaction with the physical world (Klin et al., 2002) and are less likely to show interest in interacting with others. They tend to have difficulty attending to F ECF

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others, interpreting the social intent of others, and sharing enjoyment. In toddlers and preschoolers, social deficits include reduced eye contact, reduced enjoyment in social games, lack of joint attention, and lack of interest in other children. Because of these social vulnerabilities, they struggle to learn appropriate social communication strategies including verbal speech as well as nonverbal communication strategies such as gestures and body language. They also tend to struggle to engage in age-appropriate functional and pretend play with others. As children with ASD progress through school, they can struggle with forming friendships, engaging appropriately in back-and-forth conversation, appropriate body language, and knowing how to initiate and respond to interactions with their peers appropriately. A restricted range of behaviors, interests, and activities is another hallmark feature of autism. Many children with ASD demonstrate stereotypic motor behaviors such as hand flapping, tensing and shaking, toe walking, or spinning. In addition, they may use language in repetitive or idiosyncratic ways such as echoing statements made by others or heard on television, or repeating certain sounds/words/ phrases over and over again. They may also like spinning, dropping, or lining up objects, or opening and closing doors. Second, children with ASD often are highly dependent on routines or rituals and have significant difficulty with change or transitions. Third, children with autism may be overly focused on a particular topic, object, or area of interest. For example, a child may be fixated on trains, super heroes, bunnies, the constitutional convention, or air conditioning units. Finally, children with ASD often demonstrate differences in how they respond to sensory input. They may seek out sensory input in unusual ways such as smelling or licking objects, or rubbing items on their face. In other instances, they may be highly sensitive to sensory input such as loud noises, textures, or crowded environments.

Evaluation The clinical history and observations of the child are the basis for the diagnosis of an ASD. Research indicates that ASDs may be identified as young as 18 months of age or younger. By age 2 years, it is expected that a qualified professional can reliably make the diagnosis. The American Academy of Pediatrics recommends screening all children at well-child visits at 18 months and at 24 months of age (Johnson et al., 2007). A number of questionnaires and observation measures are available to screen for ASDs. Probably the most commonly used is the Modified Checklist for Autism in Toddlers–Revised (M-CHAT-R), which is a parent-completed questionnaire designed to identify children at risk for autism in the general population. There are a number of tools used to assess ASDs, but experts believe that no single tool should be used to make a diagnosis. The Autism Diagnostic Observation Schedule-2 (ADOS-2) is considered the “gold standard” in diagnosing ASD. It consists of a semi-structured, standardized assessment of social interaction, play, and imaginative use of material for individuals suspected of having ASDs from 12 months old to adults. The ADOS often is used in conjunction with the Autism Diagnostic Interview–Revised (ADIR), a clinical diagnostic interview for diagnosing autism in children and adults with mental ages of 18 months and above that focuses on assessing reciprocal social interactions, communication, and language; and restricted and repetitive, stereotyped interests and behaviors. Both the ADOS and ADI-R are time consuming and the ADOS requires special training to administer and score. Other well-known assessments include the Childhood Autism Rating Scale–Second Edition (CARS-2) that is appropriate for children over age 2 and draws from observations on different areas of behavior associated with ASDs. Several rating scales, such as the Social Responsiveness Scale (SRS-2) and the Social Communication Questionnaire (ScQ) can be helpful for eliciting information from parents and teachers. The standard neurological examination is generally normal, although children with ASDs are often clumsy and have mild hypotonia. 02 .4.(1( 4 (

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CHAPTER 90 Autism and Other Neurodevelopmental Disabilities Macrocephaly occurs in about one-third of children with autism and generally becomes apparent around the age of 1–3 years. The fact that macrocephaly is not present at birth suggests there is an increased rate of brain growth in the first years of life that diminishes and may become subnormal in later childhood; macrocephaly in adults with autism is less common than in children with ASD (Sacco et al., 2007). Skin examination requires careful attention, given high co-occurrence with tuberous sclerosis (Gillberg, 2010). Dysmorphology examination should be performed to facilitate the diagnosis of genetic syndromes (e.g., FXS, velocardiofacial syndrome, and Smith-Magenis syndrome). Hearing impairment should be excluded by a formal audiology assessment. Electroencephalogram (EEG), including a sleep record or overnight video-EEG monitoring, is appropriate when seizures occur or if developmental regression has occurred (see the Epilepsy section). There are multiple neurometabolic causes of ASD, many of which are not usually associated with any dysmorphology. Primary inborn errors of metabolism in simple (e.g., nonsyndromic) autism are a rare occurrence. Treatable conditions include PKU (phenylketonuria), hyperammonemia/urea cycle defects, and creatine synthesis/creatine transporter defects. Other conditions include purine and pyrimidine abnormalities, Smith-Lemli-Opitz syndrome, and lysosomal storage disorders. Primary mitochondrial disease and ASD is a subject of much debate. Some investigators report a significant incidence of mitochondrial DNA changes or functional disturbances in children with ASD but whether these are the primary cause of ASD remains to be defined. The extent of the evaluation for an underlying metabolic disorder depends on clinical suspicion and the relevance to family counseling. Box 90.2 lists some disorders that can be associated with an ASD phenotype.

Medical Comorbidities Medical comorbidities frequently occur in ASD, including epilepsy, gastrointestinal dysfunction, sleep disorders, and psychiatric conditions (e.g., anxiety, depression, obsessive-compulsive disorder [OCD]). It is important to consider medical causes for any change in behavior, especially in those individuals who are nonverbal or with limited language capability. Examples of such medical conditions include, but are not limited to, the following: pain (due to migraine headaches, ear infection, fractures, etc.), gastrointestinal disorders (e.g., gastroesophageal reflux disorder [GERD], constipation), gastrourinary conditions (e.g., urinary tract infection [UTI]), hormonal imbalance/endocrine dysfunction (e.g., menstruation), and sleep disturbance (e.g., sleep apnea).

Epilepsy The association of epilepsy with autism provided one of the first clues to suggest that autism was a neurodevelopmental disorder of brain function. It is now well established that individuals with ASD have a higher risk of epilepsy than the general population. Epilepsy is commonly reported to occur in approximately one-third of individuals with ASD but the exact prevalence is unknown, with reports in the literature ranging from 5% to 46% (Spence and Schneider, 2009). Variation in estimates is likely related to multiple factors such as sample ascertainment, degree of ID, age, gender, and type of ASD (simple/nonsyndromic vs. complex/syndromic). ID and motor impairments (e.g., cerebral palsy) have been identified most commonly as significant risk factors for epilepsy in ASD, with higher rates in those with more severe cognitive impairments (Amiet et al., 2008; Hara, 2007; Parmeggiani, Barcia, Posar, & et al, 2010a, 2010b, Viscidi et al., 2013). Age of onset of epilepsy in ASD has generally been thought to occur in two peaks, one in early childhood ( 3 standard deviations [3 SD] above the mean). Other single gene disorders associated with ASD include neurofibromatosis, type 1 (NF1 gene), Duchene muscular dystrophy (DMD gene), and Timothy syndrome (CACNA1C gene) (Wisniowiecka and Nowakowska, 2019). The most common autism-related CNVs are 16p11.2 microdeletions and microduplications that are identified in about 1% of individuals with ASD. Individuals with deletions have commonly been found to have macrocephaly versus those with duplications often have microcephaly. Other recurrent CNVs found in ASD include 1q21.1, 15q13.3, 17p11.2, 22q11.2, 16p13.1, and microduplication of 7q11.23 (Wisniowiecka and Nowakowska, 2019). Mutations in genes encoding synaptic adhesion molecules like neuroligin, neurexin, contactin-associated protein (CNTNAP), and cell-adhesion molecule 1 (CADM1) suggest that impaired synaptic function underlies ASDs (Miller et al., 2005). However, knockout mouse models of these mutations do not show the full range of autistic symptoms. This could mean that gain of function as well as loss of function arising from these mutations is required for the full ASD picture. Endoplasmic reticulum stress due to these mutations may cause a trafficking disorder of synaptic receptors like gamma-aminobutyric acid B (GABAb) receptors, resulting in impaired synaptic function and signal transduction. This theory provides for epigenetic factors playing a role as well (Momoi et al., 2010). Genes encoding postsynaptic scaffold proteins (SHANK2 and SHAN3) and ion channel proteins (CACNA1A, CACNA1H, SCN1A, SCN2A) also have been implicated in ASD (Montiero and Feng 2017, Daghsni et al., 2018). Neuropathology. Based on the core symptoms of autism, neuropathological abnormalities would be anticipated and are found in regions important to social function (frontal lobe, superior temporal cortex, parietal cortex, and amygdala), language function (language cortex), and repetitive behaviors and stereotypies (orbital frontal cortex and caudate) (Amaral et al., 2008; Bauman and Kemper, 2005; Casanova and Trippe, 2009; Casanova et al., 2006; Herbert et al., 2002, 2005; Pardo and Eberhart, 2007; Schumann et al., 2010; Vargas et al., 2005). Functional imaging studies demonstrate that neural systems related to social functioning, such as emotional face recognition, are abnormal (Corbett et al., 2009). Abnormalities of mirror neurons are also seen when subjects imitate and observe emotions (Rizzolatti and Fabbri-Destro, 2010). ASDs are now considered disorders of the development of the connectivity of the neurons of the cerebral cortex, which results in disturbances in the highly specialized connections that provide for uniquely human abilities. The occurrence of mutations in genes that act on molecular signaling pathways involved in the development and maintenance of neuronal and synaptic connections has reinforced the 02 .4.(1( 4 (

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CHAPTER 90 Autism and Other Neurodevelopmental Disabilities centrality of disruption of cortical connectivity in ASD (Konopka et al., 2012; Parikshak et al., 2013; Pinto et al., 2014; Scott-Van Zeeland et al., 2010). Studies of brain structure have implicated multiple events in the prenatal and postnatal brain development, particularly neuronal organizational events. A recent study supports a prenatal onset of ASD, occurring during the second and third trimester of pregnancy. Courchesne and colleagues found focal patches of abnormal laminar cytoarchitecture and cortical disorganization of neurons, but not glia, in the prefrontal and temporal cortical tissue from 10 of 11 children with autism and from 1 of 11 unaffected children, supporting a probable dysregulation of layer formation and layer-specific neuronal differentiation prenatally (Stoner et al., 2014). Increased total brain volume, primarily due to increased white matter, is the most frequently replicated imaging finding (Verhoeven et al., 2010). Very young children with autism (18 months to 4 years) have a 5%–10% increase in brain volume, especially in the frontal lobe compared to controls, which parallels the increasing head circumference during this period. A recent study suggests that changes in brain growth rate between the ages of 6 and 12 months may predict changes in the brain that occur between the ages of 12 and 24 months and correspond with the development of ASD symptoms (Hazlett, 2017). In contrast to other white-matter structures, both volume and density of the corpus callosum are reduced (Hardan et al., 2008; Minshew, 2009), perhaps resulting in decreased interhemispheric communication (Williams and Minshew, 2007). Imaging studies also highlight the dissociation between white-matter tract overgrowth and gray-matter dendritic and synaptic underdevelopment. Spectroscopy studies suggest that the gray matter is abnormal and dendritic arborization and synaptosome density reduced. Some investigators speculate that gray-matter abnormalities trigger the white-matter overgrowth (Williams and Minshew, 2007). The white-matter abnormalities result in abnormality of connectivity. At the cytoarchitectonic level, minicolumns that determine connectivity are abnormal, especially in the dorsolateral prefrontal cortex (Casanova et al., 2006). As a result, and well delineated on diffusion tensor (DT) imaging (Keller et al., 2007; Sundaram et al., 2008), short-range connectivity is increased, and long-range connectivity is decreased (Williams and Casanova, 2010). The hyperconnected local networks may become partially isolated and acquire novel functional properties. By contrast, the decrease in long-range connections could explain the problems with top-down control and integration (Williams and Casanova, 2010). A recent study of toddlers, ages 1–4 years, with ASD found axonal overconnectivity in frontal lobes with growth pathology thought to be due to neuron excess. This is thought to lead to underfunctional connectivity and resultant impairments in social communication (Solso et al., 2016). Given that the brain mechanisms causing ASD are largely at the level of connections among neurons and are not detectable on gross structural neuroimaging, imaging is not considered a routine part of the evaluation of individuals with ASD.

multiple prompting paradigms, reinforcement schedules, and imitation and modeling. Another type of intervention, the Treatment and Education of Autistic and Related Communication-Handicapped Children (TEACCH) method, uses structured teaching to help improve skills, with the therapist functioning as a generalist in treating the whole child. Developmental and relationship-based models, such as the Developmental Individual Difference, Relationship approach (DIR or Floortime), focus on teaching skills, such as social communication and interpersonal skills. The Early Start Denver Model (ESDM) is considered an integrative approach, as it uses a combination of intensive ABA and developmental and relationship-based intervention and includes parents as therapists. Parental involvement is considered an important part of the treatment program and parent-mediated treatment may result in better parent–child interaction and reduced severity of ASD symptoms than in children in nonmediated groups (Oono et al., 2013). A variety of other interventions are used to target specific areas of development (e.g., social skills groups, video modeling, occupational therapy). Table 90.2 lists medications that have been helpful in some children.

Prognosis Based on current outcome data, children who receive early intensive behavioral intervention can show significant improvement in the core features of autism including social communication, emotional/behavioral regulation, as well as in IQ and adaptive behavior (Zwaigenbaum et al., 2015; Howelen et al.; Reichow et al.). Findings suggest that best prognosis is associated with normal IQ, intensive intervention before age 3, and intervention that includes active involvement of families or caregivers (Zwaigenbaum et al., 2015, Granpeesheh, 2009). Some Swedish studies, conducted before the introduction of early identification and intervention, demonstrated poor outcomes for many adults with ASD. In a prospective study, Billstedt et al. (2005) followed 120 individuals diagnosed in childhood and reevaluated them at ages 17 and 40 with regard to employment, higher education, independent living, and peer relationships. Outcomes were generally poor in 78% of cases, and only 4 of 120 individuals were living independently. Better outcomes were associated with childhood IQ level and existence of communicative phrase speech at age 6. Cederliund et al. (2008) found that approximately two-thirds of adults with autism showed poor social adjustment (limited independence in social relations). Even though higher-functioning individuals with autism (including those previously diagnosed as Asperger syndrome) had the best outcome, only 15%–30% had fair to good outcomes, and only 5%–15% became competitively employed, led independent lives, married, and raised families. Psychiatric problems were common in this group. Probably, some “odd” adults go undiagnosed in childhood and adolescence, thus increasing the proportion of those with ASD who ultimately function in the mainstream. Some are highly productive and original in their work (Billstedt et al., 2007; Seltzer et al., 2003).

INTELLECTUAL DISABILITY

Management Both behavioral and educational interventions target the core symptoms of ASDs. Usually, children with ASD require a combination of therapies and interventions to address their individual groups of symptoms. It is recommended that children receive educational intervention as soon as they are suspected of having ASD, with services being provided a minimum of 25 hours a week on a yearly basis. Preschool children with ASDs should receive special education preschool or a home-based behavioral modification program (Handelman and Harris, 2002). Intensive behavioral interventions, such as applied behavior analysis (ABA), based on the work of Lovaas (1987) use F ECF

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Clinical Features ID, also known as intellectual developmental disorder, requires limitations in both intellectual ability and deficits in adaptive skills, as expressed in conceptual, social, and practical adaptive skills, relative to the child’s age, experience, and environment. Specifically, the diagnosis requires that the following criteria are met: (1) Deficits in intellectual functioning (i.e., reasoning, abstract thinking, learning, both experiential and academic) that must be confirmed through both clinical evaluation and individualized, standardized IQ testing; (2) limitations in adaptive functioning that result in failure in meeting developmental

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Neurological Diseases and Their Treatment

Medications for Autism Spectrum Disorders

Hyperactivity and inattention

Psychostimulants (methylphenidate; dextroamphetamine); α-agonists (clonidine, Tenex, Intuniv, Kapvay)

Obsessive-compulsive behaviors and anxiety

Selective serotonin reuptake inhibitors: fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), fluvoxamine (Luvox), citalopram (Celexa) Anxiolytics: buspirone (BuSpar) Tricyclics: clomipramine (Anafranil) Atypical neuroleptics: risperidone (Risperdal), olanzapine (Zyprexa), ziprasidone (Geodon), aripiprazole (Abilify) α-agonists: clonidine (Catapres), guanfacine (Tenex), Intuniv, Kapvay Beta-blockers: propranolol (Inderal) Mood stabilizers: carbamazepine (Tegretol), divalproex sodium (Depakote), gabapentin (Neurontin), topiramate (Topamax), lithium (Lithium) Clonidine, Tenex, clonazepam (Klonopin), pimozide (Orap), haloperidol (Haldol), risperidone (Risperdal), baclofen (Lioresal), deep brain stimulation Naloxone (Narcan), propranolol, fluoxetine, clomipramine, lithium Neuroleptics: haloperidol, risperidone, olanzapine, ziprasidone Depakote, Lamictal, Trileptal, Tegretol, Topamax

Aggressive and impulsive behaviors

Tics/stereotypies Self-mutilation Psychosis Seizures

Modified from Soorya, L., Kiarashi, J., Hollander, E., 2008. Psychopharmacologic interventions for repetitive behaviors in autism spectrum disorders. Child Adolesc Psychiatr Clin N Am 17, 753–771.

and social standards for personal independence and social responsibility; and (3) onset of intellectual and adaptive deficits occurs during the developmental period. Moreover, the level and severity of ID (mild, moderate, severe, and profound) is defined on the basis of adaptive skills rather than the IQ score. The definition links the severity of ID to the degree of community support required to achieve optimal independence (Katz and Lazcano-Ponce, 2008). Mild ID indicates the need for intermittent support; moderate ID for limited support; severe ID for extensive support; and profound ID for pervasive support. Although both intellectual and adaptive functioning are pertinent in defining ID, impairment of adaptive function is more likely to be the presenting feature than low IQ; however, it is expected that there is an association between intellectual functioning and adaptive skills. The term global developmental delay (GDD) is used to describe children under the age of 5 years with significant delays in developmental milestones in several areas of functioning (APA, 2013b). GDD can be diagnosed using a standardized test, which shows performance at least 2 SD below the mean in at least two developmental domains: motor, speech and language, cognition, personal-social, and/or adaptive (daily living). The diagnosis of ID is not used for children under 5 years old since IQ scores are not reliable until after 5 years and because some children with a GDD diagnosis will not meet criteria for ID as they get older. The IQ definition of ID uses 100 as the mean and 15 as the SD. An IQ score of 65–75 (≈2 SD below the mean, with a variation of ±5 points) is the demarcation point. Previously, children with an IQ of 55–69 were considered mild ID, those with an IQ of 40–54, as moderate ID; those with an IQ of 25–39, severe ID; and those with an IQ under 25, profound ID. The prevalence of ID varies due to differences in diagnostic approach, population characteristics, and study design. In the general population, it is considered to be 1% when ID is defined as deficits in both adaptive and intellectual functioning (Harris, 2006; Maulik et al., 2011; Szymanski and King, 1999). The prevalence of intellectual deficits only (IQ < 75), based on IQ score alone, is 3% (Szymanski and King, 1999). Mild ID represents the majority (85%), but roughly 0.4% of the general population is severely intellectually disabled. As a rule, those with severe ID are more likely to have a definable biological cause, whereas those with mild ID tend to come from socially disadvantaged backgrounds and often have a family history of borderline intellectual function or mild ID (Kaufman et al., 2010; Stromme and F ECF

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Magnus, 2000). The prevalence of GDD (in children under 5 years) is estimated at 1%–3% (Shevell et al., 2003). The ratio of boys to girls with ID, especially mild ID, is 1.4:1. Male excess is present in ASD with ID, syndromic X-linked ID (S-XLID) (associated with a specific phenotype), and nonsyndromic X-linked ID (NS-XLID). About 15% of males with ID have X-linked intellectual disability (XLID) (Stevenson and Schwartz, 2009). About 25% of all males with severe ID have XLID, and almost 50% of all cases of mild ID are due to XLID (Partington et al., 2000; Ropers and Hamel, 2005). The recurrence of ID in families with one previous child with severe ID is reported to be between 3% and 9% (CDC, 2009).

Diagnosis and Etiology The diagnosis of ID now includes a measure of both intellectual functioning and adaptive skills. The most commonly used tests of IQ are the Wechsler Scales and the Stanford-Binet tests; however, other tests are used to assess intellectual ability, several of which are measures of nonverbal intelligence. Clinical interview with the individual and a collateral contact who knows the individual well can help assess adaptive functioning, as can standardized measures of adaptive behaviors. The most commonly used standardized measure is the Vineland Adaptive Behavior Scale-II (VABS-2), which assesses and provides a general adaptive behavior composite score. A valid determination of ID (intellectual and adaptive abilities) also considers differences in language and culture, as well as in communication, motor, sensory, and behavioral factors. Children with ID often have neurological and psychiatric comorbidities. Epidemiological studies suggest that as many as one-fifth of them have epilepsy by the age of 10 years (Airaksinen et al., 2000). The probability of developing epilepsy is fivefold greater for children with severe ID (35%) than for those with mild ID (7%). Cerebral palsy (CP) coexists in 6%–8% of the mildly ID and as many as 30% of the severely ID. Microcephaly occurs in one-fifth of XLID syndromes. Macrocephaly also occurs secondary to increased brain volume or hydrocephalus. Children with GDD and ID are at risk for physical disabilities. Impaired vision occurs in 15%–50% and impaired hearing in about 20%. An increased prevalence of psychopathology and maladaptive behavior occurs in children with ID. Table 90.3 details specific cognitive and behavioral problems in several common genetically defined ID syndromes, along with the possible neuropathological basis of these disorders. Etiology is ultimately determined in anywhere from 10% to 81% of children with GDD/ID. Evaluation of ID should be sequential; 02 .4.(1( 4 (

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TABLE 90.3 Cognitive and Behavioral Problems in Several Genetically Defined Intellectual Disability Syndromes Syndrome

IQ

Language

Down trisomy 21

Range 30–70, usually moderate, dementia in adulthood

Good vocabulary Commensurate with and conversation, IQ weaker grammar, impaired verbal short-term memory Expressive language Weak visuospaand conversation a tial and global strength, grammar processing, face preserved, loquarecognition spared cious

Williams deletion Mild to moderate 7q11

Prader-Willi dele- Mean 70, range tion 15q11–q13 profound MR to average

Fragile X males 1/2000B 6000

Moderate to severe, decline after puberty, fully methylated patients have more decline, academics decline over time

Fragile X females

Normal to mild to moderate

VCF 22q11 haplo-insufficiency (reduced gene dosage)

Borderline to mild MR

Spatial Skills

Executive

Social Skills

Neuropathology

Perseverative, impulsive

Often relative strength, but autism reported

Reduced gray-matter volumes, especially with infantile spasms

Inattentive, distractible, impersistent

Social perception spared Reduced volume with (facial emotional overall preservation expression), social of gray matter, cognition impaired, except for right overly social, musical occipital lobe, abnormal cerebellar metabolism Hypothalamic dysInternalizing, externalOromotor dysfunction Visuospatial strength, Obsessive, skin function, bifrontal, izing problems and jigsaw puzzles a picking, paternal thalamus, internal ADHD can interfere special interest imprinting in capsule, splenium with social functioning uniparental disomy of the corpus calloAggressive behavior increases likelisum abnormal maximal in young hood of autism adults, psychosis occasional with maternal uniparental disomy 10% seizures, loss Sporadic weakness of Weak attention, Strength in adaptive Poor articulation, of expression of visual-motor skills planning, shifting functioning until cluttering, verbal FMRP maximal sets puberty, normal dyspraxia, weak in hippocampus, recognition of facial word finding, poor cerebellum, cortex emotions, autistic pragmatics and and nucleus basalis features common conversational magnocellularis, skills decreased cerebellum, superior temporal gyrus, enlarged thalamus and caudate, hippocampal volume reflected in cognitive functioning Very shy, anxious Relatively weak, Generally intact Visuospatial and ADHD, poor cogninonverbal memory tive flexibility and problems working memory Poor social interactions, Decreased gyrifiWeak problem Impairments in Speak in single anxiety, increased cation, reduced solving, planning, words despite their visuoperceptual abstraction, ADHD prevalence of psychovolume bilaterally ability, NVLD ability to converse, in the occipital sis/schizophrenia but verbal skills parietal lobes, stronger than larger right caudate nonverbal nucleus, reduced cerebellar gray matter, reduced white matter in frontal lobe, cerebellum, internal capsule; correlates with psychiatric problems Continued

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TABLE 90.3 Cognitive and Behavioral Problems in Several Genetically Defined Intellectual Disability Syndromes—cont’d Syndrome

IQ

Appear to develop Rett syndrome mutations in the normally until 6–18 months, deterioX-linked gene rating to severe encoding methretardation yl-CpG-binding protein 2*

Language

Spatial Skills

Gradually lose speech and purposeful hand use

Stereotypical hand movements

Executive

Social Skills

Neuropathology

Autistic-like behavior

Progressive microcephaly, seizures

ADHD, Attention-deficit/hyperactivity disorder; FMRP, fragile X mental retardation protein; IQ, intelligence quotient; MR, mental retardation; NVLD, nonverbal learning disability; VCFS, velo-cardio-facial syndrome. *Prevalence is 1–3 per 10,000 live births. Data from Adegbola, A.A., Gonzales, M.L., Chess, A., et al., 2009. A novel hypomorphic MECPs point mutation is associated with a neuropsychiatric phenotype. Hum Genet 124 (6), 615–623; Campbell, L., Daly, E., Toal, F., et al., 2006. Brain and behaviour in children with 22q11.2 deletion syndrome: a volumetric and voxel-based morphometry MRI study. Brain 129, 1218–1228; Hooper, S.R., Hammer, J., Roberts, J.E., 2010. Down syndrome. In: Nass, R.D., Franks, Y. (Eds.), Cognitive and Behavior Abnormalities of Pediatric Diseases. Oxford University Press, New York, pp. 159–169; Mastergeorge, A., Au, J., Hagerman, R., 2010. Fragile X: a family of disorders. In: Nass, R., Frank, Y. (Eds.), Cognitive and Behavioral Abnormalities of Pediatric Diseases. Oxford University Press, New York, pp. 170–187; Renieri, A., Mari, F., Mencarelli, M.A., et al., 2009. Diagnostic criteria for the Zappella variant of Rett syndrome (the preserved speech variant). Brain Dev 31, 208–216; Robertson, L., Hall, S.E., Jacoby, P., et al., 2006. The association between behavior and genotype in Rett syndrome using the Australian Rett Syndrome Database. Am J Med Genet B Neuropsychiatr Genet 141B, 177–183; Zarcone, J., Welsh, S.S., 2010. Prader-Willi syndrome. In: Nass, R.D., Franks, Y. (Eds.), Cognitive and Behavior Abnormalities of Pediatric Diseases. Oxford University Press, New York, pp. 213–230.

key elements include the medical, family, and developmental histories, dysmorphology and neurological examinations, and appropriate laboratory and neuroimaging tests (Moeschler and Shevell, 2006; Shevell et al., 2003). The latter can include careful metabolic evaluation together with neuroimaging studies, EEG, cytogenetic studies, and genetic and ophthalmological consultations as appropriate (Mao and Pevsner, 2005; Shevell et al., 2003). Auditory and visual function must be determined, since these are common comorbidities. If a child was born in a locale without universal newborn screening, consider a screening metabolic evaluation that includes a capillary blood gas, serum lactate and ammonia levels, serum amino acids and urine organic acids, and thyroid function studies. An EEG is appropriate when the history suggests possible seizures, paroxysmal behaviors, or an underlying epilepsy syndrome. Neuroimaging is recommended as part of the diagnostic evaluation of a child with GDD (Level B; class III evidence, AAN 2003 Practice Parameter for GDD). Computed tomography (CT) contributes to the etiological diagnosis of GDD in approximately 30% of children. Magnetic resonance imaging (MRI) is more sensitive than CT, with abnormalities found in 48.6%–65.5% of children with global delay (Level C; class III evidence, AAN 2003 Practice Parameter for GDD). The chance of detecting an abnormality increases if physical abnormalities, particularly CP, are present (AAN 2003 Practice Parameter for GDD). Environmental factors play a role in the causation of ID. Nongenetic prenatal causes of ID include congenital infections; environmental toxins, such as lead, mercury, hydantoin, alcohol, and valproate; iron deficiency; and radiation exposure, especially between 9 and 15 weeks’ gestation. Smoking during pregnancy is associated with more than a 50% increase in the prevalence of ID. Perinatal conditions that may lead to ID include very preterm birth, hypoxia, stroke, trauma, and intracranial hemorrhage. Postnatal and acquired causes of ID include head trauma, hypoxia, central nervous system (CNS) hemorrhage, psychosocial deprivation, malnutrition, CNS malignancy, acquired hypothyroidism, and environmental toxins. Inherited metabolic diseases are responsible for 1%–5% of unspecified ID, with a yield of between 0.2% and 4.6%, depending on the presence of clinical indicators and the range of testing performed

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(Michelson et al., 2011). ID is rarely a unique symptom in inborn errors of metabolism. Table 90.4 lists some of the metabolic disorders that cause isolated ID, some of which are potentially treatable. Genetic defects are important causes of ID. Approximately 25%– 50% of identified cases are genetic in origin. Genetic etiologies include cytogenic abnormalities, CNVs, for example, submicroscopic deletions/duplications/rearrangements, and single-gene disorders. Recent years have seen important progress in identifying the genes involved in ID. To date, 450 genes have been implicated in ID, with 400 attributed to syndromic ID and 50 to nonsyndromic ID. Despite the advancements in genetic testing, only a few specific well-characterized single-gene disorders with a recognizable clinical phenotype (e.g., FMR1-fragile X and MECP2-Rett syndrome) are routinely tested for during the diagnostic process (Sherr et al., 2013). The diagnostic evaluation should focus on clues for a genetic versus acquired etiology for ID. If a family history of consanguinity exists or a close family member (sibling, aunt/uncle, or first cousin) is known to have GDD/ID, testing specific to the known disorder should be performed. A history of pregnancy losses/stillbirths, postnatal deaths of prior offspring, or birth defects should raise suspicion for a genetic etiology (Srour and Shevell, 2014). Observed dysmorphic features may prompt specific testing for such entities as Down syndrome, FXS, Rett syndrome, Prader-Willi/Angelman, or congenital hypothyroidism (Jones, 2006). Increasingly sophisticated genetic testing is becoming more readily available. The AAN 2011 Evidence Report for genetic and metabolic testing on children with GDD/ID found that CMA testing is abnormal on average in 7.8% of subjects with GDD/ID and in 10.6% of those with syndromic features. Karyotype studies are abnormal in at least 4% of subjects with GDD/ID and in 18.6% of those with syndromic features. Mutations in X-linked genes may explain up to 10% of all cases of GDD/ID. FMR1 testing has a combined yield of at least 2% in males and females with mild GDD/ID. MECP2 mutations are found in 1.5% of girls with moderate/severe GDD/ID and in less than 0.5% of males with GDD/ID (Michelson et al., 2011). CMA has emerged as the most commonly ordered initial diagnostic test in individuals with unexplained GDD/ID. A 2010 consensus

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TABLE 90.4

Disorder Creatine transporter deficiency

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Expressive Intellectual Speech Psychiatric Disability Disturbances Disturbances Epilepsy

Cerebellar Brain Involvement MRI

Mild to moderate

Severe

Autistic-like behavior

4-Hydroxybu- Mild to tyric aciduria moderate

Severe

Adenylosuccinate lyase deficiency

Moderate to severe

Moderate

Nonprogressive 50% of cases; Autistic-like, ataxia, ceresome patients attention bellar atrophy may be deficit, (not constant) resistant to hyperactivity, anxiety, obses- conventional therapy, others sive-compuldemonstrate sive disorder, EEG abnormalaggression ities without seizures Autistic-like 80% of cases, May be present often resistant (nonprogresto therapy sive ataxia, cerebellar atrophy)

Sanfilippo B

Mild to severe Mild

Hyperactivity, aggressiveness

50% of cases, in No general, good response to conventional therapy

Not frequent

May appear in later stages

Other Signs

Diagnostic Tests

Usually normal Hypotonia, slight High creatine/cre(low or absent pyramidal atinine in urine; creatine peak signs, dyslow creatine in spectrosmorphy, often peak in MRS; copy) short statured fibroblast creatine incorporation; mutations SLC6A8 Hypotonia, 4-Hydroxybutyric 40% of cases movement disacid in urine; involving orders, sleep SSDH activity cerebellum, disturbances in fibroblasts; subcortical SSDH mutations white matter, and/or pallidum

Not specific; cerebellar atrophy and white-matter high intensity may be present Similar to Sanfilippo A

Nonspecific dysmorphic features

SAICAR and S-Ado in urine; ADLS activity and mutations

GAGs: heparin Mildly coarse sulfate facies and abundant thick hair in childhood and adolescence, which sometimes normalizes late in adulthood

EEG, Encephalogram; GAGs, glycosaminoglycans; MRS, magnetic resonance spectroscopy. From García-Cazorla, A., Wolf, N.I., Serrano, M., et al., 2009. Mental retardation and inborn errors of metabolism. J Inherit Metab Dis 32, 597–608.

statement indicated that CMA should be used instead of karyotyping as the first-line cytogenetic diagnostic test for individuals with GDD/ID, ASD, or multiple congenital anomalies (Miller et al., 2010). Advancements in technology have allowed genome-wide analyses to move into clinical practice. Whole-exome sequencing (WES) or whole[-genome sequencing (WGS) are such techniques that potentially can identify a causative mutation in an individual with GDD/ ID for whom conventional testing (CMA or karyotype) has been unrevealing. This type of testing is not without its limitations and challenges (Flore and Milunsky, 2012).

Management Available evidence demonstrates the benefits of early intervention through a variety of programs, at least with respect to short-term outcomes, and suggests that early diagnosis of a child with global delay may improve long-term outcome (Shevell et al., 2003). The management of children with ID focuses on finding the appropriate educational setting for children with mild ID, vocational training for those

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with moderate ID, and determining home or institutional placement for those with severe and profound ID. Advances in genetic diagnosis have had immediate benefits for families, allowing for carrier testing, genetic counseling, prenatal diagnosis, and preimplantation genetic diagnosis. Some of the gene discoveries have also pointed to potential strategies for treatment, for example, FXS. In a recent study, Jaffrey and colleagues studied stem cells from donated human embryos that have a genetic mutation resembling that in FXS (Colak et al., 2014). They found a malfunction in fragile X cells in which messenger RNA sticks to mutated DNA segments during early cell development, thereby blocking the gene’s expression and, as a result, preventing the cell from producing a protein critical to the transmission of signals between neurons. The malfunction appears to occur suddenly before the end of the first trimester in humans and after 50 days in cultured stem cells. A drug compound was used to bind to the fragile X gene’s RNA before the malfunction occurs, allowing the gene to continue producing the critical brain protein. This represents a potential prevention or treatment strategy for FXS (Colak et al., 2014).

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LEARNING DISABILITY Learning disability (LD) occurs in 5%–15% of school-aged children and is characterized by persistent difficulties learning academic skills in reading, writing, or mathematics. Most educational institutions abide by the Individuals with Disabilities Education Act (IDEA, 2004), which subsumes all of these learning problems under the general category of Learning Disabled. The IDEA (2004) states that “a specific learning disability means a disorder in one or more of the basic psychological processes involved in understanding or in using language, spoken or written, that may manifest itself in the imperfect ability to listen, think, speak, read, write, spell or do mathematical calculations” (CFR 300.8, 10).

TABLE 90.5 Common Soft Signs Associated With Learning Disabilities Cranial nerves

Head turns with eyes Mouth opens when eyes open Difficulty with grimace Excess upper-extremity posturing on stressed gait Excess overflow during finger tapping and sequencing Unsustained one-foot stand Difficulty with hopping Excess choreiform movements with arms extended Dysrhythmic rapid alternating movements Excess overflow during rapid alternating movements Ballistic finger-nose-finger test Difficulty with tandem gait Extinction on double simultaneous stimuli Poor finger localization Minor reflex asymmetries

Motor

Cerebellar

Dyslexia

Clinical Features

Sensory

The best-studied and probably the most common learning disability (LD) is dyslexia. It occurs in as many as 10% of school-aged children and in 80% of LDs. Males are more often affected. Developmental dyslexia is marked by reading achievement that falls substantially below that expected given the individual’s chronological age, measured intelligence, and age-appropriate education (ICD-10). As with other LDs, major neurological abnormalities are not present, but minor abnormalities (soft signs) may be detected (Denckla, 1985) (Tables 90.5 and 90.6). Major sensory functions must be normal and the child must have been in a social and educational environment conducive to learning to read. It should be noted that the nomenclature in the DSM-5 uses the term Specific Learning Disorder with Impairment in Reading and describes dyslexia as an alternative term used to refer to difficulties with word recognition, decoding, or spelling (APA, 2013a).

Diagnosis and Etiology Most school systems abide by the IDEA (2004), which uses the Response to Intervention (RTI) model for the identification of dyslexia and other learning disorders. This model emphasizes evidence-based practices for monitoring progress, screening, and offering intervention for struggling readers (Fletcher and Vaughn, 2009). While this method is useful for providing early intervention, the RTI model does not explain why a child is having reading difficulties or rule out differential diagnoses. Thus, children with early reading problems should have a formal neuropsychological evaluation to examine their pattern of strengths and weaknesses and to exclude comorbid problems (e.g., ADHD) that might affect treatment. Deficits in phonological awareness frequently underlie reading difficulties and persist even into adolescence (Shaywitz et al., 1999) and adulthood. Measures that assess phonological functioning (e.g., segmenting words [say cowboy without the boy, say smack without the m], word and nonword blending, sound matching of first and last syllables) best differentiate dyslexic from normal readers. The double-deficit hypothesis of developmental dyslexia proposes that deficits in phonological processing and naming speed represent independent sources of dysfunction in dyslexia (Vukovic and Siegel, 2006). Although phonological processing issues appear to be the primary and/or most common cause of dyslexia, neuropsychological studies have identified other deficit clusters in dyslexics. For example, Crews et al. (2009) identified three dyslexia subtypes: (1) no language or memory deficit, (2) global language and memory deficit, and (3) global memory deficit. Few children fail to read because of visual perceptual difficulties or extraocular motility problems. However, processing by the lateral geniculate magnocellular system (important for monitoring motion, stereopsis, spatial localization, depth, and figure-ground perception) may not appropriately modify the

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DTR

DTR, Deep tendon reflexes. Modified from Denckla, M.B., 1985. Revised neurological examination for subtle signs. Pharmacol Bull 21, 773–789.

Natural History of Soft Signs

TABLE 90.6 Neurological System Affected Cranial nerves

Age of Appearance or Disappearance

Soft Sign Head does not move with eyes Sticks tongue out for 10 s Toe-heel walk Heel walk without associated movements Hop 10 times Hops indefinitely One-foot stand for 30 s No longer drifts up and down with pronated and supinated arms Rigid tripod Dynamic tripod Choreiform movements Athetoid movements Tandem No overflow during rapid alternating movements Stereognosis, graphesthesia No longer extinguishes on double simultaneous stimulation

Motor

Cerebellar

Sensory

6–7 years 6–7 years 3 years 5 years 5 years 7 years 7 years 3–4 years

5 years 7–8 years 7–10 years 2–4 years 6 years 7–8 years 6 years 8 years

information received from the fast parvocellular system (crucial for color perception, object recognition, and high-resolution form perception) (Amitay et al., 2002; Angélique et al., 2002). The standard neurological examination is normal. Routine imaging is normal and unnecessary, except perhaps in children with atypical features (Box 90.3). Dyslexia has a significant genetic component with heritability estimated at 54%–84% (Astrom et al., 2007; DeFries et al., 1987; Scerri and Schulte-Korne, 2010). Dyslexia-susceptibility-1-candidate-1 (DYX1C1) was the first gene reported to be associated with dyslexia, possibly with

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BOX 90.3

Atypical Features in Dyslexia

Female gender Left-handed without family history Strongly left-handed, early declaration Dyslexic without family history No history of developmental language problems Large discrepancy between verbal and spatial skills Neurological abnormalities or seizures

a memory-deficit dyslexia phenotype (Dahdouh et al., 2009). Numerous candidate dyslexia susceptibility genes have subsequently been identified from cytogenic, linkage, association, and biological studies (e.g., DYX1C1 at DYX1, KIAA0319 and DCDC2 at DYX2, MRPL19, and C20RF3 close to DYX3, ROBO1 at DYX5, and KIAA0319L at DYX8), including several that affect neuronal migration (Anthoni et al., 2007; Cope et al., 2005; Hannula-Jouppi et al., 2005; Harold et al., 2006; Meng et al., 2005; Paracchini et al., 2006; Schumacher et al., 2006; Taipale et al., 2003). Pathological studies suggest that those with dyslexia have both atypical planum temporale asymmetries and areas of cortical dysplasia, reflecting abnormal neuronal migration, particularly in the left hemisphere (Galaburda et al., 2006). Structural imaging demonstrates that in about two-thirds of normal adults, the left planum temporale is larger than the right, but by contrast, only 25% of dyslexics have this same left/right planum asymmetry (Eckert and Leonard, 2000). Dyslexics with atypical asymmetry tend to have more severe language and/or reading deficits. In a group of children with dyslexia with or without ADHD, the presence of an extra sulcus in the left pars triangularis was associated with poor expressive language ability. In those with adequate expressive language functioning, left pars triangularis length related to phonological awareness, phonological short-term memory, and rapid automatic naming (RAN). Right pars triangularis length related to RAN and semantic processing (Kibby et al., 2009). Evidence of decreased gray matter has been found not only in the left temporal lobe and bilaterally in the temporoparietooccipital juncture but also in the frontal lobe, caudate, and thalamus (Brown et al., 2001). Interhemispheric transfer of information may be abnormal in dyslexia (Beaton et al., 2006). Structural differences of the corpus callosum exist in normal versus dyslexic readers. Theoretically, the splenium is critical because it contains axons linking the planum temporale and angular gyrus. Functional imaging studies demonstrate that fluent reading requires functional integrity of three left hemisphere regions—an inferior frontal region and two posterior systems (a temporal-parietal system and a ventral occipital-temporal system). Developmentally, the temporal-parietal system predominates initially and is required for learning to integrate the printed word with its phonological and semantic features. The occipital-temporal system constitutes a late-developing rapid sight word identification system that underlies word recognition in skilled readers. Disruption of both posterior systems may occur in developmental dyslexia. In contrast to normal readers, dyslexics may rely on left and right inferior frontal and right posterior regions (Blau et al., 2010; Pugh et al., 2000). Thus, they make inefficient use of the posterior system. Functional imaging also implicates the cerebellum, an area that other studies suggest is crucial for language functioning (Fulbright et al., 1999). Positron emission tomography (PET) studies have shown reduced activation within the left insula (Paulesu et al., 1996) and within temporal, parietal, and occipital left hemisphere regions (McCrory et al., 2005). Connectivity abnormalities in dyslexics occur in two areas associated with working memory. Within a “phonological” left-lateralized

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prefrontal network, increased functional connectivity occurs in left prefrontal and inferior parietal regions. Within an “executive” bilateral frontoparietal network, dyslexics showed a decreased connectivity pattern in bilateral dorsolateral prefrontal and posterior parietal regions and increased connectivity in the left angular gyrus, left hippocampal cortex, and right thalamus (Wolf et al., 2010). Abnormalities of very short-range connectivity (e.g., angular gyrus, striate cortex), in association with larger gyri, may explain reading difficulties (Casanova et al., 2010; Silani et al., 2005). In a study using diffusion tensor imaging (DTI), positive correlations were found with three tests of reading ability (word reading, decoding, and reading fluency) in the bilateral white matter, particularly in the frontal lobes but also involving the thalamus, and temporoparietal regions (Lebel et al., 2013).

Management Although dyslexia does not disappear, most children with early reading problems learn to read at average to above-average levels if they are diagnosed by the age of 8–9 years (third to fourth grade) and evidence-based reading instruction is provided. Children diagnosed later, even if remediated, are likely to continue to have reading problems. Three out of four children with reading problems at the end of third grade are still having trouble in seventh grade. In the Connecticut Longitudinal Study, dyslexic children (diagnosed after the third grade) never caught up to average or superior high school readers (Shaywitz et al., 1999). Early identification and provision of evidence-based reading instruction, systematic, phonetic, and multisensory approaches such as the Orton Gillingham or Wilson method can reduce the percentage of children reading below grade level in fourth grade from 37% to 6% (Bakker, 2006). However, large population studies suggest that some degree of reading disability persists into adulthood in most, and occupational attainment is lower in some (Undheim, 2009). The magnitude of phonological impairment alone does not appear to fully predict reading outcome. Phonological deficits appear to interact with other cognitive factors, such as nonverbal IQ and linguistic skills, particularly syntactic processing in determining long-term outcome (Peterson et al., 2009; Wiseheart et al., 2009). Compensated readers, who are accurate but not fluent, demonstrate a relative underactivation in posterior neural systems for reading located in left parietotemporal and occipitotemporal regions. Persistently poor readers, who are both not fluent and less accurate, activate posterior reading systems but engage them differently from nonimpaired readers; they rely more on memory-based rather than analytic word identification strategies (Shaywitz et al., 2003). The majority of highrisk responder children benefit from systematic reading instruction and develop adequate reading abilities with successful recruitment of temporoparietal and visual association areas for reading (Simos et al., 2005). In another study correlating outcome with anatomy, 8- to 10-year-old poor readers had significantly lower fractional anisotropy (FA) in the left anterior centrum semiovale than good readers; 100 hours of intensive remedial instruction resulted in improved decoding ability and increased FA, consistent with enhanced myelination (Keller and Just, 2009). Although vision problems can interfere with reading, they are not the cause of dyslexia. Eye exercises, behavioral vision therapy, and special tinted filters or lenses are not effective treatments for dyslexia (American Academy of Pediatrics, 2009).

Dyscalculia

Clinical Features Developmental dyscalculia (DD) can involve any or all aspects of mathematics, from difficulties representing and manipulating numeric information nonverbally, to learning and remembering arithmetic

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facts, to executing arithmetic procedures. The prevalence of dyscalculia is approximately 6%–14% (Shalev, 2007). A developmental Gerstmann syndrome (right/left disorientation, finger agnosia, dysgraphia, dyscalculia, and sometimes, constructional apraxia) occurs in as many as 2% of school-aged children. The mean IQ of children with dyscalculia is generally normal; one-fourth show symptoms of ADHD and approximately one-fifth are dyslexic. As with dyslexia, the DSM-5 uses the nomenclature Specific Learning Disorder with impairment in mathematics to refer to problems with number sense, calculation or math reasoning (APA, 2013a).

Evaluation and Etiology Comprehensive neuropsychological evaluations are recommended in individuals suspected of having dyscalculia. Children with neuropsychological signs of both left and right hemisphere dysfunction can have dyscalculia. Both groups have similar problems on arithmetic batteries, but those with left hemisphere dysfunction seem to perform significantly worse in addition, subtraction, complex multiplication, and division and also make more visuospatial errors (Shalev and GrossTsur, 2001). Imaging studies show that parietal and frontal abnormalities predominate. Children with DD have been shown to have weaker brain activation in the intraparietal sulcus (IPS) and inferior frontal gyrus of both hemispheres for approximate calculation than typically achieving children (Kucian et al., 2006). Evidence of parietal dysfunction (Grafman and Romero, 2001; Price et al., 2007) and reduced gray-matter volumes in frontal and parietal areas (Rotzer et al., 2008) are also reported in DD. Deficits in parietal and frontal lobe function in children with DD relate to poor spatial working memory (Rotzer et al., 2009). Several studies implicate deficit in working memory, a factor associated with DD (Camos, 2008).

Management Math remediation is appropriate for the child with isolated difficulties or with mathematics difficulties in combination with other learning difficulties.

Disorder of Written Communication In addition to reading and mathematics disorders, the DSM-5 Specific Learning Disorder classification includes a specifier for disorder of written expression. This is coded as “Specific Learning Disorder with Impairment in Written Expression” (DSM-5; American Psychiatric Association, 2013). The IDEA (2004) also identifies written expression as one of the eight areas of eligibility under the category of Specific Learning Disability. Under both classification systems, a disorder in written expression can include a variety of problems in writing, including difficulty expressing oneself in writing, spelling difficulties, and poor handwriting. Thus, the etiology and clinical presentation of writing disabilities is heterogeneous and most individuals who have difficulties in written expression also have other learning or behavioral difficulties, including dyslexia, motor coordination disorder/ dysgraphia, language disorders, or ADHD. Katusic et al. (2009) found that 75% of children with written language disorders also had problems with reading, and Berninger and May 2011 found that writing disability is associated with dysgraphia, dyslexia, and/or oral language impairments.

Developmental Coordination Disorder Diagnosis

Developmental coordination disorder (DCD) refers to problems with motor coordination that (1) are substantially below expectations for the individual’s age and opportunity for skill learning and use, (2) interfere with activities of daily living appropriate for age, and (3)

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Developmental Coordination Disorder, DSM-5 Diagnostic Criteria

BOX 90.4

A. The acquisition and execution of coordinated motor skills is substantially below that expected given the individual’s chronological age and opportunity for skill learning and use. Difficulties are manifested as clumsiness (e.g., dropping or bumping into objects) as well as slowness and inaccuracy of performance of motor skills (e.g., catching an object, using scissors or cutlery, handwriting, riding a bike, or participating in sports). B. The motor skills deficit in Criterion A significantly and persistently interferes with activities of daily living appropriate to chronological age (e.g., self-care and self-maintenance) and impacts academic/school productivity, prevocational and vocational activities, leisure, and play. C. Onset of symptoms is in the early developmental period. D. The motor skills deficits are not better explained by intellectual disability (intellectual developmental disorder) or visual impairment and are not attributable to a neurological condition affecting movement (e.g., cerebral palsy, muscular dystrophy, degenerative disorder). Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (© 2013). American Psychiatric Association.

BOX 90.5

Development of Pencil Grip

Ulnar/vertical—1.5–3 years Radial—acceptable until 3.5 years Tripod (static)—50% by 3 years, 80% by 4 years Tripod (dynamic)—5–6 years

negatively affect academic achievement, prevocational and vocational activities, and social integration. DCD is not better explained by other conditions, such as ID, visual impairment, neurological conditions, such as cerebral palsy, neuromuscular disease, or neurodegenerative disorders, vertigo, ASD, or ADHD (APA, 2013a; see Box 90.4). A wide range of motoric difficulties are often considered synonymous with DCDs, including clumsiness, mild gross motor delay, decreased dexterity, visual motor problems, motor learning difficulty, dysgraphia, dyspraxia, and even adventitious movements (Blank et al., 2012; Mcnab et al., 2001). Generally, children with DCD are competent in the basic developmental motor skills such as walking, but it is in everyday activities such as tying shoe laces, buttoning a coat, riding a bike, or writing homework assignments where the greatest impact of the disorder is apparent (Box 90.5). Approximately 5% of schoolaged children have DCD, with prevalence estimated to be three to four times greater in males (Kirby et al., 2014). Neither socioeconomic status nor education level is a factor. A diagnosis of DCD is typically made at school age and is rarely made in children under age 5 years (Blondis, 1999), although delayed achievement of early motor milestones, problems with sucking or swallowing in infancy, persistent drooling (after 2½ years old), toe walking, or wide-based gait after 14 months may be associated with later DCD (Summers et al., 2008; Taft and Barowsky, 1989). Longitudinal studies suggest that the frequency of DCD changes with age (Hadders-Algra, 2002; Hadders-Algra et al., 2004). DCD does not necessarily resolve and continues into adolescence and adulthood (Losse et al., 1991). The presence of early neurological symptoms increases the frequency. In that respect, it is not surprising that children born prematurely (10%, >1% if mutation known) Targeted exome (~300 nuclear mito genes)

Common Large-scale mtDNA PM 3243, 8344, 8993 rearrangements (LPCR, SB: >5%) (RFLP: >1%)

Urine –ve

–ve

Histopathology (COX/SDH, Gomori trichrome) Biochemistry (RCEA, BN-PAGE)

–ve –ve

–ve

Muscle

Muscle

Full mtDNA sequencing (NGS)

Large-scale rearrangements (LPCR, SB) mtDNA copy number (RT-PCR) –ve

–ve Blood Functional studies Modeling Additional families

Novel mutations/genes Exome/genome (research)

Fig. 93.6 Queen Square Mitochondrial Disease Investigation Pathway. (1) Mitochondrial DNA (mtDNA) deletion screen can be performed on blood from patients younger than 20 years of age. (2) Perform respiratory chain enzyme assays even if histochemistry normal if strong clinical suspicion. (3) Sequence mtDNA even if respiratory chain enzyme assays normal if strong clinical suspicion. BN-PAGE, Blue native polyacrylamide gel electrophoresis; COX, cytochrome c oxidase; LPCR, long-range polymerase chain reaction; NGS, next-generation sequencing; PM, point mutation RCEA, respiratory chain enzyme analysis; RFLP, restriction fragment length polymorphism; RRF, ragged-red fiber; RT-PCR, real-time polymerase chain reaction; SB, Southern blot; SDH, succinate dehydrogenase. Italicized, laboratory techniques.

defect in patients with PEO, although point mutations in tRNA genes (e.g., A3243G mutation) and a duplication of mtDNA have also been reported. Autosomal dominant or recessive PEO due to defects in nuclear genes involved in mtDNA maintenance results in multiple mtDNA deletions. It tends to present in adulthood and may be associated with multisystem involvement such as neuropathy, ataxia, tremor, parkinsonism, depression, cataracts, pigmentary retinopathy, deafness, rhabdomyolysis, and hypogonadism. Mutation in POLG1 is one of the more common nuclear genes to cause this syndrome. KSS is defined by the triad of PEO and onset before age 20, with at least one of the following: pigmentary retinopathy, cerebellar ataxia, heart block, and/or elevated CSF protein (>100 mg/dL). Patients often have a progressive limb myopathy and frequently require a pacemaker for atrioventricular block. Many patients with KSS have delayed motor milestones, are small of stature, and have cognitive impairment. Some clinical features of MELAS and MERRF may overlap with KSS. The clinical course in KSS is progressive, and many patients with CNS or cardiac complications die in the third or fourth decade. Nearly all cases of KSS are sporadic and usually caused by a single large clonal mtDNA deletion that arises in the mother’s oocyte. F ECF

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Mitochondrial Myopathies without Progressive External Ophthalmoplegia The clinical spectrum of isolated mitochondrial myopathy varies from mild nondisabling proximal limb weakness to severe infantile myopathy with lactic acidosis and death by 1 year. Exercise intolerance is common. Some of these cases present in adult life, but careful questioning usually elicits a history of lifelong exercise intolerance. A sporadic form of myopathy related to somatic mutations in the cytochrome b gene of mtDNA is associated with progressive exercise intolerance and weakness and, in some cases, attacks of rhabdomyolysis (Andreu et al., 1999). Less frequently, sporadic patients with exercise intolerance have been found to have mtDNA mutations in genes encoding subunits of complexes I or IV (DiMauro and Hirano, 2005). Some patients with mitochondrial myopathy without PEO will develop progressive PEO in later life, and others may have overlapping deficits with MERRF and MELAS.

Mitochondrial Peripheral Neuropathy Patients with complex mtDNA-associated mitochondrial phenotypes involving the CNS (e.g., MERRF, MELAS) often have a mild axonal sensorimotor neuropathy that may be subclinical. A peripheral neuropathy can be the dominant clinical feature in some patients. Mutations in the mitofusin 2 (MFN2) gene, which encodes a protein that influences 02 .4.(1( 4 (

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CHAPTER 93 Mitochondrial Disorders mitochondrial dynamics, is a cause of Charcot-Marie-Tooth disease. Some families with MFN2 mutations have additional clinical features, including optic atrophy (Züchner et al., 2006). Mutations in POLG can cause a prominent large-fiber sensory neuropathy with significant proprioceptive loss in the SANDO (sensory ataxic neuropathy dysarthria and ophthalmoplegia) syndrome. Axonal motor and sensorimotor polyneuropathy may also be a feature of dominant optic atrophy caused by mutations in the OPA1 gene encoding a mitochondrial dynamin-like protein and MT-ATP6 mutations, encoding the ATP6 subunit of the mitochondrial ATP synthase (Pitceathly et al., 2012).

Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes MELAS is a maternally inherited encephalomyopathy clinically characterized by short stature, stroke-like episodes, migrainous headaches, vomiting, seizures, and lactic acidosis. The stroke-like deficits are sometimes transient but can be permanent and cause progressive encephalopathy with dementia. Ataxia, deafness, muscle weakness, cardiomyopathy, and diabetes are common as the disease progresses. A typical radiological feature is that the stroke involves the cerebral cortex, spares the white matter (see Fig. 93.4), mostly affects the parietal and occipital cortices, and does not conform to vascular territories. Neuroimaging may show additional lesions that have no clinical correlates. The onset is generally in childhood or early adult life. Most patients have RRF on muscle biopsy. Approximately 80% of patients with MELAS have an A-to-G point mutation at np-3243 (tRNALeu[UUR] gene, MT-TL1). Another point mutation at np-3271 of the tRNALeu(UUR) gene accounts for 10% of cases of MELAS.

Myoclonic Epilepsy with Ragged-Red Fiber Myopathy MERRF is a maternally inherited encephalomyopathy characterized by myoclonus, epilepsy, cerebellar ataxia, and myopathy with RRF. Onset is usually in childhood or early adulthood. The syndrome begins with stimulus-sensitive myoclonic epilepsy in childhood, which may be photosensitive. Worsening ataxia and mental retardation are seen in later childhood. Patients may also develop cardiomyopathy, short stature, deafness, optic atrophy, PEO, cutaneous lipomas, and neuropathy. Overlapping clinical features of MERRF and MELAS can occur in the same patient or among different members of the same family (Verma et al., 1996). The clinical course in MERRF is variable, but it is typically progressive. Approximately 80% of MERRF cases have a point mutation at np-8344 of the tRNALys gene (MT-TK2). As with other mtDNA mutations, the time of onset and severity of the disease have been related to the quantitative burden of mutant mtDNA.

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related phenotypes even within the same family: NARP and MILS. Other point mutations in the same gene have been reported with the NARP and MILS. The severity of the syndrome corresponds to the mutant mtDNA load in the tissues. A mutation load greater than 90% of mtDNA tends to cause the more severe phenotype of MILS.

Subacute Necrotizing Encephalomyelopathy (Leigh Syndrome) Leigh syndrome is a familial or sporadic mitochondrial disorder characterized by psychomotor regression and lesions in the basal ganglia and brainstem (see Fig. 93.5). Some cases display a maternal inheritance, such as mtDNA np-8993 and np-8344 mutations (MILS). Others follow an autosomal (pyruvate carboxylase, SURF1 gene mutations with COX deficiency, complex I deficiencies) or sex-linked (PDH E1 gene mutations) pattern of inheritance. More than 50% of cases present in the first year of life, usually before 6 months of age. Lateonset varieties with a greater degree of clinical heterogeneity are also reported. The precise clinical boundaries of Leigh syndrome have not been defined; there is clinical heterogeneity even among members of the same family. Leigh syndrome and congenital lactic acidosis are described further in Chapter 91.

Leber Hereditary Optic Neuropathy Patients with LHON usually present with a subacute bilaterally sequential and isolated optic neuropathy. LHON is expressed predominantly in males of the maternal lineage, and the greater susceptibility of males to vision loss in LHON remains unexplained. The age of onset is typically between 15 and 35 years, and the vision loss is painless, central, and usually occurs in one eye weeks or months before involvement of the other eye. Fundoscopic abnormalities may be seen in patients with LHON and in their asymptomatic relatives. During the acute phase of vision loss, there may be hyperemia of the optic nerve head, dilatation and tortuosity of peripapillary vessels, circumpapillary telangiectasia, nerve-fiber edema, and focal hemorrhage. Vision loss in LHON affects central or centrocecal fields and is usually permanent. A minority of patients show objective improvement, sometimes to a dramatic degree. Three primary point mutations at mtDNA np-11778 (69%), np-14484 (14%), and np-3460, all within coding regions for complex I subunits, account for 80%–95% of cases of LHON worldwide. These mutations are found in blood and are often homoplasmic. Patients with np-14484T>C have a better chance of some visual recovery. Some families have additional members with associated cardiac conduction abnormalities, especially preexcitation syndromes. There may also be a movement disorder such as dystonia or other mild neurological or skeletal abnormalities. Occasionally LHON is associated with an MS-like illness.

Sensorineural Deafness

MNGIE is an autosomal recessive disease with secondary alterations of mtDNA. There is typically a combination of ptosis, PEO, severe gastrointestinal dysmotility leading to episodes of pseudo-obstruction and cachexia, peripheral neuropathy, leukoencephalopathy on brain MRI (see Fig. 93.3), and evidence of mitochondrial dysfunction (e.g., lactic acidosis or RRF in muscle biopsy) (Hirano et al., 2004). Onset is usually in the late teens, and most patients die before age 40. MNGIE is caused by mutations in the gene encoding thymidine phosphorylase. The disease can be diagnosed by blood tests demonstrating loss of thymidine phosphorylase activity or elevation of plasma thymidine and deoxyuridine.

Sensorineural hearing loss (SNHL) is a feature of many mitochondrial diseases and commonly occurs in MELAS, maternally inherited diabetes and deafness (MIDD), MERRF, or KSS. The presence of SNHL in a patient with a complex multisystem phenotype suggests a possible mitochondrial disease. SNHL may also occur in isolation. The np-1555A>G mitochondrial mutation (which confers sensitivity to aminoglycoside-induced deafness and may cause nonsyndromic deafness) is present in 1 in 500 of the general population. Mutations in the tRNA gene for serine (UCN) may also cause isolated deafness. SNHL is also a feature of some nuclear-encoded mitochondrial disorders such as dominant optic atrophy associated with OPA1 mutations.

Neuropathy, Ataxia, Retinitis Pigmentosa Syndrome

Mitochondrial DNA Depletion Syndrome

NARP syndrome is a relatively rare disorder due to a point mutation at np-8993 of the mitochondrial ATPase-6 gene encoding subunit 6 of complex V, giving rise to two maternally inherited and clinically

Mitochondrial DNA depletion syndrome (MDDS) is an autosomal recessive disorder caused by a quantitative reduction in the amount of mtDNA. A myopathic and a hepatocerebral form have been described.

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Both forms are usually fatal in childhood, although patients with Navajo neurohepatopathy may survive into their late teens. MDDS may be caused by recessive defects of the mtDNA replication machinery (POLG or PEO1) or from defects of maintaining the deoxyribonucleoside triphosphate pool necessary for mtDNA replication.

MANAGEMENT OF MITOCHONDRIAL DISEASES Treatment of Associated Complications Treatment of mitochondrial disease is mainly symptomatic (but see later for treatment options that can be beneficial in mitochondrial diseases in specific scenarios), empirical, and often palliative (DiMauro and Mancuso, 2007; Pitceathly and McFarland, 2014). Patients and families with confirmed mitochondrial disease require management and support in a multidisciplinary clinical team setting. This is often coordinated by a neurologist with close links to a range of different disciplines such as rehabilitation medicine, physiotherapy, occupational therapy, cardiology, endocrinology, ophthalmology, audiology, and speech therapy. There is usually no specific treatment for most mitochondrial disorders, and therefore monitoring and treatment of complications arising from the disease are vital for improving quality of life and reducing morbidity.

Hearing and Vision Hearing aids and, in severe cases, cochlear implantation are especially important to improve hearing in patients who have coexistent visual impairment from optic atrophy, pigmentary retinopathy, or cortical visual loss. Ptosis can be helped with eyelid props and surgery. Cataracts should be excluded as a cause of visual impairment.

Seizures MELAS, MERRF, and Leigh syndrome are typically associated with seizures. Sodium valproate has been shown to inhibit mitochondrial OXPHOS and may cause clinical worsening, including precipitation of fatal hepatic failure in some cases of Alpers syndrome caused by POLG mutations. The treatment of myoclonus can be problematic, and many patients require several anticonvulsants, including piracetam, levetiracetam, and/or clonazepam.

Movement Disorders Dystonia is often seen in Leigh syndrome, and treatment with anticholinergics may occasionally be helpful. Intramuscular electromyography (EMG)-guided botulinum toxin can be helpful for severe focal dystonia.

Diabetes Oral hypoglycemics and/or comparatively low doses of insulin are often sufficient to treat diabetes. Metformin should be avoided because of the risk of lactic acidosis. One study suggested that long-term CoQ10 administration prevented the progressive insulin secretory defect, exercise intolerance, and hearing loss in MIDD patients (Suzuki et al., 1998).

Respiratory The combination of diaphragmatic and axial skeletal muscle weakness, with aspiration from bulbar weakness, can precipitate acute respiratory failure. Functional vital capacity (FVC) monitoring in patients with significant myopathy is important. Patients with bulbar weakness are also at risk of developing obstructive sleep apnea. CNS mitochondrial disease, especially Leigh syndrome, may cause central hypoventilation. A sleep study is mandatory if nocturnal hypoventilation is suspected, and noninvasive nocturnal ventilation can improve patients’ quality of life.

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Gastrointestinal Gastrointestinal symptoms are common in patients with mitochondrial disease. These include swallowing difficulties, failure to thrive in children, weight loss/cachexia, constipation, pseudo-obstruction, nausea, and vomiting. Bulbar weakness can be compounded by cerebellar incoordination to cause severe dysphagia, especially in KSS and Leigh syndrome. Patients therefore require monitoring by speech and language therapy supplemented by videofluoroscopy assessment. The requirement for a percutaneous endoscopic gastrostomy (PEG) should be considered if there is a high probability of aspiration pneumonia. Weight loss can be dramatic, especially in the MNGIE syndrome, when it may be accompanied by recurrent pseudo-obstruction.

Heart Cardiac screening is important in patients with mitochondrial disease. Tachyarrhythmia and bradyarrhythmia may require insertion of a permanent pacemaker or implantable cardiac defibrillator, especially in KSS and some cases of PEO. Preexcitation syndromes such as Wolff-Parkinson-White may cause supraventricular tachycardias in patients with np-3243A>G cardiomyopathy and in some patients with LHON. Progressive left ventricular hypertrophy may be a particular feature in patients with the np-3243A>G and np-8344A>G mutations and may progress to left ventricular failure due to cardiomyopathy. Cardiac problems should ideally be referred to a cardiologist with a specialist interest in inherited cardiac muscle disease, where patients can be monitored with echocardiography and electrocardiography and treated with agents such as angiotensin-converting enzyme inhibitors.

Genetic Counseling, Prenatal Diagnosis, and Reproductive Options If a nuclear gene mutation is identified, genetic counseling and prenatal diagnosis can be offered to the patient. Primary mtDNA mutations present in the male will not be transmitted. If an mtDNA mutation is identified in a woman with mitochondrial disease, it is more difficult to provide accurate genetic counseling advice. Most large-scale deletions of mtDNA are sporadic, and the risk of transmission is relatively low. Some mtDNA point mutations are also sporadic. For heteroplasmic mtDNA point mutations, the factors that determine the amount of a particular point mutation that will be transmitted to offspring are poorly understood. Although a heteroplasmic point mutation will be transmitted in the maternal line, because of the genetic bottleneck for mtDNA (where only a small number of mtDNA molecules in the mother are passed on to the next generation), large shifts in the proportion of mutant from mother to offspring may occur. It is therefore not possible to offer women who harbor heteroplasmic disease-causing point mutations accurate advice regarding the risk of transmission. The offspring of a patient with a homoplasmic point mutation such as in LHON will be homoplasmic for the mutation, but they may not all develop the disease. Unknown non-mtDNA factors may be important in determining disease expression. At present, a number of reproductive choices exist for patients with mitochondrial disease harboring both mitochondrial and nuclear gene mutations. These include ovum donation (for mtDNA mutations) and preimplantation genetic diagnosis (for both mtDNA and nDNA mutations). Mitochondrial donation, which involves oocyte manipulation techniques aimed at replacing maternal mutant mtDNA with healthy donor mtDNA, has also recently been licensed in the United Kingdom for patients with mtDNA mutations. Individuals at risk of inheriting an mtDNA mutation may request predictive genetic testing. If they have any symptoms suggestive of mitochondrial phenotype, diagnostic genetic testing is appropriate.

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Pharmacological Approaches

Removal or Neutralization of Toxic Metabolites

There are certain treatment options that can be beneficial in mitochondrial disease for specific indications. These include CoQ10 in disorders that impair CoQ10 biosynthesis (Quinzii et al., 2007), allogeneic bone marrow transplantation in MNGIE (Halter et al., 2015), and riboflavin supplementation in adults with riboflavin transporter disorders (Foley et al., 2014). Despite a Cochrane review of treatments for mitochondrial disorders identifying more than 1300 reports using numerous strategies aimed at improving mitochondrial function, the majority were open-label studies comprising small patient cohorts. Of the 30 randomized trials, no treatment showed a significant benefit on a clinically meaningful endpoint (Kerr, 2013; Pfeffer et al., 2012). It is therefore likely that vitamins and cofactors traditionally used in mitochondrial disease do not confer a major therapeutic benefit. However, a number of promising new approaches are currently being evaluated at the preclinical and early clinical phase with the hope that these will ultimately be licensed for clinical use, particularly given increasing interest from industry in developing treatments for rare diseases (Pitceathly et al. 2020 a more detailed review of emerging therapies for mitochondrial disorders).

The pathophysiological mechanism of MNGIE syndrome (thymidine phosphorylase deficiency) is considered to result from an imbalance of intramitochondrial nucleosides, leading to stalling of the mtDNA replication apparatus. A rationale for treatment is thus to restore intramitochondrial nucleoside balance by removing accumulated nucleosides. In one study, renal dialysis was used to remove accumulated plasma thymidine and deoxyuridine in patients with MNGIE, but these metabolites reaccumulated within 24 hours of dialysis. Diuretics have also been used to increase renal excretion of thymidine and deoxyuridine but without success. Bicarbonate may be used to correct acute or chronic lactic acidosis. Dichloroacetate (DCA) is an inhibitor of PDH and thus maintains PDH in its active (phosphorylated) state, resulting in reduced lactate production. DCA can be effective in lowering lactate levels in acute acidotic states. A double-blind placebo-controlled trial aimed to investigate the efficacy of DCA in the MELAS syndrome but had to be terminated prematurely because of reversible peripheral nerve toxicity (Kaufmann et al., 2006).

Coenzyme Q10 Deficiency CoQ10 is a lipophilic mobile electron carrier and antioxidant located in the inner mitochondrial membrane. Disorders of CoQ10 biosynthesis are clinically heterogeneous. Presentations include recurrent rhabdomyolysis with seizures, multisystem disorder of infancy with prominent nephropathy, ataxia with or without seizures, Leigh syndrome, and pure myopathy. These disorders respond well to CoQ10 supplementation if treatment is started early, but very large doses may be necessary because of poor uptake into the mitochondrion. The results of randomized controlled trials using CoQ10 in other mitochondrial disorders have yielded conflicting results. Many specialists recommend CoQ10 to all patients with a proven diagnosis of mitochondrial disease up to 200 mg 3 times daily in adults.

Other Pharmacological Approaches Although a number of pharmacological agents have been studied in mitochondrial disease, a Cochrane systematic review concluded that there was insufficient evidence to recommend any standard treatment (Pfeffer et al., 2012). There are anecdotal reports of benefit of various agents (e.g., riboflavin, succinate, l-carnitine, α-lipoic acid, creatine [Tarnopolsky et al., 1997], and vitamins C, E, and K), but the clinical heterogeneity and unpredictable natural history of mitochondrial disease, with a frequently relapsing-remitting course, makes interpretation of the effectiveness of any given agent in a single individual difficult. The few randomized double-blind clinical trials that have been performed yielded inconclusive or conflicting results. Novel pharmacological approaches have emerged which are aimed at stimulating mitochondrial biogenesis via the transcriptional coactivator PGC-1α. Drugs that may stimulate this pathway include bezafibrate and resveratrol, and these have demonstrated protective properties in animal models of Parkinson disease (Khan et al., 2010), Huntington disease (Ho et al., 2010; Maher et al., 2011), Alzheimer disease (Anekonda and Reddy, 2006), and other diseases including a mouse model of mitochondrial myopathy (Wenz et al., 2008). Finally, idebenone, a CoQ analog, has been approved by the European Medicines Agency to treat LHON, and an international consensus statement established the indication in patients with acute, subacute, or dynamic clinical course but did not recommended the treatment for chronic patients (Carelli et al. 2017).

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Enzyme and Metabolite Replacement

Thymidine Phosphorylase Replacement Therapy A number of strategies have been used to replace thymidine phosphorylase activity in patients with MNGIE. Replacement by repeated platelet or encapsulated red cell transfusions has been shown to produce transient benefit. Allogeneic stem cell transplantation has proven to be the most successful method of restoring thymidine phosphorylase activity in MNGIE patients but is associated with a high level of mortality, possibly due to the advanced clinical state of the patients (Halter et al., 2011). More recently, allogeneic bone marrow transplantation has been shown to restore thymidine phosphorylase enzyme function in patients with MNGIE and improve clinical manifestations in the long term; thus it should be considered for selected patients with an optimal donor (Halter et al. 2015). L-Arginine

Therapy in MELAS

The precise mechanisms leading to stroke-like episodes in MELAS have not been determined. Dehydration, fasting, sepsis, and seizures are all likely to contribute, thus emphasizing the importance of adequate hydration, electrolyte and acid-base balance, nutritional support, antibiotics, and anticonvulsants. A possible role of l-arginine therapy has been reported based on the possibility that impaired vasodilation might be a factor in the acute setting. The effects of administering l-arginine, a nitric oxide precursor, were assessed in patients with acute MELAS stroke-like episodes. The authors suggested that oral administration within 30 minutes of a stroke significantly decreased frequency and severity of stroke-like episodes. In a further study, the same group found that 2 years of supplementation with oral l-arginine improved endothelial function to control levels and normalized plasma levels of l-arginine in patients. It was suggested that l-arginine therapy improved endothelial dysfunction and may have potential in the prevention and treatment of stroke-like episodes in MELAS.

Folate Deficiency Low CSF folate levels were first reported in KSS 25 years ago. More recently, rapid clinical response to folinic acid was reported in an 8-year-old boy with an mtDNA deletion associated with cerebral folate deficiency and leukoencephalopathy. It seems likely that the folate deficiency is secondary in KSS; at present, the prevalence of CSF folate deficiency in patients with mitochondrial disorders is not known. If central folate deficiency is suspected, CSF must be analyzed

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because blood folate levels do not accurately reflect CNS folate status. Treatment with folinic acid rather than folate is necessary because the latter does not cross the blood–brain barrier.

Carnitine Deficiency Primary systemic carnitine deficiency generally shows dramatic response to replacement therapy (up to 200 mg/kg daily in 2–4 divided doses in adults; maximum 3 g per day). Early replacement therapy may prevent the neurological deficits.

Gene Therapy

Resistance Exercise Training to Shift mtDNA Genotype The proportion of mutant mtDNA in muscle correlates with the degree of reduction in oxidative capacity. Recently there has been increasing interest in the role of exercise therapy to improve muscle respiratory chain oxidative capacity by potentially reducing mutant mtDNA load—a process known as gene shifting. Certain mtDNA mutations such as deletions and some tRNA point mutations are present in high levels in mature skeletal muscle, but for reasons that remain unclear, they are absent from the muscle satellite cell population, which harbors only wild-type mtDNA. Previous experimental work demonstrated that activation of satellite cells has the potential to introduce wild-type mtDNA into mature skeletal muscle, thereby lowering the proportion of mutant mtDNA and reversing the respiratory chain defect. Certain types of exercise protocols have the potential to induce satellite cell activation and promote entry of wild-type mtDNA into mature muscle. Endurance training has been demonstrated to improve aerobic capacity (Taivassalo et al., 2006) and OXPHOS capacity and exercise tolerance (Jeppesen et al., 2009) in patients with mitochondrial myopathy. A 12-week progressive overload leg resistance exercise training protocol has demonstrated increased muscle strength and improved muscle oxidative capacity, although there was no measurable reduction in deleted mtDNA (Murphy et al., 2008) and exercise has been accompanied by an increase in mutant mtDNA load in one study (Taivassalo et al., 2001).

Other Gene Therapy Approaches for mtDNA Mutations An allotropic expression strategy used a mitochondrial targeting sequence added to an ATP6 gene, recoded using the nuclear rather than the mitochondrial genetic code, to rescue the NARP phenotype in a cell-culture model. Cell growth was restored, and ATP synthesis improved. More recently, a similar approach was used in a rat model of LHON with an ND4 mutation. Other approaches have attempted to introduce cytosolic tRNAs into the mitochondrion, eliminate mutant mtDNAs using restriction enzymes targeted to the mitochondrion, reduce deleted mtDNA molecules in cultured cells by growing under ketogenic conditions, and shift heteroplasmy with zinc finger nucleases that bind to mutant mtDNA molecules, leading to their selective degradation. A range of techniques for manipulating mtDNA and their products is in the early stages of development (Kyriakouli et al., 2008). A novel strategy involves the exchange of maternal mtDNA with that of a healthy donor (Craven et al., 2010). This technique requires in vitro fertilization with the parent ovum and sperm, removal of the pronucleus from the resulting zygote, and fusion into an enucleated donor oocyte (cytoplast). The reconstituted zygote can then be implanted into the mother’s uterus for development. Inevitably, this process requires the molecular diagnosis to have been made in the host woman (and excluded in the donor) and is an important potential therapy for female mutation carriers (Tachibana et al., 2013).

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MITOCHONDRIAL DYSFUNCTION IN NEURODEGENERATIVE DISEASE Mitochondrial Dysfunction and Parkinson Disease Mitochondrial dysfunction is now established as an important component of the etiology and pathogenesis of PD (Schapira et al., 2014). Detailed analysis using laser capture of dopaminergic neurons from parkinsonian brains has demonstrated a greater proportion of deleted mtDNA than that in age-matched controls. Mutations in the nuclear genes parkin, PINK1, and DJ1 encoding the corresponding mitochondrial proteins cause autosomal recessive PD. Parkin mutations predominantly cause parkinsonism in patients younger than 30 years. Mitochondrial dysfunction and increased oxidative stress have been described in parkin-deficient Drosophila, mouse models, and peripheral tissues in patients with parkin-mutation-positive PD. Parkin is a ubiquitin E3 ligase and regulates expression of PGC1α through interaction with parkin-interacting substrate protein, which represses expression of PGC1α and nuclear respiratory factor 1. Both parkin and PINK1 proteins control mitochondrial turnover via autophagic destruction (mitophagy) of impaired mitochondria. Mutations in parkin or PINK1 impair mitophagy, causing the accumulation of defective mitochondria. This process can be reversed by upregulation of parkin or PINK1 proteins and the removal of defective mitochondria. The demonstration of abnormal expression of autophagy proteins in the brain of patients with Parkinson disease has further drawn attention to the importance of degradation pathways to the pathogenesis of the disease. The upregulation of the translation inhibitor 4E-BP counteracts the effects of PINK1 or parkin mutants in Drosophila, and rapamycin, a drug that activates 4E-BP and autophagy, is also protective in these mutants. Mutations in DJ1 are a rare cause of familial PD. DJ1-knockout mice demonstrate downregulated mitochondrial uncoupling proteins 4 and 5, impaired calcium-induced uncoupling, and increased oxidant damage. DJ1 may have a protective role in the reduction of protein misfolding and aggregation which may be a result of oxidative stress and can reduce α-synuclein aggregation. Genetic causes of Parkinson disease, other than those encoding mitochondrial proteins, can also affect mitochondrial function. α-Synuclein is a major component of Lewy bodies and neurites present in the brains of patients with Parkinson disease. Point mutations or multiplications of the α-synuclein gene cause familial PD. α-Synuclein is predominantly cytosolic, but a fraction has been identified in mitochondria and has been noted to interact directly with mitochondrial membranes, including at the neuronal synapse, and to inhibit complex I in a dose-dependent manner that shows regional expression of the protein. In addition to genetic causes, several environmental factors have been associated with both mitochondrial dysfunction and PD or parkinsonism, including a range of mitochondrial complex I inhibitors that are toxic to dopaminergic neurons.

Mitochondrial Dysfunction and Alzheimer Disease Apart from age, important risk factors for Alzheimer disease include apolipoprotein ε4 status and mutations of amyloid precursor protein or presenilin. Abnormalities of mitochondrial structure or function, or mtDNA defects in the brain and other tissues, of patients with Alzheimer disease have been described (Picone et al., 2014). The presence and relevance of these findings have remained controversial, and the data derived have not always been reproducible. Polymorphism of the TOMM40 gene (2 kilobases away from the APOE 4 gene on chromosome 19) has been described as an important risk factor for Alzheimer disease and its age of onset. TOMM40 protein forms part of a pore in the outer mitochondrial membrane and is involved in

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CHAPTER 93 Mitochondrial Disorders the transportation of cytoplasmic proteins into the mitochondrion. Amyloid precursor protein accumulates in this pore. Presenilins 1 and 2 and γ-secretase are associated with the mitochondria-associated membrane, a connection site between the endoplasmic reticulum and the mitochondrion that is dependent on mitofusin 2 function. Mitochondria-associated membranes contain acyl-CoA cholesterol acyltransferase—an important enzyme in cholesterol metabolism that is needed for the formation of amyloid β, which in turn can localize to mitochondria. Impaired mitochondria-associated membrane function may affect intracellular calcium homoeostasis and be relevant to calcium dysregulation by the endoplasmic reticulum and abnormal neuronal calcium handling detected in Alzheimer disease models and patients. Triple-transgenic mice expressing amyloid and tangle pathology similar to that noted in Alzheimer disease had pronounced mitochondrial abnormalities, such as reduced OXPHOS, decreased activities of complexes I and IV, lowered mitochondrial membrane potential, and increased free-radical generation. The potential contribution of mitochondria to Alzheimer disease continues to develop into a pivotal role in the downstream biochemical events that affect intracellular bioenergetics and homoeostasis.

Mitochondrial Dysfunction and Huntington Disease Huntington disease is caused by an unstable CAG triplet repeat expansion in exon 1 of the huntingtin gene. Mitochondrial defects have been described in patients with Huntington disease in vivo, in postmortem brain and muscle, and in cell and animal models of the disease (Schapira et al., 2014). The mitochondrial defects in Huntington disease are associated with abnormalities of calcium handling, increased susceptibility to calcium-induced opening of the mitochondrial permeability pore, and reduced respiration. Mutant huntingtin protein associates with mitochondrial membranes, can impair axonal trafficking of mitochondria, and can reduce synaptic ATP concentrations. Mutant huntingtin protein interacts with, and increases the sensitivity of, the inositol-1,4,5-trisphosphate receptor at the mitochondria-associated membrane and contributes to calcium dysregulation in Huntington disease. Mutant huntingtin protein also sensitizes cells to free radical–mediated damage, reduces ATP production and mitochondrial fusion, and induces increased fragmentation. These changes were prevented by overexpression of mitofusin 2. The role of mitochondrial quality control is further supported

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by the finding that the calcineurin-mediated dephosphorylation of dynamin-like protein 1 is increased in cells of patients with Huntington disease and leads to increases in mitochondrial translocation, promotion of fragmentation, and an increased cell susceptibility to apoptosis. Mutant huntingtin protein has an important role in transcription regulation, and the expression of a range of mitochondrial proteins is modified in Huntington disease striatal neurons, including the downregulation of COX subunit 2, mitofusin 1, mitochondrial transcription factor A, and PGC1α. This correlates with disease severity and increased expression of dynamin-like protein 1. The regulation of PGC1α by mutant huntingtin protein is of particular interest because of the potential to manipulate the expression of this molecule with drugs. Mutant huntingtin protein binds to the PGC1α promoter and blocks transcription of target genes in Huntington disease models and patient muscle. In view of the important regulatory role for PGC1α in mitochondrial biogenesis, this process might contribute to the mitochondrial dysfunction seen in Huntington disease, including impaired defense against free radicals.

Other Neurodegenerative Diseases Mitochondrial dysfunction has been identified in several other neurodegenerative diseases. Secondary abnormalities of mitochondrial morphology and function have been recorded in amyotrophic lateral sclerosis (Palomo and Manfredi, 2014), whereas in other disorders the causative gene mutation involves a mitochondrial protein (see Table 93.1)—for example, Friedreich ataxia and hereditary spastic paraplegia. Mutations in the MFN2 gene are a common cause of autosomal dominant Charcot-Marie-Tooth type 2 disease, an early-onset axonal sensorimotor neuropathy. A proportion of patients have additional abnormalities, such as optic atrophy or deafness. Mutations of OPA1 cause autosomal dominant optic atrophy, but the phenotype can include peripheral neuropathy, deafness, ataxia, and ophthalmoplegia with multiple mtDNA deletions. The part that both mitofusin 2 and optic atrophy protein 1 play in fission–fusion might at least partly explain both the pathophysiology of neuronal-axonal dysfunction and the overlapping phenotypes of mutations affecting these proteins, although an additional role in mtDNA maintenance cannot be excluded. The complete reference list is available online at https://expertconsult. inkling.com/.

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94 Prion Diseases Boon Lead Tee MD, Michael D. Geschwind MD PhD FAAN

OUTLINE Human Prion Diseases, 1430 Introduction, 1430 Epidemiology, 1430 History of Creutzfeldt-Jakob Disease Nomenclature, 1431 What Are Prions?, 1431 Function of PrPC, 1432 Prion Protein Pathogenicity, 1433 Clinical Aspects of Human Prion Diseases, 1434 Sporadic Prion Disease, 1434

Diagnosis of Creutzfeldt-Jakob Disease, 1437 Diagnostic Tests for Sporadic Jakob-Creutzfeldt Disease, 1438 Genetic Prion Disease, 1442 Octopeptide Repeat Insertions, 1444 Acquired Prion Disease, 1444 Treatment of Human Prion Diseases, 1450 Management of Prion Diseases, 1451 Differential Diagnosis, 1451

Prion (pronounced pree-ahn) diseases (PrDs) are a group of uniformly fatal neurodegenerative diseases caused by the transformation of an endogenous protein, PrP (prion-related protein), into an abnormal conformation (misfolded protein) called the prion. The term prion is derived from the term proteinaceous infectious particle and was named by Stanley Prusiner, who discovered prions (Prusiner, 1998). For many years, prion diseases were mistakenly thought to be due to “slow viruses,” in part owing to the transmissibility of the diseases and the long incubation period between exposure and symptom onset (Brown et al., 1986b; Gajdusek, 1977). Research by Prusiner and others, however, determined that the infectious agent did not contain nucleic acid, a component of viruses. Furthermore, treating prion-contaminated material with methods that inactivated viruses and other microorganisms did not prevent these diseases from being experimentally transmitted; yet methods that denatured or destroyed proteins prevented transmission, strongly supporting the theory that the causative agent was a protein (Gajdusek, 1977; Prusiner, 1982). The identification of the gene-encoding human PrP (Oesch et al., 1985), PRNP, and mutations of this gene in patients with familial prion disease (Goldgaber et al., 1989; Hsiao et al., 1989) further helped support the prion hypothesis. In 1997, Prusiner received the Nobel Prize in Physiology or Medicine for his work on identifying the prion (Prusiner, 1998). Through animal models, identification of prion gene mutations causing prion disease in humans, and in vitro production of prions with transmissibility, it essentially has been proven that the prion protein is necessary and sufficient to cause prion disease (Pritzkow et al., 2018; Prusiner, 2013). Although PrDs occur in animals and humans, this chapter focus on human PrDs, discussing animal prion diseases only relevant to human disease.

spontaneously (sporadic), genetically, and through transmission (acquired) (Prusiner, 1998). Approximately 85% of human prion diseases are sporadic, 15% are genetic, and fewer than 1% are acquired (e.g., iatrogenic) (Begue et al., 2011; Klug et al., 2013; Nozaki et al., 2010; Prusiner, 1998). Sporadic prion disease, or sporadic JakobCreutzfeldt disease (sJCD), is thought to occur spontaneously. Genetic prion diseases (gPrD) are due to a mutation in PRNP and historically have been classified into three forms based on clinical and pathological features: familial JCD (fJCD), Gerstmann-Sträussler-Scheinker disease (GSS), and fatal familial insomnia (FFI). As noted in the gPrD section, however, this classification is somewhat antiquated. Although acquired (infectious) prion diseases are the least common form of human prion disease, they are perhaps the most notorious, in part owing to their occurrence through inadvertent transmission of prions from animals to humans and from human to human. Because the genetic and acquired forms of human prion disease are less common, they will be discussed in less detail in this chapter than the much more common form, sJCD.

HUMAN PRION DISEASES Introduction Perhaps one reason many find PrDs so fascinating is that they are unique in medicine because they can occur in three ways in humans:

Epidemiology The incidence of human prion diseases is about 1–1.5 per million per year in most developed countries, with some variability from year to year and between countries (Begue et al., 2011; Holman et al., 2010; Jansen et al., 2012; Klug et al., 2013; Litzroth et al., 2015; Maddox et al., 2020; Nozaki et al., 2010). Thus, annually there are about 6,000 human prion cases worldwide, including about 400–500 in the United States (Holman et al., 2010; Maddox et al., 2010). The incidence of cases can vary from year to year, particularly in countries with smaller populations in which a small fluctuation in cases can have a big impact on incidence (http://www.eurocjd.ed.ac.uk/ surveillance%20data%201.html; Begue et al., 2011; Ladogana et al., 2005; Litzroth, Cras, De Vil & Quoilin, 2015; Nozaki et al., 2010; Ruegger et al., 2009). The peak age of onset of sJCD occurs around a unimodal, relatively narrow peak of about 68 years (Brown et al., 1994; Collins et al., 2006; Holman et al., 2010). Because sJCD tends

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“Refolding” model PrPc

PrPSc

History of Creutzfeldt-Jakob Disease Nomenclature The history of the nomenclature for JCD is quite interesting. In 1921 and 1923, Alfons Jakob published four papers describing five unusual cases of rapidly progressive dementia. He stated that his cases were nearly identical to a case described earlier by his professor Hans Creutzfeldt in 1920. This disease was referred to for many decades as Jakob’s disease or Jakob-Creutzfeldt disease until Clarence J. Gibbs, a prominent researcher in the field, started using the term CreutzfeldtJakob disease (CJD) because the acronym was closer to his own initials (Gibbs, 1992). It turns out that the cases Jakob described were very different than Creutzfeldt’s case, and that only two of Jakob’s five cases actually had the disease that we now call JCD or CJD (prion disease), whereas Creutzfeldt’s case did not (Katscher, 1998). Therefore, the name for prion disease should be Jakob’s disease or possibly Jakob-Creutzfeldt disease. Unfortunately many continue to use the term CJD, either for historical reasons or because the term JC disease (JCD) can be easily confused with progressive multifocal leukoencephalopathy (PML) caused by the JC virus. In this chapter, we will use the more historically accurate terms Jakob-Creutzfeldt disease and JCD. Prion diseases also have been historically called transmissible spongiform encephalopathies (TSEs) due to two properties common to many prion diseases: transmissibility and, on neuropathology, spongioform changes. We will not use the older term TSE because some gPrDs might not be transmissible (Weissmann & Flechsig, 2003) and not all human prion diseases have spongiform changes (now called vacuolation due to fluid-filled vesicles in the dendrites) on pathology (Budka et al., 1995; Kretzschmar et al., 1996).

What Are Prions? Before further discussion, it is important to understand what a prion is. Just as the nomenclature for human prion diseases is complicated, unfortunately so is the terminology for the biology of prions. The normal prion protein (PrP) is referred to as PrPC, in which the C stands for the normal cellular form. Prion proteins, PrPC, can be transformed into prions, an abnormal, “infectious” form of PrP often called either PrPSc or PrPRes (Sc refers to the abnormally shaped PrP found in scrapie—the prion disease of sheep and goats—and Res refers to the fact that prion being partially resistant to digestion by proteases (enzymes that digest proteins). In this chapter we use the term PrPSc. PrPC and PrPSc essentially have identical amino acid sequences (except in gPrD; see later) but different three-dimensional structures, with the former mainly consisting of α-helical structure with little or no β-sheet structure and the latter mainly having β-sheet structure (Baldwin et al., 1994; Sarnataro et al., 2017), possibly stacked as a solenoid (Wille & Requena, 2018). Prions are characterized by the intrinsic ability of their structures to act as a template and convert the normal physiological PrPC into the pathological disease-causing form, PrPSc. Per the current prion model, when PrPC comes in contact with PrPSc, PrPC changes shape into that of PrPSc. Thus, PrPSc acts as a template for the misfolding of PrPC into PrPSc. It is believed that it is the accumulation of prions, PrPSc, in the brain that leads to nerve cell injury and death (Prusiner, 1998, 2013), although some data suggest that it is the transformation of PrPC into PrPSc, and not the accumulation of PrPSc, that causes neuronal injury and subsequent disease (Mallucci et al., 2007). Sporadic JCD can present quite variably despite all cases having

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A “Seeding” model PrPc

Very, very slow

PrPSc

Rapid

Rapid

B Fig. 94.1 Models for the conformational conversion of cellular prion protein (PrPC) to scrapie prion protein (PrPSc). A, The refolding model. Conformational change is kinetically controlled, a high-activation energy barrier preventing spontaneous conversion at detectable rates. Interaction with exogenously introduced PrPSc causes PrPC to undergo an induced conformational change to yield PrPSc. This reaction could be facilitated by an enzyme or chaperone. In the case of certain mutations in PrPC, spontaneous conversion to PrPSc might occur as a rare event, explaining why familial Creutzfeldt-Jakob disease (JCD) or Gerstmann-Sträussler-Scheinker disease arise spontaneously, albeit late in life. Sporadic JCD might come about when an extremely rare event (occurring in about one in a million individuals per year) leads to spontaneous conversion of PrPC to PrPSc. B, The seeding model. PrPC (purple rectangles) and PrPSc (or a PrPSc-like molecule, Orange circles) are in equilibrium, with PrPC strongly favored. PrPSc is stabilized only when it adds onto a crystal-like seed or aggregate of PrPSc (green circles). Seed formation is rare, but once a seed is present, monomer addition ensues rapidly. To explain exponential conversion rates, aggregates must be continuously fragmented, generating increasing surfaces for accretion. (From Weissmann, C., Enari, M., Klöhn, P.C., et al., 2002. Transmission of prions. Proc. Natl. Acad. Sci. USA 99(16), 378–316, 383.)

PrPSc with an identical amino acid sequence; one reason for this is that there are different strains of PrPSc, each with slightly different biological and physicochemical properties. Such prion strain diversity contributes clinicopathologically to variabilities in tissue tropism, host affinity, and clinical presentations (Bartz, 2016; Morales, 2017; Safar et al., 1998). Although it is not known how prions spread throughout the brain, at least two models have been proposed: a refolding model and a seeding model, which are not mutually exclusive (Fig. 94.1). Importantly, mice that are devoid of PrPC can neither be infected with nor replicate prions (Bueler et al., 1993; Katamine et al., 1998; Prusiner, 1998). Furthermore, when an explant of neuronal tissue overexpressing PrPC is explanted into a PrPC knockout mouse and inoculated with prions, the explant shows extensive PrPSc accumulation and neurodegeneration, but host brain tissue shows no toxicity despite containing PrPSc derived from the graft (Brandner et al., 1996a, 1996b; Weissmann et al., 1996). These studies provide strong evidence that PrPC is necessary for prion disease. Furthermore, propagation capacity of different prion strains is shown to be partly related to surrounding cellular cofactors (Fernandez-Borges et al., 2018).

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PRNP

A

–8

Codons 1

23

M129V

50

PrPC

100

E219K

150

200

Cu2+

Y

β1

B

PrPSc

PrPSc

αB

Y

αC

β2

GPI

S-S

Type Type 1 2

Y

Protein X

Y

αC

GPI

S-S

C

r

αB

82 97

r

αA

Protein X

231 254 Cell membrane

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P102L

GSS amyloidogenic peptide

D Fig. 94.2 The Prion Protein. A, The prion protein gene (PRNP) is located on the short arm of the human chromosome 20. Nonpathogenic polymorphism includes deletion of one of the octarepeat segments, methionine-valine polymorphism at the 129 position, and glutamine-lysine polymorphism at position 219. B, Post-translational modification truncates the cellular prion protein (PrPC) at positions 23 and 231 and glycosylates (Y) at positions 181 and 197. The glycosylphosphatidylinositol (GPI) attached to serine at position 231 anchors the C-terminus to the cellular membrane. The intracellular N-terminus contains five octarepeat segments, P(Q/H)GGG(G/-)WGQ (blue blocks), that can bind copper ions. The central part of the protein contains one short α-helical segment (α-helix A encompassing residues 144–157 [green block]), flanked by two short β-strands (red blocks), β1(129–131) and β2(161–163). The secondary structure of the C-terminus is dominated by two long α-helical domains: α-helix B (residues 172–193) and α-helix C (residues 200–227), which are connected by a disulfide bond. The blue arrows indicate binding sites of the protein X within α-helices B and C. The dashed frame marks a segment between positions 90 and 150, which is crucial for the binding of PrPC to scrapie prion protein (PrPSc). C, PrPSc has increased β-sheet content (red dashed block). D, Unlike PrPSc, which is anchored to the membrane, Gerstmann-Sträussler–Scheinker (GSS) amyloidogenic peptides are truncated and excreted into the cellular space, where they aggregate and fibrillize into GSS amyloid deposits. This example is an 8-kD PrP fragment associated with the most common GSS/P102L mutation. A synthetic form of this peptide (90–150 residues), exposed to acetonitrile treatment to increase β-sheet content, is the only synthetically generated peptide that when injected intracerebrally into P102L-transgenic mice is able to induce the GSS disease. (From Sadowski, M., Verma, A., Wisniewski, T., 2008. Infection of the nervous system: prion diseases. In: Bradley, W., Daroff, R., Fenichel, G., et al. (Eds.), Neurology in Clinical Practice, fifth ed. Butterworth-Heinemann, Philadelphia.)

Function of PrPC The function of PrPC is still not entirely known (Castle & Gill, 2017; Gill & Castle, 2018; Wulf et al., 2017). It is evolutionary conserved, so it probably plays an important role in neuronal development and function (Kanaani et al., 2005). In humans, it is encoded by PRNP, located on the short arm of chromosome 20 (Basler et al., 1986; Oesch et al., 1985). PrPC protein typically consists of a highly conserved central hydrophobic segment (HD) and a C-terminal hydrophobic region that is commonly attached to the outer cell membrane by a glycosylphosphatidylinositol (GPI) anchor and an amino terminal flexible tail (Borchelt et al., 1992, 1993; Sarnataro et al., 2017; Tarboulos et al., 1992) (Figs. 94.2 and 94.3). PrPC is primarily membrane bound and resides primarily on nerve cell membranes and on other cells in the body, including lymphocytes. Mice that have had both copies of the open reading frame (ORF) of their PrP gene, Prnp, deleted (PrP−/−)

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have a normal lifespan and appearance (Bueler et al., 1992; Manson et al., 1994). Furthermore, conditional knockout mice, in which the gene is not removed until after the mouse has already developed, also appear normal and unaffected by gene removal (Legname, 2017). Although the mice essentially were clinically asymptomatic, deeper phenotyping revealed several abnormalities, as discussed below. PrPC binds to many proteins and cellular constituents. Animal and cell models have suggested a variety of possible functions of PrPC, including cell signaling, adhesion, proliferation, differentiation, and growth (Castle & Gill, 2017; Didonna, 2013; Gill & Castle, 2018; Wulf et al., 2017). Studies with various Prnp knockout mice models of mixed genetic backgrounds found they develop peripheral nerve demyelination (Nishida et al., 1999); have increased susceptibility to ischemic brain injury (Spudich et al., 2005; Weise et al., 2006); altered sleep and circadian rhythm (Nuvolone et al., 2016; Tobler et al., 1997); altered

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1433

Signal peptide

β-Cleavage

α-Cleavage N1

Octarepeats

C2

HD

Amyloidogenic region

α

N-glycosylation sites

C1 α α GPI anchor

Fig. 94.3 Schematic of Prion Protein (PrPC) Attached to Cell Membrane. This figure shows an outline of the structure of the cellular prion protein, including posttranslational modifications and representation of PrPC cleavages. A secretory signal peptide resides at the extreme N-terminus. Hydrophobic segment (HD) defines the hydrophobic region; α indicates alpha-helix and the arrows β-sheets; hexagons define N-glycosylation; the glycosylphosphatidylinositol (GPI) anchors PrP to the cell membranes. α-Cleavage acts in the HD generating N1 and C1 fragments, whereas β-cleavage acts in the octarepeat region generating N2 and C2. (From Sarnataro, D., Pepe, A., Zurzolo, C., et al., 2017. Cell biology of prion protein. Prog. Mol. Biol. Transl. Sci. 150, 57–82, Figure 2.)

hippocampal neuropathology and physiology, including deficits in hippocampal-dependent spatial learning and hippocampal synaptic plasticity (Colling et al., 1997; Criado et al., 2005); and olfactory dysfunction (Le Pichon et al., 2009). The octarepeat peptide regions of PrPC have even been implicated in playing an involved role in multidrug resistance of gastric cancer cells (Wang et al., 2012). There also have been several studies suggesting PrPC binds β-amyloid (Aβ), a major protein in Alzheimer disease (AD), and might play a role in the pathogenesis of AD (Kudo et al., 2013; Gunther & Strittmatter, 2010). Some studies in mice suggest that PrPC mediates the toxic effects of Aβ oligomers and might be necessary for memory deficits to occur in AD (Gimbel et al., 2010; Nygaard & Strittmatter, 2009). In fact, in one study infusion of anti-PrPC antibodies ameliorated cognitive deficits in an AD mouse model (Chung et al., 2010). This possible role of PrPC in binding to Aβ and causing dysfunction in AD is still controversial, however. In one study, with human APP (J20) crossed onto a PrPCdeficient background still had the neurological impairment that was present in the J20 mice, suggesting PrPC might not be a major mediator of Aβ-induced impairment (Cisse et al., 2011). For reasons that were unclear at the time, many phenotypes identified in certain Prnp knockout mice were not reproducible in knockout mice with different genetic backgrounds, resulting in confusion regarding the physiological role of PrPC in transgenic knockout mice models (Prnp -/-) (Wulf et al., 2017). One possible reason is that some reported findings were caused by knocking out genes adjacent to Prnp rather than Prnp itself; this is because the experiments were done with mice of mixed genetic backgrounds, which may harbor variable Prnpflanking genes that can lead to poorly controlled Mendelian segregation of these polymorphic alleles. This led to systematic genetic confounds and in some cases incorrect conclusions regarding the function of PrPC, such as the inhibition of macrophage phagocytosis (Aguzzi et al., 2013; Castle & Gill, 2017; Nuvolone et al., 2013; Striebel et al., 2013a, 2013b;

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Weissmann & Flechsig, 2003; Wulf et al., 2017). Using Prnp knockout mice with pure genetic backgrounds that do not possess flanking genes (Manson et al., 1994; Nuvolone et al., 2016), investigators found few of the prior putative phenotypes reported in Prnp knockout mice of impure genetic backgrounds (Castle & Gill, 2017; Wulf et al., 2017). Thus, genotype-phenotype relationships in impure mice strains need to be interpreted with caution and earlier experiments investigating the role of PrPC with impure mice models need to be replicated with Prnp mice with pure genetic backgrounds (Castle & Gill, 2017; Manson et al., 1994; Wulf et al., 2017). Phenotypes that remain in Prnp knockout mice with pure genetic background include chronic demyelinating peripheral neuropathy, suggesting a role for PrPC in myelin maintenance (Nuvolone et al., 2013), altered circadian rhythm and sleep pattern (Tobler et al., 1996), and altered synaptic plasticity (Wulf et al., 2017). Given the findings from Prnp mice with pure backgrounds, it seems that PrPC interacts with other membrane proteins, can regulate transport and regulation of these proteins, can modulate their functionality, and can even signal distinct biological pathways via its N-terminal tail cleavage products and scavenge Aβ amyloid aggregates (Wulf et al., 2017).

Prion Protein Pathogenicity Prion disease is generally regarded as a gain of function disease for at least two reasons: (1) deletion or reduction (e.g., hemizygous) of Prnp in mice results in mice that are normal or largely asymptomatic; and (2) the prion protein expression level in mice models is directly associated with the rate of disease progression (Fischer et al., 1996; Minikel et al., 2016; Weissmann & Flechsig, 2003; Wulf et al., 2017). Nevertheless, some of the roles for PrPC suggest that dysfunction in prion diseases might be due not only to pathogenicity of misfolded PrPC into prions but also to loss of normal function of PrPC (Castle & Gill, 2017).

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Post-translational modification of prion protein and the GPI anchor may play a role in the pathogenesis of prion diseases. Different proteolytic processing of the prion protein generates protein fragments that have variable functions. For instance, the hydrophobic domain (HD) region in PrPC (amino acid 106–126) (see Fig. 94.3) is considered to have amyloidogenic properties (Tagliavini et al., 1993). In the normal state, α-cleavage occurs in this region, causing a loss of the amyloidogenic tendency and generating both a tethered C terminal protein (C1), which helps maintain myelin integrity, and a free N terminal fragment (N1), which has anti-apoptotic activity. In contrast, β-cleavage, which occurs more frequently in prion disease, generates a membrane-bound C terminal protein (C2) that retains the amyloidogenic core, and a free N terminal fragment (N2), the latter of which is speculated to have antioxidant instead of anti-apoptotic properties. It is believed that a higher-stress environment favors β-cleavage that tends to reduce oxidative stress but promote prion aggregation (Guillot-Sestier et al., 2009; Linsenmeier et al., 2017; Sarnataro et al., 2017). When Prnp−/− transgenic mice that retain the region encoding the C1 protein (i.e., less amyloidogenic) were inoculated with prions, they remained asymptomatic and showed resistance to protease-resistant PrP accumulation (Westergard et al., 2011). As aforementioned, these studies involved transgenic mice with mixed genetic backgrounds and further study replications using pure genetic mice models is warranted. Regarding the role of the GPI anchor attaching PrPC to the cell membrane, anchorless transgenic mice, which encode PrPC without the GPI anchor, remained asymptomatic when inoculated with PrPSc but still showed diffuse amyloid PrPSc plaques in the brain (Chesebro et al., 2005). Another version of anchorless transgenic mice, however, had spontaneous late-onset neurological symptoms and GSS-like pathology (i.e., amyloid plaques) (Stohr et al., 2011). The former anchorless PrPC study suggests that PrPSc deposition alone might not be sufficient to cause neurotoxicity, but both studies suggest the GPI anchor might be involved in prion disease pathophysiology.

CLINICAL ASPECTS OF HUMAN PRION DISEASES Sporadic Prion Disease As noted above, nomenclature in prion diseases can be confusing, with the terms JCD or CJD used to refer to just sporadic JCD or to all human prion diseases interchangeably. To reduce confusion in this chapter, we refer to all human prion diseases as prion disease (PrD), whereas sJCD will be used to refer only to sporadic JCD. The rarity of sJCD and the fact that its incidence is similar (∼1–1.5/million) in most countries with appropriate surveillance suggest that it is unlikely to be due to an environmental cause and likely arises as a rare stochastic event in otherwise healthy persons, possibly through the spontaneous transformation of the prion protein PrPC into PrPSc or through a somatic mutation that results in the formation of a prion protein that is more susceptible to changing into PrPSc (Alzualde et al., 2010; Will et al., 1998; see Watts et al., 2006, for a discussion on possible origins of sJCD). Sporadic JCD is typically a very rapid disease with a median survival of about 4.5–6 (range 1–130) months (Collins et al., 2006; Parchi et al., 1999b) and mean survival of about 8±11 months (Brown et al., 1994). About 85% of patients die within 1 year from onset of symptoms (Collins et al., 2006), and ∼ 50%–60% die in less than 5–6 months (Brown et al., 1994; Collins et al., 2006). The median age of onset is 60–67 years old, with a range from 12 to 95 (Brown et al., 1994; Collins et al., 2006; Parchi et al., 1999b) (Table 94.1). Occurrence of sJCD at young (20s–40s) (Belay et al., 2001; Martindale et al., 2003; Murray

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et al., 2008) or old (>80) ages is uncommon (Collins et al., 2006). Patients younger than 20 years of age are extremely rare, although a few have occurred, including a 13-year-old in the United States (Blase et al., 2014) and an unpublished case of a 12-year-old girl with sJCD in Spain (biopsy-proven with no PRNP mutation; M. Geschwind, personal communication). Sporadic JCD individuals with younger age of onset were reported to have longer survival and higher tendency to present with non-cognitive features including affective disorder, behavioral change, or sleep illnesses (Appleby et al., 2007; Corato et al., 2006). Symptoms of sJCD vary widely but typically include cognitive changes (dementia), behavioral and personality changes, difficulties with movement and coordination, visual symptoms, and constitutional symptoms (Appleby et al., 2009; Brown et al., 1986a; Rabinovici et al., 2006). Cognitive problems are often among the first symptoms in sJCD and typically include mild confusion, memory loss, and difficulty concentrating, organizing, or planning. Motor manifestations of sJCD include extrapyramidal symptoms (bradykinesia, dystonia, tremor), cerebellar symptoms (gait or limb ataxia), and later in the disease, myoclonus (sudden jerking movements). Whereas the cognitive and motor symptoms are often obvious, other common early symptoms may be subtle. These include behavioral or psychiatric symptoms (i.e., irritability, anxiety, depression, or other changes in personality) and constitutional symptoms (i.e., fatigue, malaise, headache, dry cough, lightheadedness, vertigo, etc.). Visual symptoms typically present as blurred or double vision, cortical blindness, or other perceptual problems; they are due to problems with processing of visual information in the brain and not due to retinal or cranial nerve abnormalities. Other symptoms such as aphasia, neglect, or apraxia (inability to do learned movements) due to cortical dysfunction might also occur and can be presenting features. Sensory symptoms such as numbness, tingling, and/or pain are less well-recognized symptoms and are probably under-reported, given the magnitude of the other symptoms in sJCD (Brown et al., 1994; Lomen-Hoerth, 2010; Rabinovici et al., 2006; Will, 2004). sJCD can sometimes be classified based on the initial presenting symptoms (within the first few weeks of onset), into cognitive, Heidenhain (visual presentation), affective (mood disorders presentation), classic (cognitive symptoms and ataxia), and Brownell-Oppenheimer (ataxia presentation) variants, with cognitive and cerebellar symptoms being the most common initial presentations (Appleby et al., 2009; Rabinovici et al., 2006; Tsuji & Kuroiwa, 1983; Will et al., 2004). Each of these sJCD variants can have distinctive disease courses as well as electroencephalogram (EEG) and magnetic resonance imaging (MRI) findings (Appleby et al., 2009; Meissner et al., 2009). Classic and visual variants often progress most rapidly with the shortest survival time. Affective variants tend to have a younger age of onset and longest disease duration. In contrast, Oppenheimer-Brownell variants usually have an older onset age and lack presence of periodic sharp-wave complexes on EEG or basal ganglia hyperintensity on brain MRI (Appleby et al., 2009). Clinical symptomatology and course appear to vary, in part, based on the molecular classification of sJCD based on the prion type and a PRNP polymorphism (see later discussion) (Parchi et al., 1999b). Sporadic JCD usually progresses rapidly over weeks to months from the first obvious symptoms to death. The end stage is usually an akinetic-mute state (no purposeful movement and not speaking) (Brown et al., 1994). Most patients with prion disease die from aspiration pneumonia. Typical neuropathological features of sJCD include neuronal loss, gliosis (proliferation of astrocytes), vacuolation (i.e., spongiform changes), and deposition of PrPSc; except for PrPSc deposition, the other features are found in many other neurodegenerative and other neurological conditions and are not specific for JCD

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TABLE 94.1 Characteristic

that the term vacuolation is the more appropriate term to describe the spongiform changes, as these are not holes but rather fluid-filled vesicles formed in distal dendrites near synapses (BouzamondoBernstein et al., 2004). Clinical and other features of several prion diseases are summarized in Table 94.1.

Major Characteristics of Major Types of Human Prion Diseases

sJCD

Average age at 67 onset (years) Average duration 8 of disease (months) Average incubation N/A periods (range)

vJCD

fJCD

28

Variable among All ages kindreds, 23–55 Variable among 12 kindreds, 8–96

14

17 years (12–23 years); blood transfusion, 7 years (6.5–8 years)

Most prominent early signs

iJCD

N/A

Cognitive and/ Psychiatric abnormalor behavioral ities, sensory sympdysfunction toms (later dementia, ataxia, and other motor symptoms) Cerebellar dysfunc- >40 97 tion (%)

Cognitive and/ or behavioral dysfunction

DWI/FLAIR MRI positive

Yes for most mutations

Yes, >92%

Yes, pulvinar sign

PSWCs on EEG Amyloidosis

Yes, 65% No (rarely at end stage) Sparse plaques Severe in all cases in 5%–10% Yes Presence of PrPSc in No the lymphoreticular system

>40

Neurosurgical, 18 months (12–28); dura graft, 6 years (1.5–23 years); hGH, 5 years (4–36 years) Cognitive dysfunction, ataxia

>40

FFI

GSS

Kuru

50

40

All ages

18

60 Variable among kindreds, 60–240 N/A

11

N/A

12 years (5–50 years)

Insomnia, Ataxia, tremor, extrapy- Ataxia, autonomic ramidal symptoms tremor instability

No

Variable; some positive in deep nuclei or cerebellum Yes Yes Sporadically seen Sporadically seen

Unclear

100 in P102L mutation, 100 less common in most other mutations Variable; most negative N/A

No No

No Very severe

No

No

No

Yes

N/A 75% of cases Unlikely

DWI, diffusion-weighted imaging; EEG, Electroencephalogram; fJCD, familial Creutzfeldt-Jakob disease; FFI, familial fatal insomnia; FLAIR, fluidattenuated inversion recovery; hGH, human growth hormone; iJCD, iatrogenic Creutzfeldt-Jakob disease; GSS, Gerstmann-Sträussler-Scheinker; mo, months; N/A, not available or not applicable; PrPSc, scrapie prion protein; PSWCs, periodic sharp wave complexes; sJCD, sporadic Creutzfeldt-Jakob disease; vJCD, variant Creutzfeldt-Jakob disease; yrs, years. Modified from Sadowski M, Verma A, Wisniewski T. Infections of the nervous system. Chapter 59G. Prion diseases. In: Bradley WG, Daroff RB, Fenichel GM, Jankovic J,editors. Neurology in Clinical Practice. 5th ed. Newton, MA: Butterworth-Heinmann; 2008. p. 1566-82; and from these other references: Brandner, S., Whitfield, J., Boone, K., Puwa, A., O’Malley, C., Linehan, J.M., et al., 2008. Central and peripheral pathology of kuru: pathological analysis of a recent case and comparison with other forms of human prion disease. Philos. Trans. R. Soc. Lond. B, Biol. Sci. 363 (1510), 3755–3763; Brown, P., Brandel, J.P., Preece, M., Sato, T., 2006. Iatrogenic Creutzfeldt-Jakob disease: the waning of an era. Neurology 67 (3), 389–393. Brown, P., Gibbs, C.J., Jr., Rodgers-Johnson, P., Asher, D.M., Sulima, M.P., Bacote, A., et al., 1994. Human spongiform encephalopathy: the National Institutes of Health series of 300 cases of experimentally transmitted disease. Ann. Neurol. 35 (5), 513–529. Brown, P., Preece, M., Brandel, J.P., Sato, T., McShane, L., Zerr, I., et al., 2000. Iatrogenic Creutzfeldt-Jakob disease at the millennium. Neurology 55 (8), 1075–1081; Collie, D.A., Summers, D.M., Sellar, R.J., Ironside, J.W., Cooper, S., Zeidler, M., et al., 2003. Diagnosing variant Creutzfeldt-Jakob disease with the pulvinar sign: MR imaging findings in 86 neuropathologically confirmed cases. AJNR Am. J. Neuroradiol. 24 (8), 1560–1569; Collinge, J., Whitfield, J., McKintosh, E., Beck, J., Mead, S., Thomas, D.J., et al., 2006. Kuru in the 21st century—an acquired human prion disease with very long incubation periods. Lancet 367 (9528), 2068–2074; Heath, C.A., Cooper, S.A., Murray, K., Lowman, A., Henry, C., Macleod, M.A., et al., 2011. Diagnosing variant Creutzfeldt-Jakob disease: a retrospective analysis of the first 150 cases in the UK. J. Neurol. Neurosurg. Psychiatry 82 (6), 646–651; Huillard d’Aignaux, J.N., Cousens, S.N., Maccario, J., Costagliola, D., Alpers, M.P., Smith, P.G., et al., 2002. The incubation period of kuru. Epidemiology 13 (4), 402–408; Kong, Q., Surewicz, W.K., Petersen, R.B., Zou, W., Chen, S.G., Gambetti, P., et al., 2004. Inherited prion diseases. In: Prusiner, S.B., (Ed.), Prion Biology and Diseases, second ed. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, pp. 673–775; Lewis, A.M., Yu, M., DeArmond, S.J., Dillon, W.P., Miller, B.L., Geschwind, M.D., 2006. Human growth hormone-related iatrogenic Creutzfeldt-Jakob disease with abnormal imaging. Arch. Neurol. 63 (2), 288–290; Parchi, P., Giese, A., Capellari, S., Brown, P., Schulz-Schaeffer, W., Windl, O., et al., 1999. Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann. Neurol. 46 (2), 224–233; Valleron, A.J., Boelle, P.Y., Will, R., Cesbron, J.Y., 2001. Estimation of epidemic size and incubation time based on age characteristics of vCJD in the United Kingdom. Science 294 (5547), 1726–1728; Vitali, P., Maccagnano, E., Caverzasi, E., Henry, R.G., Haman, A., Torres-Chae, C., et al., 2011. Diffusion-weighted MRI hyperintensity patterns differentiate CJD from other rapid dementias. Neurology 76 (20), 1711–1719; Will, R.G. 2003. Acquired prion disease: iatrogenic CJD, variant CJD, kuru. Br. Med. Bull. 66, 255–265.

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Molecular Classification of Jakob-Creutzfeldt Disease Sporadic JCD has historically been divided into approximately six major molecular subtypes based on the genetic polymorphism at codon 129 in PRNP (MM, MV, or VV; Table 94.2) (Parchi et al., 1999b) (also see later discussion and Figs. 94.2 and 94.7) and the molecular weight of protease-resistant fragment of PrPSc (type 1 or 2). When PrPSc is extracted from brain tissue, and partially digested with proteinase, depending on the conformation of PrPSc, cleavage can occur at either of two sites (codon 82 or 97; see Fig. 94.2) resulting in, either a longer 21-kD (type 1) or a shorter 19-kD (type 2) peptide fragment is found when run on a Western blot. This classification, to some extent, separates sJCD cases based on their clinicopathological features into the six subtypes: MM1/MV1, VV2, MV2, MM2-thalamic, MM2-cortical, and VV1. MM1 and MV1 present clinicopathologically very similarly and are often, therefore, grouped together. They comprise the most common forms (∼70%, the vast majority of which are MM1) and usually present as classic sJCD with rapidly progressive dementia and a duration of just a few months. VV2 (∼16%) typically starts with ataxia, and has dementia later in the course, as well as a short disease duration. The remaining four types—MV2 (9%), MM2thalamic (2%), MM2-cortical (2%), and VV1 (1%)— have median durations of about 1–1.5 years. MV2 presents similarly to VV2 with ataxia but has focal amyloid “kuru” plaques in the cerebellum. MM2thalamic presents often with insomnia, followed later by ataxia and dementia, with most pathology confined to the thalamus and inferior olives and very little vacuolation; some researchers in the prion field call this form sporadic fatal insomnia (sFI), as it has some overlapping pathology with the genetic prion disease FFI (Parchi et al., 1999a), but this is simply the MM2-thalamic variant of sJCD (Parchi et al., 1999b). MM2-cortical patients have progressive dementia with large

confluent vacuoles in all cortical layers with prolonged median duration of 15.7 months. VV1 patients also typically present with progressive dementia but have severe cortical and striatal pathology with sparing of the brainstem nuclei and cerebellum. Unlike MM2-cortical, sJCD VV1 patients generally do not have large confluent vacuoles but

A

B

TABLE 94.2 Distribution of PRNP Codon 129 Polymorphism in Normal Population and Several Human Prion Diseases Normal population sJCD iJCD vJCD*

MV (%)

MM (%)

VV (%)

51 12–17 20 99

12 17 23 0

C

*All but two clinical cases of vJCD have been MM; one probable and one definite vJCD case were codon 129 MV, and some subclinical cases with vJCD prions in the lymphoreticular system have been identified (see text). iJCD, Iatrogenic Creutzfeldt-Jakob disease; sJCD, sporadic Creutzfeldt-Jakob disease; vJCD, variant Creutzfeldt-Jakob disease. Data from Brown, P., Preece, M., Brandel, J.P., Sato, T., McShane, L., Zerr, I., et al., 2000. Iatrogenic Creutzfeldt-Jakob disease at the millennium. Neurology 55 (8), 1075–1081; Collins, S.J., Sanchez-Juan, P., Masters, C.L., Klug, G.M., van Duijn, C., Poleggi, A., et al., 2006. Determinants of diagnostic investigation sensitivities across the clinical spectrum of sporadic Creutzfeldt-Jakob disease. Brain 129(Pt 9), 2278–2287; Garske, T., Ghani, A.C., 2010. Uncertainty in the tail of the variant creutzfeldt-Jakob disease epidemic in the UK. PLoS One 5 (12), e15626; Knight, R., 2017. Infectious and sporadic prion diseases. Prog. Mol. Biol. Transl. Sci. 150, 293–318; Parchi, P., Giese, A., Capellari, S., Brown, P., Schulz-Schaeffer, W., Windl, O., et al., 1999. Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann. Neurol. 46 (2), 224–233; Peden, A., McCardle, L., Head, M.W., Love, S., Ward, H.J., Cousens, S.N., et al., 2010. Variant CJD infection in the spleen of a neurologically asymptomatic UK adult patient with haemophilia. Haemophilia 16 (2), 296–304.

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D Fig. 94.4 Neuropathology of Prion Disease. A, In sporadic Creutzfeldt-Jakob disease (sJCD), some brain areas may have no (hippocampal end plate, left), mild (subiculum, middle), or severe (temporal cortex, right) spongiform change (hematoxylin and eosin [H & E] stain). B, Cortical sections immunostained for PrPSc in sJCD: synaptic (left), patchy/perivacuolar (middle), or plaque-type (right) patterns of PrPSc deposition. C, Large kuru-type plaque (H & E stain). D, Typical “florid” plaques in variant JCD (H & E stain). (Modified from Budka, H., 2003. Neuropathology of prion diseases. Br Med Bull. 66, 121–130. Copyright © 2003 Oxford University Press.)

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TABLE 94.3

Several Commonly Used Diagnostic Criteria for Probable sJCD

1998 WHO Revised 2007 UCSF Criteria Criteria (Geschwind (Geschwind et al., 2007; et al., 2007; WHO, 1998) Young et al., 2005) I. Clinical Features

Progressive dementia with two of the following: Myoclonus Visual or cerebellar disturbance Pyramidal/extrapyramidal signs Akinetic mutism

II. Diagnostic Test

Typical EEG* OR Elevated CSF protein 14-3-3 (with total disease duration < 2 years)

III. Other

1437

Routine investigations should not suggest an alternative diagnosis

2017 European Consortium (Hermann et al., 2018; UK National CJD Research & Surveillance Unit [NCJDRSU], 2017)

2009 European Consortium

Rapidly progressive dementia with Progressive dementia with two of the following: two of the following: Myoclonus Myoclonus Visual or cerebellar Visual disturbance disturbance Cerebellar signs Pyramidal or Pyramidal/ extrapyramidal signs extrapyramidal signs Akinetic mutism Akinetic mutism Focal cortical signal (e.g.: neglect, aphasia, acalculia, apraxia) Typical EEG*OR Typical EEG*OR Typical MRI† Elevated CSF protein 14–3-3 (with total disease duration 1 neocortical gyrus, ideally with sparing of the precentral gyrus and apparent diffusion coefficient map supporting restricted diffusion. (See Table 1 in Vitali et al., 2011.) UCSF MRI criteria were updated in 2017 (See Table 2 in Staffaroni et al., 2017.) ‡Typical MRI for European criteria: High signal abnormalities in caudate nuclear and putamen or at least two cortical regions (temporal-parietal-occipital, but not frontal, cingulate, insular or hippocampal) either on DWI or FLAIR MRI. Reproduced permission from Tee, B.L., Longoria Ibarrola, E.M., Geschwind, M.D., et al., 2018. Prion disease. Neurol Clin. 36 (4):865–897.

have faint synaptic PrPSc staining (Parchi et al., 1999b). Complicating matters is the fact that anywhere from six (Collins et al., 2006) to as high as 50% (Polymenidou et al., 2005) of sJCD cases have both type 1 and 2 prions (Puoti et al., 1999). The clinicopathological presentation of each patient with mixed types appears to depend in part on the relative ratio of these prion types (Collins et al., 2006; Polymenidou et al., 2005; Puoti et al., 2012). As shown in Table 94.2, heterozygosity at codon 129 in the prion gene PRNP is somewhat protective against prion disease. Additionally, a study from the UK Medical Research Council Prion Unit suggested that codon 129 alone affects rate of decline in sJCD independent of prion typing, with homozygosity (MM or VV) associated with faster decline than codon 129 heterozygosity (Thompson et al., 2013).

DIAGNOSIS OF CREUTZFELDT-JAKOB DISEASE Several criteria exist for the diagnosis of sJCD. Unfortunately, most patients will only fulfill existing criteria at later stages of the disease (Paterson et al., 2012), because most criteria are designed for epidemiological purposes, to ensure that all deceased, non-pathologically proven cases have a sufficient non-pathological diagnosis (Brandel, et al., 2000; WHO, 1998; Zerr et al., 2009). Thus, most epidemiological criteria designed for JCD surveillance do not allow diagnosis at early disease stages and are not very helpful when evaluating a patient early

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in the disease course. Criteria generally categorize patients by level of diagnostic certainty into definite, probable, and possible. Definite criteria require pathological evidence of the presence of PrPSc in brain tissue (by biopsy or autopsy) (Budka, 2003; Kretzschmar et al., 1996). Probable criteria usually require a positive ancillary diagnostic test (e.g., EEG, cerebrospinal fluid [CSF] marker, or brain MRI) in addition to certain symptoms. Several probable criteria are shown in Table 94.3. The most commonly used probable criteria are based on the World Health Organization (WHO) Revised Criteria (1998) and require dementia plus at least two of four clinical signs or symptoms, and positive ancillary test (Geschwind, 2015; WHO, 1998; Zerr et al., 2009). Pyramidal findings are motor abnormalities on neurological exam (e.g., hyperreflexia, focal weakness, extensor response). Extrapyramidal findings in sJCD typically include rigidity, slowed movement (bradykinesia), tremor, or dystonia, typically due to problems in the basal ganglia or its connections. Myoclonus is sudden quick jerking of a limb or the trunk that can be spontaneous or stimulus induced, often by loud noise. Akinetic mutism describes patients who are without purposeful movement and mute; this typically and it occurs at the very end stage of the disease. WHO 1998 possible JCD criteria are the same as for probable criteria but do not require the ancillary testing (WHO, 1998). Many patients will not meet WHO revised criteria for probable sJCD until late in the disease course (Hermann et al., 2018). Criteria utilizing brain MRI were proposed in 2007 (Geschwind, 2015;

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Fig. 94.5 A typical electroencephalogram in a sporadic Creutzfeldt-Jakob disease patient, with diffuse slowing and 1-Hz periodic sharp wave complexes (black arrows).

Geschwind et al., 2007), and, in 2009, modified European sJCD criteria also allowed inclusion of brain MRI (see later discussion) (Zerr et al., 2009) (see Table 94.3). To increase the diagnostic accuracy, especially at the early stages of sJCD, explicit details of MRI criteria (discussed in detail in next section) have been proposed and continue to be updated (Staffaroni et al., 2017; Vitali et al., 2011; Zerr et al., 2009). The German prion surveillance group recently proposed to ammend research diagnostic criteria to allow diagnosis of probable sJCD with either (1) progressive cognitive impairment or (2) one of the cardinal sJCD symptoms and a positive real-time quaking-induced conversion assay (RT-QuIC; see next section). Compared with WHO diagnostic criteria, this diagnostic criterion increased the sensitivity level of premorbid diagnosis from 74% to 97% among 65 definite sJCD individuals (Hermann et al., 2018). Thus, the more prion specific biomarkers such as RT-QuIC were incorporated into the 2009 and 2017 European sJCD criteria (see Table 94.3).

Diagnostic Tests for Sporadic Jakob-Creutzfeldt Disease A typical EEG in sJCD has sharp or triphasic waves (periodic sharp wave complexes, or PSWCs) occurring about once every second (Fig. 94.5); this EEG finding, however, is found in only about two-thirds of sJCD patients, typically only after serial EEGs and often not until later stages of the illness (Steinhoff et al., 2004; Zerr et al., 2000). The presence of PSWCs is very dependent on molecular classification; for example, they are found in 73% of MM1 and 53% of MV1 cases, but in only 12%–18% of MV2, VV2, and VV1/2 cases (Collins et al., 2006; Zerr et al., 2000). These EEG findings are relatively specific, but PSWCs are sometimes seen in other conditions including AD, Lewy body disease, toxic-metabolic and anoxic encephalopathies, PML, Hashimoto encephalopathy (Seipelt et al., 1999; Tschampa et al., 2001), and even voltage-gated potassium channel complex associated encephalopathy (Savard et al., 2016). The first CSF biomarker for sJCD diagnosis, the 14-3-3 protein, was proposed in 1996, but the clinical utility of this and other biomarkers is controversial, in part because of varying degrees of sensitivity and specificity reported. The 14-3-3 protein was one of the first CSF

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proteins touted as a diagnostic marker for JCD, but its utility is controversial (Chapman et al., 2000; Forner et al., 2015; Geschwind et al., 2003), particularly as it is elevated in many non-prion neurological conditions (Foutz et al., 2017; Satoh et al., 1999). This test is usually a Western blot that is read subjectively, or at best semiquantitatively, as positive, negative, or inconclusive. We believe that enzyme-linked immunosorbent assay (ELISA) tests, which provide quantitative values, are notoriously unreliable in the United States, although they have been reported to be very reliable in some other countries, including Germany (Hermann et al., 2018). The range of sensitivities in studies with 50 or more sJCD subjects vary from 51% to 95% (Castellani et al., 2004; Chohan et al., 2010; Collins et al., 2006; Forner et al., 2015; Hamlin et al., 2012; Ladogana et al., 2009; Sanchez-Juan et al., 2006; Zerr et al., 1998, 2000). Two larger European studies have found this protein to have a sensitivity and specificity of about 85%; the control patients, however, are probably not sufficiently characterized in some of these studies (Table 94.4) (Collins et al., 2006; Sanchez-Juan et al., 2006). Data from the US National Prion Disease Pathology Surveillance Center (NPDPSC) on 420 pathology-confirmed sJCD and non-prion cases in the United States found the sensitivity and specificity of the 14-3-3 Western blot to be only 74% and 56%, respectively (Hamlin et al., 2012). By restricting controls to pathology-proven cases, however, many studies exclude nonprion cases with clinical phenotypes that mimic JCD and often have elevated 14-3-3, but who eventually recover; these cases often include patients with strokes, seizures, autoimmune encephalopathies, and other conditions. Many dementia experts consider the 14-3-3 protein merely a marker of rapid neuronal injury that has poor specificity for sJCD (Chapman et al., 2000; Foutz et al., 2017; Geschwind et al., 2003; Hamlin et al., 2012; Satoh et al., 1999). Other potential sJCD CSF biomarkers include total-tau (t-tau), neuron-specific enolase (NSE), and the astrocytic protein S100β (Hamlin et al., 2012). The sensitivity and specificity of these biomarkers for sJCD vary greatly among studies. One large multicenter European study examined four CSF biomarkers: 14-3-3, t-tau, NSE, and S100β. As not

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TABLE 94.4 Calculated Sensitivities and Specificities of Various Biomarkers in sJCD Based on Literature Review SENSITIVITY (n) Definite

Definite + Probable§

Specificity (n)

EEG*

59.6% (2473)

59.7% (2488)¶

83.8% (99)

CSF Biomarkers 14-3-3 protein (WB) 14-3-3 protein (ELISA) Total tau NSE S100B RT-QuIC

86.7% (2675) 80% (55) 85.8% (618) 81% (42) 75.8% (442) 90.1% (455)

86.3% (4266) 89.6% (201) 85.9% (1489) 74.5% (644) 79.7% (1058) 88.9% (468)

88.1% (2209) 84.2% (183) 86.5% (1642) 93.5% (186) 85.7% (1293) 99.6% (498)

Nasal Mucosa† RT-QuIC Brain MRI DWI‡

97.9% (97) 98.2% (57)

97.3% (111) 94% (184)

100% (116) 93.8% (195)

For this table, we combined results from several papers to ascertain the sensitivities and specificities of various biomarkers in sJCD using published literature. *Typical EEG findings: Periodic sharp waves complexes. †Includes both olfactory mucosa brush and swab. ‡Only included literature based on DWI, not just T2 or FLAIR sequences. §Unclear whether possible sJCD were included in Sanchez-Juan et al. (2006). ¶Levy et al. (1986) was published prior to WHO diagnostic criteria, 15 cases were clinically diagnosed without autopsy. CSF, Cerebrospinal fluid; DWI, diffusion-weighted imaging; EEG, electroencephalography; ELISA, enzyme-linked immunosorbent assay; MRI, magnetic resonance imaging; NSE, neuron-specific enolase; RT-QuIC, real-time quaking-induced conversion; S100B, S100 calcium-binding protein B; WB, Western blot. References for each category were as follows:

EEG: Collins et al., 2006; Levy et al., 1986; Steinhoff et al., 2004; Zerr et al., 2000. 14-3-3 protein (WB): Beaudry et al., 1999; Collins et al., 2000, 2006; Hamlin et al., 2012; Hsich et al., 1996; Kenney et al., 2000; Sanchez-Juan et al., 2006; Van Everbroek et al., 2003; Zerr et al., 1998, 2000; Baldeiras et al., 2009; Castellani et al., 2004; Chohan et al., 2010; Forner et al., 2015; Geschwind et al., 2003. 14-3-3 protein (ELISA): Geschwind et al., 2003; Kenney et al. 2000; Matsui et al., 2011. Total Tau: Baldeiras et al., 2009; Chohan et al., 2010; Coulthart et al., 2011; Hamlin et al., 2012; Sanchez-Juan etal., 2006; Van EverBroek et al., 2003. NSE: Beaudry et al., 1999; Sanchez-Juan et al., 2006; Pocchiari et al., 2000. S100B: Beaudry et al., 1999; Sanchez-Juan et al., 2006; Baldeiras et al., 2009; Chohan et al., 2010; Coulthart et al., 2011. RT-Quic: Atarashi et al., 2011; Bongianni et al., 2017; Foutz et al., 2017; McGuire et al., 2012, 2016; Orru et al., 2014, 2015; Sano et al., 2013. Brain MRI: Forner et al., 2015; Shiga et al., 2004; Tian et al., 2010; Young et al., 2005

all patients were tested for all four biomarkers, nor were they necessarily tested using the same samples, this study did not allow proper comparison of these biomarkers. Nevertheless, they found the sensitivity and specificity of the 14-3-3 to be 85% and 84%, t-tau (cutoff > 1300 pg/mL) 86% and 88%, NSE 73% and 95%, and S100β 82% and 76%, respectively (Sanchez-Juan et al., 2006). A Canadian study, with 126 pathology-proven sJCD and 843 probable non-JCD cases, found CSF t-tau to be better than 14-3-3 and S100β (Coulthart et al., 2011). A study at our center similarly found CSF t-tau to be a better diagnostic marker than either 14-3-3 or NSE (Forner et al., 2015). The sensitivity and specificity of these CSF biomarkers in other forms of prion disease such as variant JCD and gPrD are usually much lower than for sJCD (Foutz et al., 2017; Hamlin et al., 2012; Sanchez-Juan et al., 2006). The ratio between T-tau and phosphorylated tau (T-tau/P-tau) also has been assessed as a diagnostic tool for sJCD, with reported sensitivities ranging from 63% to 94% and specificities ranging from 92% to 97% (Forner et al., 2015). Additional biomarkers, such as CSF and serum glial fibrillary acidic protein (GFAP) and serum neurofilament

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light chain (NfL), are also being evaluated for diagnosis and prognosis of prion diseases but are not yet in clinical practice. Given the nonspecificity of elevated NfL, it is unlikely to be used as a diagnostic marker but appears to show great potential as a prognostic marker in symptomatic prion disease (Kovacs et al., 2017; Staffaroni et al., 2019; Steinacker et al., 2016; Thompson et al., 2018; van Eijket al., 2010). Total-tau might be the best CSF non-prion diagnostic biomarker protein for sJCD, but it still is not close to the diagnostic utility of brain MRI (Forner et al., 2015; Shiga et al., 2004). Most of the above biomarkers are not testing for prions, PrPSc, but are markers of rapid neuronal injury and can be elevated in various acute or rapidly progressive neurological disorders (Geschwind, 2015, 2016; Lattanzio et al., 2017). The relatively new RT-QuIC test enables detection of prions by amplifying them. It works by first mixing the sample to be tested for prions with a substrate containing PrPC (usually either recombinantly-derived or from healthy rodent brain). Then, by continuous shaking, PrPSc in samples are brought into contact with PrPC, allowing conversion into PrPSc, which aggregates into

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amyloid fibrils. These amyloid fibrils will fluoresce when thioflavin T is added. The fluorescent signal can be read on an automated plate reader (Atarashi et al., 2011; McGuire et al., 2012, 2016). Currently, this technique is used to detect prions in several human tissues, including brain, CSF, olfactory mucosa, skin biopsies, all layers of the eye, and even extra-ocular muscle (Orru et al., 2017, 2018), but does not work with blood or blood-contaminated CSF (Cramm et al., 2016; Shi et al., 2013). The sensitivity of RT-QuIC in sJCD CSF varies greatly in the literature, but is most commonly reported to be about 85%. In our University of California, San Francisco (UCSF) sJCD cohort, sensitivity was only around 60%, with testing being performed at two independent laboratories (unpublished data). In contrast, the specificity of RT-QuIC is very high, with many studies reporting 98% or higher (Atarashi et al., 2011; Bongianni et al., 2017; Foutz et al., 2017; Franceschini et al., 2017; Lattanzio et al., 2017; McGuire et al., 2016). Thus, in our opinion, a negative test does not exclude disease, but a positive test in the appropriate clinical context has great diagnostic value. MRI has been shown to be highly sensitive and specific (91%– 96%) for diagnosing sJCD (Shiga et al., 2004; Vitali et al., 2011; Young et al., 2005). The first MRI abnormalities reported in JCD were basal ganglia hyperintensities on T2-weighted sequences (Gertz et al., 1988; Rother et al., 1992). Later, cortical gyral hyperintensities (Urbach et al., 1998) were identified, and found to be more evident on fluid-attenuated inversion recovery (FLAIR) than T2-weighted sequences, and most evident on diffusion-weighted imaging (DWI) sequences. These cortical hyperintensities are commonly referred to as cortical ribboning. DWI has higher sensitivity than FLAIR (Fujita et al., 2012; Vitali et al., 2011). Whenever JCD is suspected, a brain MRI that includes diffusion sequences (e.g., DWI, ADC, and, if possible, exponential ADC [eADC]) should be obtained (Staffaroni et al., 2017). Some typical MRI features on FLAIR, DWI, and ADC sequences in sJCD and vJCD are shown in Fig. 94.6. Unfortunately, many radiologists, even at academic centers, are still not familiar with the findings indicative of prion disease, and a majority of sJCD MRIs are misread (Carswell et al., 2012; Geschwind et al., 2010). Several MRI criteria for sJCD diagnosis have been proposed and modified or improved over the years (Staffaroni et al., 2017). MRI (particularly DWI and FLAIR sequences) was first included in sJCD diagnostic criteria (UCSF sJCD diagnostic criteria) in 2007 (Geschwind et al., 2007; Young et al., 2005). MRI was subsequently incorporated into European sJCD criteria in 2009 (Zerr et al., 2009) (see Table 94.3). We believe that these European criteria are a step forward but have several limitations. First, many patients in the study did not have DWI MRI sequences, and the criteria allow for FLAIR hyperintensities alone without requiring diffusion abnormalities. This is a problem because FLAIR abnormalities in prion disease are more difficult to detect and less specific than diffusion abnormalities for sJCD. For example, deep nuclei hyperintensities on T2-weighted/FLAIR sequences can be seen in many conditions other than JCD, including metabolic and autoimmune conditions (Rosenbloom et al., 2015; Vernino et al., 2002; Vitali et al., 2008a, 2008b). Second, T2/FLAIR or DWI hyperintensities in the frontal and insular cortices, cingulate, and hippocampus were excluded in European 2009 criteria because of the high levels of artifact found in these regions that resulted in many false positives. We have found, however, that these artifacts, which are usually due to CSF–brain interface, can often be avoided by acquiring MRIs in multiple planes (e.g., axial and coronal), using an attenuation diffusion coefficient (ADC) map to confirm the presence of restricted diffusion, and improving image quality using various

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proprietary methods, such as readout segmentation of long variable echo trains (RESOLVE) (Staffaroni et al., 2017). Unfortunately, the European 2009 MRI criteria neither require the use of DWI nor include the ADC map sequences to confirm true restricted diffusion. This is important because the DWI sequence is a combination of both T2 and diffusion, so a T2 shine-through effect can make certain regions appear bright on DWI despite normal diffusion. Especially when the deep gray nuclei (basal ganglia and/or thalamus) are involved in sJCD, the ADC map typically is hypointense and shows reduced levels of diffusion (Staffaroni et al., 2017; Vitali et al., 2011). Evidence suggests that the reduced diffusion on MRI in JCD is from restricted flow of water molecules inside vacuoles in the dendritic tree (Geschwind et al., 2009; Manners et al., 2009). Basic laboratory studies such as complete blood cell count (CBC), chemistry, liver function tests, erythrocyte sedimentation rate (ESR), antinuclear antibody (ANA), and so forth, are generally unremarkable in sJCD. CSF is typically normal with a mildly elevated protein (typically < 100 mg/dL). CSF shows normal red blood cells (RBCs) and white blood cells (WBCs). Pleocytosis (>10 WBCs), an elevated immunoglobulin (Ig)G index, or the presence of oligoclonal bands is unusual in sJCD and should lead to considering other conditions, particularly infectious or autoimmune disorders. As noted earlier, an EEG that is “typical” or classic for JCD has PSWCs (see Fig. 94.5), but often there is just slowing on EEG in sJCD. Variably protease-sensitive proteinopathy (vPSPr) is a recently described, although very rare, form of sJCD (Head et al., 2013; Puoti et al., 2012; Zou et al., 2010). One hallmark of prion diseases has been that part of PrPSc is resistant to proteases, but the degree of protease sensitivity of PrPSc is strain dependent (Safar et al., 1998). In vPSPr, the vast majority of patients’ PrPSc is protease sensitive, so standard immunohistochemical techniques that depend on identifying the protease-resistant core of PrPSc for diagnosis are insufficient (hence, the term “variably protease-sensitive”). Another key feature of vPSPr has been that when PrPSc is detected on Western blot, there is no diglycosylated PrPSc band, only the mono- and unglycosylated band, and there are also some smaller bands for a total of five bands (Xiao et al., 2013). The United States National Prion Disease Pathology Surveillance Center (US NPDPSC) and United Kingdom National JCD Surveillance and Research Unit (UK NCJCDSRU) estimated the prevalence of vPSPrs to be 0.7% and 1.7% respectively, among all sporadic PrDs (Notari et al., 2018; UK National CJD Research & Surveillance Unit (NCJDRSU), 2018). As of 2018, about 37 cases of vPSPr have been reported in the literature (Notari et al., 2018), although there are likely many more cases. The distribution of codon 129 genotype in vPSPr differs substantially from that of sJCDs, with ∼65% being VV, 24% MV, and 11% MM (Notari et al., 2018). The codon 129 genotype also appears to affect the clinical presentation, age of onset, and the electrophoretic profile on Western blot. Many of these cases presented with psychiatric symptoms, speech/language problems, and frontal lobe dysfunction (Puoti et al., 2012). Unlike other sporadic prion diseases, most had negative ancillary tests (MRIs, EEGs, and CSF 14-3-3), making diagnosis more challenging. Although their mean age was commensurate with classic sJCD (late 60s), their mean disease duration was much longer, at about 2.5 years (Gambeti et al., 2011; Head et al., 2013; Notari et al., 2018; Zou et al., 2010). As the awareness of the disease rises, the spectrum of presentation continues to widen, including reports of vPSPr presenting as amyotrophic lateral sclerosis (ALS)/ frontotemporal dementia (FTD) spectrum disorder (Cannon et al.,

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Fig. 94.6 Brain magnetic resonance images (MRIs) in sporadic Jakob-Creutzfeldt disease (sJCD) and variant Jakob-Creutzfeldt disease (vJCD). Brain MRI in 59-year-old woman with sJCD showing both cortical (solid arrows) and subcortical (dashed arrows) abnormalities on fluid-attenuated inversion recovery (FLAIR) (A), diffusion-weighted imaging (DWI) (B), and apparent diffusion coefficient (ADC) (C) sequences in sporadic Jakob-Creutzfeldt disease (sJCD). This MRI shows a common pattern in sJCD, including cortical gyral (“cortical ribboning”; solid arrows) and deep nuclei (dashed arrows) hyperintensities on FLAIR and DWI sequences and corresponding hypointensity on ADC sequences. The DWI hyperintensities with corresponding ADC hypointensity confirm that there is restricted diffusion of water molecules, which is found in more than 95% of sJCD cases. Note that as seen in most brain MRIs in prion disease when restricted diffusion is present, the hyperintensities are much more evident on DWI than on FLAIR sequences. Brain MRI in a 20-year-old woman with variant JCD (vJCD) showing, on FLAIR (D) and DWI (E) sequences, hyperintensity of bilateral thalamic hyperintensity in the mesial pars (mainly dorsomedian nucleus) and posterior pars (pulvinar) of the thalamus, sometimes called the double hockey stick sign, which can be seen in many prion diseases. Importantly, this MRI also shows the pulvinar sign, in which the posterior thalamus (pulvinar; dashed arrow) is more hyperintense than the anterior putamen; this sign has much higher specificity for vJCD compared to other forms of prion disease. (D and E) F ECF

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PRNP variants G127V

E219K

M129V

Y145X Q160X Y163X D178Efs25X 1

51

91

Octapeptide Repeat Region

β1

α1

α2

β2

α3

R148H V176G 2-OPRD P84S A117V 2-OPRI D167G P102L G114V 3-OPRI D167N 4-OPRI V180I P105L A133V 5-OPRI P105S 6-OPRI/6-OPRI D178N-129V T183A P105T G131V 7-OPRI/7-OPRI D178N-129M H187R 8-OPRI 365-388dup T188R 9-OPRI S132I T188K 12-OPRI

Y226X Q227X 231 253 GPI anchor signal

A224V P238S Y218N M232R Q217R I215V Q212P E211D E211Q V210I

T188A

Legend T193I R208H Mutation usually associated with genetic JCD K194E Mutation usually associated with GSS V203I E196K Mutation usually associated with FFI F198S D202N Nonsense mutation F198V D202G Risk polymorphism E200K Low or intermediate penetrance variants E200G Fig. 94.7 Schematic of Prion Protein Gene (PRNP) Disease-Associated Variants. Mutations are color coded based on clinicopathological classification as genetic Jakob-Creutzfeldt disease (JCD), Gerstmann-Sträussler-Scheinker (GSS), fatal familial insomnia (FFI), or nonsense mutations. PRNP mutations present in the UCSF cohort are in bold. Most mutations are shown below the gene schematic; nonsense mutations and polymorphisms associated with prion disease risk are above the gene schematic. Low or intermediate penetrance variants are based on Minikel et al. (2016) (not all low/intermediate penetrance variants are shown). For the F198V mutation, the clinical presentation was not classifiable as genetic JCD, GSS, or FFI, and neuropathology was not reported (Zheng et al., 2008). Variants that are probably benign (largely based on Minikel et al., 2016) are not included (e.g., G54S, P39L, E196A, R208C) (Beck et al., 2010; Minikel et al., 2016). OPRD, Octapeptide repeat deletion; OPRI, octapeptide repeat insertion. (Reproduced with permission from Takada, L.T., Kim, M.O., Cleveland, R.W., Wong, K., Forner, S.A., Gala, II, et al., 2017. Genetic prion disease: Experience of a rapidly progressive dementia center in the United States and a review of the literature. Am. J. Med. Genet. B Neuropsychiatr. Genet. 174 [1]:36–69.)

2014; Ghoshal et al., 2014; Vicente-Pascual et al., 2018). Such atypical features and varied presentations can make these cases difficult to diagnose.

Genetic Prion Disease Background on genetic prion disease Genetic forms of prion disease (gPrD) are caused by autosomal dominant pathogenic variants (i.e., mutations) in the human PrP gene, PRNP. More than 60 PRNP variants, mostly point mutations but some stop codons, insertions, and deletions, have been reported, but several of these are of low penetrance (e.g., less than 1%) and some are likely non-pathogenic (Kim et al., 2018; Minikel et al., 2016). Most PRNP variants considered as mutations are essentially 100% (i.e., fully) penetrant, meaning that a person with a mutation is virtually guaranteed to develop prion disease if they live a normal lifespan (Kim et al., 2018; Mead, 2006; Takada et al., 2017, 2018). Diagnosis of gPrD is made by identification of a pathogenic variant in PRNP. For a variant to be considered pathogenic, it should fulfill published guidelines for considering a variant to be causal for a disease (MacArthur et al., 2014; Richards et al., 2015) (Fig. 94.7 and Fig. 94.2). Based on a study combining data from nine prion disease surveillance centers, 85% of gPrDs are

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attributed to five mutations‒‒E200K, V210I, V180I, P102L, D178N; with the first three presenting as JCD, P102L presenting as GSS and D178N as either CJD or FFI (Kim et al., 2018; Minikel et al., 2016; Takada et al., 2017). Several PRNP variants reported to be mutations in some literature, such as V210I, V180I, and M232R, have higher than expected prevalence in the general population and most carriers lack a family history of prion or other neurodegenerative disease. The penetrance of these three variants is estimated to be 10%, 1%, and 0.1%, respectively (Kim et al., 2018; Minikel et al., 2016; Takada et al., 2017). It usually is easiest to test for PRNP from blood (or saliva) while a patient is still alive; alternatively, in some countries, JCD surveillance centers can extract DNA from frozen brain autopsy tissue and sequence PRNP in order to identify variants (Kim et al., 2018). gPrDs are sometimes referred to as familial, but this term can be a misnomer because a family history is not always present or known. In a large European study, 47% of patients ultimately shown to have a PRNP variant causing gPrD did not have positive family history of dementia or prion disease. It is possible that this was because relatives were misdiagnosed or there was reduced penetrance of the PRNP variant or, less likely, that they were de novo mutations (Kovacs et al., 2005).

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CHAPTER 94 Prion Diseases Although gPrDs historically were divided according to their clinical and pathological characteristics into familial JCD (fJCD), GSS, and FFI, this classification was developed prior to the discovery of PRNP. It is clear that several PRNP mutations such as H187R, the octapeptide insertion (OPRI) mutations, octapeptide deletion, and stop codon mutations do not fit into one of these three historical categories (Kim et al., 2018). Most PRNP mutations are associated with fJCD, more than a dozen are associated with GSS, and only the D178N PRNP mutation (usually with codon 129 cis methionine) results in FFI. Most forms of fJCD usually present clinically and pathologically as an RPD similarly to sJCD. GSS usually presents as a more slowly progressive ataxic, parkinsonian disorder often with dementia somewhat later in the course. FFI usually begins with dysautonomia and insomnia; motor and cognitive dysfunction usually appear later in the disease course. These are described in greater detail below. Many cases with PRNP mutations that can present as either fJCD or GSS, such as many of the OPRI mutations (discussed below), have features that blend these two phenotypes. Most PRNP mutations result in a younger age of onset (typically 40s–60s) than sJCD (Kim et al., 2018; Mead, 2006). Typically, however, there is great variability in clinical presentation and disease course within a PRNP mutation; in fact, even within a gPrD family, there can be great clinical variability (Takada et al., 2017, 2018; Webb et al., 2008). Several PRNP polymorphisms have been identified that affect one’s risk for developing non-genetic forms of prion disease and may also affect the way genetic and non-genetic PrD present. The most important polymorphism is at codon 129, which can be either a methionine (M) or valine (V) see Figs. 94.2 and 94.7 and Table 94.2). Although many older studies suggest that codon 129 can affect the age of onset in many gPrD mutations, a very comprehensive study suggests that codon 129 does not have this effect (Minikel et al., 2016), but it often affects the rate of disease progression as shown in sJCD (Mead et al., 2016). Regarding how PRNP variants lead to gPrD, it is presumed that a mutation results in a protein PrPMUT that is more susceptible to misfolding and changing conformation into the abnormally shaped, disease-causing form, PrPSc (see above discussions for more about prion proteins PrPC and PrPSc) (van der Kamp & Daggett, 2010). Presumably the nascent PrPMUT maintains a normal conformation for most of a patient’s life and does not begin transforming shape into PrPSc until a patient gets older, which is why the disease usually does not occur until adulthood. Alternatively, and possibly more likely, some transformation of PrPMUT into PrPSc occurs throughout life, with small amounts of PrPSc being removed by normal cellular protein degradation pathways but, due to the aging process, the cellular pathways for clearing out misfolded proteins do not work as efficiently. The increasing accumulation of PrPSc causes transformation of nascent PrPMUT and PrPC (from the normal PRNP allele) into PrPSc in an exponential manner, resulting in disease (Kim et al., 2018; Kong et al., 2004; Prusiner, 1998) (see Fig. 94.1).

Familial Jakob-Creutzfeldt Disease More than 20 PRNP missense variants (P105T, G114V, R148H, D178N (with codon 129 cis V) V180I, T183A, T188A, T188K, T188R, T193I, K194E, E196A, E196K, E200K, E200G, V203I, R208H, V210I, E211Q, I215V, A224V, M232R, and P238S), an insertion, and octapeptide repeat insertions (OPRI) with four or fewer 24-base-pair repeats typically present as fJCD (although often there is a great phenotypic variability in OPRI variants). Most of these patients present similarly to sJCD, often with overlapping clinical, MRI, and EEG findings. The E200K variant, causing an fJCD presentation, is the most common

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pathogenic PRNP variant worldwide (Kim et al., 2018; Kong et al., 2004; Mead, 2006). Several other reported PRNP variants are shown above the PrP gene in Fig. 94.7.

Gerstmann–Sträussler–Scheinker Disease Gerstmann-Sträussler-Scheinker disease was first reported by Dimitz in 1913 (Dimitz, 1913), followed shortly after by Gerstmann in 1928 and 1936 (Gerstmann, 1928; Gerstmann et al., 1936). They described a dominantly inherited neurological illness that occurred in members of an Austrian family that presented initially with cerebellar ataxia followed by gait difficulty, speech and swallowing problems, nystagmus, pathological reflexes, and behavioral and cognitive changes (Dimitz, 1913; Gerstmann, 1928; Gerstmann et al., 1936). In 1980, Schlote et al. first introduced the name Gerstmann-Sträussler-Scheinker disease (GSS) based on the author names of early literature (Schlote et al., 1980). Subsequent neuropathological studies showed presence of prion amyloidosis, in which prions often form large uni- or multicentric prion amyloid plaques in the brain parenchyma and/or have a prion cerebral amyloid angiopathy (CAA), with or without coexisting spongiform changes (Schlote et al., 1980; Seitelberger, 1962, 1981). These large prion amyloid plaques were initially called “kuru plaques” and considered a nearly pathognomonic neuropathology feature that separates GSS from most other prion diseases. Nonetheless, these plaques are also seen in a minority of sJCD cases, albeit more sparsely (see Fig. 94.4) (Parchi et al., 1990b; Wadsworth et al., 2006), and differ from the florid plaques of variant JCD (Sikorska et al., 2008) (see later discussion and Fig. 94.4). As the common pathological feature is PrP amyloid deposition, some experts adopted the umbrella term “dominantly inherited PrP cerebral amyloidosis” to describe various clinical syndromes that have autosomal dominant PRNP mutations and PrP amyloid plaques in the brain (Ghetti et al., 2018). Typically, these patients present as GSS clinical syndrome, which is commonly described as subacute progressive ataxia, parkinsonism, and behavioral changes, followed by cognitive impairment at the later stages, similar to that described by Gerstmann et al. (Ghetti et al., 2018). Some patients with dominantly inherited PrP cerebral amyloidosis, however, can present with psychosis and cognitive decline or even syndromes mimicking Alzheimer disease (AD) or FTD. The age of clinical symptom onset ranges widely, from the teens to the seventies (Ghetti et al., 2018). In 1989, three PRNP variants P102L (Hsiao et al., 1989) and two ORF insertions (Collinge et al., 1989; Owen et al., 1989) were identified in three families with GSS. Since then, at least 24 PRNP mutations have been shown to cause dominantly inherited PrP cerebral amyloidosis, including 19 missense mutations (P84S, P102L, P105L, P105S, P105T, A117V, G131V, S132I, A133V, R136S, V176G, H187R, F198S, D202N, E211D, Q212P, Q217R, Y218N, and M232T), at least five stop codon mutations (Y145X, Q160X, Y163X, Y226X, and Q227X; see below) and several OPRIs (see Fig. 94.7) (Ghetti et al., 2018; Jansen et al., 2010, 2011; Kim et al., 2018; Kong et al., 2004). OPRI mutations with a higher number of repeats typically present as GSS, but there are many exceptions and considerable phenotypic variability within and between OPRI mutations and even within OPRI families (OPRIs discussed in more detail below) (Giovagnoli et al., 2008; Kim et al., 2018; Kong et al., 2004; Mead et al., 2006). Although stop codon mutations are prion amyloidoses and have some overlapping features with GSS, they are distinct and, thus, are discussed in a separate section below. Most reports suggest that the PRNP codon 129 polymorphism modifies the clinical phenotype and neuropathological features of dominantly inherited PrP cerebral amyloidosis, which make it important to consider codon 129 genotype in combination

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with PRNP mutations (Collinge, 2001; Dlouhy et al., 1992; Furukawa et al., 1995; Ghetti et al., 2018). Most dominant inherited PrP cerebral amyloidosis have longer disease duration than sJCD or many other gPrDs, ranging from a few months to 15 years or more (Kim et al., 2018). Thus, these patients sometimes are incorrectly diagnosed with other neurodegenerative conditions, such as multiple system atrophy (MSA), spinocerebellar ataxias, idiopathic PD, AD, or even Huntington disease (see Table 94.1) (Collinge et al., 1992; Kim et al., 2018). Less commonly, patients with mutations typically associated with GSS can have an fJCD-like presentation (similar to typical sJCD), with a rapidly progressive course leading to death within a few months from onset (Liberski, 2012). GSS generally has a distinct neuropathology from most other prion diseases, with large PrPSc amyloid plaques called kuru plaques. These plaques also are seen in a minority of sJCD cases, albeit more sparsely (see Fig. 94.4) (Parchi et al., 1999b; Wadsworth et al., 2006), but differ from the florid plaques of variant JCD (Sikorska et al., 2008) (see later discussion and Fig. 94.4). The amyloid deposits seen in GSS contain fragments of PrPSc (see Fig. 94.2). Because of the large deposits of prion amyloid in GSS, it might be possible to detect these pathological changes noninvasively prior to clinical onset through the use of amyloid-binding agents such as 2-(1-(6-[(2-[18F] fluoroethyl) (methyl) amino]-2-naphthyl) ethylidene) malononitrile ([18F]FDDNP) and PET scans (Kepe et al., 2010).

Fatal Familial Insomnia FFI usually starts with progressively worsening insomnia and dysautonomia. Autonomic symptoms often include tachycardia, hyperhidrosis, and hyperpyrexia. Progressive insomnia is often accompanied by disruption of circadian rhythm and is eventually associated with hallucinations. Importantly, insomnia is not unique to FFI; many other prion diseases, including sJCD, also can have early and/or prominent insomnia. Cognitive and motor deficits typically develop later in the disease course. FFI is caused by a single PRNP missense variant, D178N, usually with codon 129 M on the same chromosome (cis) (see Fig. 94.7). Persons with D178N but cis codon 129 V usually present with fJCD, not FFI. Age of onset is similar to sJCD, but most FFI patients survive slightly longer, about 18 months. Although brain MRI, including diffusion imaging, is usually normal, fluorodeoxyglucose (FDG)-PET imaging reveals thalamic and cingulate hypometabolism, often even before disease onset (Cortelli et al., 2006). Neuropathology of FFI includes profound thalamic gliosis and neuronal loss causing atrophy. Involvement of regions outside of the thalamus is greater in FFI with codon 129 MV than with MM (Budka, 2003; Cortelli et al., 2006, 2007).

Octopeptide Repeat Insertions The prion protein is normally composed of 253 amino acids. In the N-terminal domain, there is an unstable repeat region consisting of a nonapeptide repeat (Pro-Gln-Gly-Gly-Gly-Gly-Trp-Gly-Gln), termed R1, followed by four nearly identical octapeptide repeats (Pro-HisGly-Gly-Gly-Trp-Gly-Gln). Some of the octapeptide repeats, however, have slightly different nucleotide sequences, and thus are termed R2, R3, and R4 to differentiate them (Hansen et al., 2011). Insertions of two or more octapeptides (OPRIs) and a deletion of two octapeptides (OPRD) have been associated with gPrD (Capellari et al., 2002; Kim et al., 2018; Takada et al., 2017). Two functional studies suggest that OPRIs, unlike other PRNP pathogenic variants, do not necessarily lead to protein conformational change, but rather result in PrPC that is more protease resistant and prone to aggregation, which in turn facilitates the formation of PrPSc (Moore et al., 2006; Priola & Chesebro,

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1998). Literature suggests that individuals with one to four additional OPRIs often present clinically as sJCD and tend to have a mid-late adulthood age of onset and short clinical course. In contrast, individuals with five to seven OPRIs first manifest symptoms around their early to mid-adulthood with more variable presentations and lengthier disease course (Croes et al., 2004; Kim et al., 2018). Those with eight or more additional octapeptide repeats more commonly manifest as a GSS phenotype (Gambetti et al., 2003). As with many other gPrDs, particularly those causing GSS or other slower forms of PrD, OPRIs rarely show typical sJCD findings on EEG, MRI, or CSF surrogate biomarkers (e.g., 14-3-3, NSE and total tau) (Kim et al., 2018; Takada et al., 2017).

PRNP Nonsense Mutations Pathogenic PRNP nonsense variants (stop codons) are very rare, and only a few families have been reported. Reported pathogenic nonsense variants (stop codons) occur at the C terminal of PrPC at codon 145 or higher and cause premature translational cessation, resulting in a truncated protein (Guerreiro et al., 2014; Minikel et al., 2016). Nonsense variants tend to present quite differently than other PRNP mutations. They often have relatively early onset (20s–50s) with long disease durations, ranging from 1 year to more than 3 decades. Early cognitive impairment and personality changes are common, and patients with nonsense variants can have phenotypes resembling AD or FTD. Other common early features include chronic diarrhea, other gastrointestinal upset, dysautonomia, and/or sensory neuropathy (Fong et al., 2017; Ghetti et al., 1996; Jayadev et al., 2011; Kim et al., 2018; Mead et al., 2013; Takada et al., 2017). It is not known if these stop codon variants are fully penetrant, but there have been cases in which parent carriers of symptomatic children are asymptomatic (Fong et al., 2017). Based on the available limited data, codon 129 in PRNP does not appear to play a role in age of onset (Kim et al., 2018). Interestingly, on autopsy, most of the reported cases were found to have PrPSc-amyloid plaques, PrPSc amyloid angiopathy, and tau containing neurofibrillary tangles (Finckh et al., 2000a, 2000b; Ghetti et al., 1996; Jansen et al., 2010; Mead et al., 2013; Owen et al., 1989), suggesting a link between prionopathies and tauopathies.

Conclusions Regarding gPrD Confirmation of a known pathogenic PRNP variant in a patient with neurological symptoms consistent with the known presentation of a known clinical syndrome (e.g., fJCD, GSS, or FFI) generally is sufficient for diagnosis of gPrD. Pathology of gPrDs can aid in the diagnosis, but pathology alone often is insufficient for ascertaining that the diagnosis is definitively of a genetic etiology. GSS and FFI have rather distinct pathologies, but testing for a PRNP mutation after appropriate genetic counseling is important, particularly because many gPrD cases do not have a clearly positive family history and/or appear clinically similar to sJCD (Goldman et al., 2004).

Acquired Prion Disease

Background on Acquired Prion Diseases Acquired forms of prion disease occur because of the transmissibility of prions (Brown et al., 1994). Although considered infectious, prion diseases are not as easy to transmit as many other infectious diseases such as respiratory-transmitted pathogens (e.g., certain viruses or Mycobacterium tuberculosis) or through exposure to bodily fluids (e.g., human immunodeficiency virus [HIV] and hepatitis). A relatively large amount of prions (probably several thousand proteins) are necessary to transmit prion disease. Thus, human prion diseases are not contagious; physical contact and

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CHAPTER 94 Prion Diseases even intimacy are not known to transmit prions between persons. Acquired prion diseases include kuru (now essentially extinct but at one time occurring among the Fore tribe in Papua New Guinea as a result of endocannibalism), iatrogenic JCD (iJCD), and the highly publicized variant JCD (vJCD), occurring primarily in the United Kingdom and France and caused by consumption of beef contaminated with bovine spongiform encephalopathy (BSE, or mad cow disease) (Collinge et al., 2006; Will, 2003; Will et al., 2000). Kuru, one of the first identified forms of transmitted human prion disease, is a neurodegenerative disease of the Fore ethnic group of the central highlands of Papua New Guinea. In the Fore language, kuru means “to shake or tremble.” It was transmitted through a practice in which deceased relatives were honored by ritualized endocannibalism. Although it is not known how this disease began, it was presumably through cannibalism of a person with sJCD. Because women and children consumed the less-desirable tissues, including brain and spinal cord, which contained higher levels of prions, they were more likely than adult males to contract prion disease (Gajdusek et al., 1996). The disease was essentially eliminated with the cessation of ritual cannibalism several decades ago; rare cases have occurred recently, however, suggesting an incubation period as long as 50 years or more (Collinge et al., 2006), particularly in those who are heterozygous at codon 129 in PRNP. The fact that heterozygotes have longer incubation periods could suggest a similar phenomenon might occur with vJCD (see later discussion). Genetic risk factors, and more recently protective alleles, have been identified in the Fore population (Mead et al., 2009).

Iatrogenic PrD Approximately 400 cases of iJCD have occurred from the use of cadaveric-derived human pituitary hormones, dura mater grafts,

corneal transplants, reuse of cleaned and sterilized EEG depth electrodes implanted directly into the brain, other neurosurgical equipment, and blood transfusion (Aarsland et al., 2005; Brown et al., 2000, 2006, 2012; Tullo et al., 2006; Will, 2003) (Table 94.5). Because the prion is a protein, not a virus or bacterium, it is not susceptible to typical decontamination methods that would inactivate such microorganisms (see Prion Decontamination) (BellingerKawahara et al., 1987a, 1987b; Prusiner, 1998). This difficulty in inactivating prions has, in part, led to transmission of prion disease between patients. Most of the pituitary-derived (mostly human grown hormone and some gonadotrophin) cases occurred from contaminated batches in France, the United Kingdom, and the United States. As of 2012, 226 cases related to human growth hormone and four cases from gonadotrophins had been reported (Brown et al., 2012), but cases with long incubation periods continue to develop from exposures decades ago (Maddox et al., 2020). These patients typically present with a cerebellar dysfunction (Appleby et al., 2013; Brown et al., 2012). Methods have since been instituted to prevent prion transmission through such hormones (Brown et al., 2006). In the United States, pituitary hormone recipient patients exposed to JCD were informed of their potential risk for developing prion disease, whereas this was not always the case in other countries. As of 2012, the incubation period was estimated to be a mean of 17 years, which varies between countries, with a range of 5–42 years (Brown et al., 2012). As of 2013, 228 cases of iJCD have been linked to exposure to contaminated batches of dura mater (mostly Lyodura brand), with a majority (154 as of 2017) of cases occurring in Japan (Ae et al., 2018; Brown et al., 2012). These exposures stopped after 1987, the year when a sodium hydroxide disinfection step was added to the processing protocol (Brown et al., 2000; Brown et al., 2006; Brown et al., 2012). New cases from remote past exposure continue to be

TABLE 94.5

Iatrogenic Jakob-Creutzfeldt Disease Cases Through July 2017

Transmission Source

Case Number

Countries Reported Mean Incubation Period Cases in Years (Range) Clinical Signs

Growth hormone

238

Cerebellar

Gonadotrophins hormone Dura mater grafts

4

Majority in France, United 17 (5–24) Kingdom and United States Australia 13.5 (12–16)

Cerebellar, visual, dementia

Corneal transplant

2

Japan, France, Germany, 12 (1.3–30) Spain, United Kingdom, Australia, Canada, Italy, and United States in descending order United States, Germany 15.75 (1.5–30) United Kingdom and France Switzerland United Kingdom

Visual, dementia, cerebellar Dementia, cerebellar Psychiatric, sensory, dementia, cerebellar

238

Neurosurgical instru4 ments Brain depth electrodes 2 Packed red blood cells 3*

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1.6 (1.4–2.2) 1.5 (1.3–1.7) 7.53 (6.5–8.3)

References Bonda et al. (2016), Brown et al. (2013), UK National CJD Surveillance Unit (2018) Cochius et al, (1990, 1992), Healy and Evans (1993) Bonda et al. (2016), Centers Disease Control (CDC, 1987)

Cerebellar

Dementia, cerebellar

Hammersmith et al. (2004), Heckmann et al. (1997), Maddox et al. (2008) el Hachimi et al. (1997), Will and Matthews (1982) Bonda et al. (2016), Brown et al. (2000) Llewelyn et al. (2004), Peden et al. (2004), Wroe et al. (2006)

*This does not include the two asymptomatic vJCD cases (Brown et al., 2000; Collins et al., 2006; Garske and Ghani, 2010; Knight, 2010, 2017; Parchi et al., 1999; Peden et al., 2004, 2010). Data adapted from Brown, P., Brandel, J.P., Sato, T., Nakamura, Y., MacKenzie, J., Will, R.G., et al., 2012. Iatrogenic Creutzfeldt-Jakob disease, final assessment. Emerg. Infect. Dis. 18 (6), 901–907. https://doi.org/10.3201/eid1806.120116 and Bonda, D.J., Manjila, S., Mehndiratta, P., Khan, F., Miller, B.R., Onwuzulike, K., et al., 2016. Human prion diseases: surgical lessons learned from iatrogenic prion transmission. Neurosurg. Focus. 41 (1), E10. https://doi.org/10.3171/2016.5.FOCUS15126; Table published with permission from Tee, B.L., Longoria Ibarrola, E.M., Geschwind, M.D., et al., 2018. Prion disease. Neurol. Clin. 36 (4), 865–897.

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identified worldwide, however (Iwasaki et al., 2018; Van Iseghem et al., 2019). Symptoms typically include dementia with cerebellar and visual dysfunction. The mean incubation period is about 12 years, with a range of 1.3 to at least 30 years (Ae et al., 2018; Brown et al., 2012; Van Iseghem et al., 2019). Six iJCD cases have been linked to neurosurgical procedures (including two EEG depth electrodes) and at least two to corneal implants (Brown et al., 2012). A few other cases might have occurred through neurosurgical or other surgical procedures, but in such cases it is often difficult to determine whether a case is iatrogenic or sporadic (Brown et al., 2006). Although it appears that the number of iJCD cases is declining, prion contamination still occurs, despite World Health Organization (WHO) and other recommended practices for managing potential prion-contaminated tissues, leaving patients at risk for iJCD. Improved identification of prion disease should help prevent future iJCD cases, but cases will likely be missed by screening, and, thus, strict application of efficient decontamination procedures is still critical to prevent transmission. Unfortunately, the true risk of iJCD is still unknown; many of the decontamination procedures tested were based on models using animal prions, which appear easier to decontaminate than human prions (Peretz et al., 2006). Rather than trying to decontaminate neurosurgical equipment used during surgery on potential or suspected prion subjects, some medical centers dispose of all such equipment through incineration rather than take the risk of reusing it (UCSF Medical Center, 2012). The most recently identified form of iJCD has been the transmission of vJCD through blood products (Ironside, 2012) (see next section).

Variant Jakob-Creutzfeldt Disease Perhaps the most notorious form human PrD is variant JCD, first identified in 1995 (Will et al., 1996). There is strong epidemiological and experimental evidence that it is caused by inadvertent ingestion of beef contaminated with BSE (mad cow disease) or, in a few cases, blood or blood product transfusion from asymptomatic carriers of vJCD (Diack et al., 2014; Ironside, 2012; Knight, 2017; Zou et al., 2008). It is believed that BSE occurred through the practice of feeding scrapie-infected sheep products to cattle (Bruce et al., 1997; Scott et al., 1999; Wilesmith et al., 1988). In general, vJCD differs from sJCD in several ways. Patients with vJCD generally are much younger, with a median age of around 27 (range 12–74) and almost all cases have occurred in persons younger than age 50. The mean disease duration is longer, about 14.5 months, versus about 7 months for sJCD. As of 2017, 231 cases had been identified worldwide (Knight, 2017). Although psychiatric symptoms often occur early in sJCD (Rabinovici et al., 2006; Wall et al., 2005), in vJCD profound psychiatric symptoms are often the initial symptoms for several months before obvious neurological symptoms begin. A relatively unique symptom in vJCD is persistent painful paresthesias in various parts of the body. The EEG only rarely shows the classic PSWCs and then only at the end stage of disease (Binelli et al., 2006). Brain MRI often shows the “pulvinar sign,” in which the pulvinar (posterior thalamus) is brighter than the anterior putamen on T2-weighted or DWI MRI (Collie et al., 2003) (see Fig. 94.6); this finding is rare in other human prion diseases (Haik et al., 2002; Martindale et al., 2003; Petzold et al., 2004; Zeidler et al., 2000). Diagnostic criteria for probable vJCD are shown in Table 94.6 (Heath et al., 2010). Although several features of vJCD overlap those of sJCD, vJCD’s younger age of onset, MRI findings, prominent early psychiatric features, persistent painful sensory symptoms, and movement disorder such as chorea might help differentiate these conditions.

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Definitive diagnosis of vJCD is based on neuropathological evidence of the variant form of PrPSc in brain biopsy or autopsy. Because vJCD is typically acquired peripherally, PrPSc can be found in the lymphoreticular system, including tonsillar tissue (Will, 2004). Brain pathology of vJCD typically shows abundant PrPSc deposition; multiple fibrillary PrP plaques surrounded by a halo of spongiform vacuoles, often referred to as “florid” plaques; other PrP plaques; and amorphous pericellular and perivascular PrP deposits, which are especially prominent in the cerebellar molecular layer. The florid plaques are called such because they have the appearance of a flower with a dense center and surrounding ring of vacuoles, and are considered pathognomonic for vJCD (Budka, 2003) (see Fig. 94.4). The Western blot characteristics of vJCD PrPSc also differ from those seen in other forms of prion disease; in vJCD, they are called type 2B, which have a 19-kD unglycosylated (lower) band and a prominent diglycosylated (upper) band (Ironside, 2012; Will, 2004; Will et al., 2000). As of July 1, 2019, 228 probable or definite cases of vJCD had been documented, almost all in the United Kingdom (U.K.) (UK National CJD Research & Surveillance Unit, 2019). France has the

TABLE 94.6 Current Diagnostic Criteria for Variant Creutzfeldt-Jakob Disease Definite: IA and neuropathological confirmation of vJCD* Probable: I and 4/5 of II and IIIA and IIIB; or I and IV Possible: I and 4/5 of II and IIIA I Progressive neuropsychiatric disorder Duration of illness > 6 months Routine investigations do not suggest an alternative diagnosis No history of potential iatrogenic exposure No evidence of a familial form of TSE II Early psychiatric features† Persistent painful sensory symptoms‡ Ataxia Myoclonus or chorea or dystonia Dementia III EEG does not show the typical appearance of sporadic JCD§ in the early stages of illness Bilateral pulvinar high signal on MRI scan IV Positive tonsil biopsy¶ *Spongiform change and extensive prion protein deposition with florid plaques throughout the cerebrum and cerebellum. †Depression, anxiety, apathy, withdrawal, delusions. ‡Includes frank pain and/or dysesthesias. §The typical appearance of the EEG in sporadic JCD consists of generalized triphasic periodic complexes at approximately 1 per second. These may occasionally be seen in the late stages of vJCD. ¶Tonsil biopsy is not recommended routinely nor in cases with EEG appearances typical of sporadic JCD but may be useful in suspect cases in which the clinical features are compatible with vJCD and MRI does not show bilateral pulvinar high signal. EEG, Electroencephalography; MRI, magnetic resonance imaging; TSE, transmissible spongiform encephalopathy; vJCD, variant JakobCreutzfeldt disease. Modified from Heath, C.A., Cooper, S.A., Murray, K., Lowman, A., Henry, C., MacLeod, M.A., Will, R.G., 2010. Validation of diagnostic criteria for variant Creutzfeldt-Jakob disease. Ann. Neurol. 67 (6), 761–770.

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second highest number of vJCD cases (n = 27), which probably have the same origin as those in the U.K. (Brandel et al., 2009). No cases of vJCD are thought to have been acquired in the Western Hemisphere; the six vJCD cases identified in North America—four patients in the United States and two in Canada are believed to have acquired it elsewhere (Coulthart et al., 2016; Maheshwari et al., 2015; UK National CJD Research & Surveillance Unit, 2019). Three of the North American cases were born and raised in the Saudi Arabia and are believed to have been exposed to BSE-contaminated beef there (Coulthart et al., 2016). The peak of the vJCD epidemic was in 2000, although it is not known whether other peaks will occur, particularly in persons with different genetic susceptibility to vJCD or iatrogenically through blood products (Andrews, 2010). A few studies have assessed the presence of latent vJCD in the UK and found it to be much higher than expected. In the first large study, researchers found vJCD prions by immunostaining in 3 of 11,246 appendix samples collected from 1995 to 2000, for an incidence of about one in 4,000. Another similar study, the National Anonymous Tonsil Archive, found one positive sample among a subset of 9,160 tested (de Marco et al., 2010; Garske & Ghani, 2010). A larger and more definitive follow-up study analyzing 32,441 anonymized appendix samples found an incidence of about 1 in 2000, double the previous estimate. About half of these positive appendix cases were homozygous for valine or heterozygotes at codon 129 in PRNP, unlike most affected vJCD cases who are methionine homozygous (Gill et al., 2013). Thus, it is estimated that as many as 1 in 2000 persons in the UK population are asymptomatic carriers with vJCD prions in their lymphoreticular system (subclinically infected). For these carriers, it is not clear if they will ever develop vJCD or if and when they will be infectious and passing it on to others, such as through medical/ surgical procedures or blood products (Salmon, 2013). As of 2019, four patients had acquired vJCD infection through non-leukodepleted (WBCs removed) blood transfusions received before 1999; three patients (all codon 129 MM) had probable or definite vJCD, with incubation periods of about 6–8.5 years (Health Protection Agency, 2007; Llewelyn et al., 2004; Wroe et al., 2006). The fourth patient (heterozygous, MV, at codon 129) died from non-neurological causes five years after receiving a contaminated blood transfusion but at autopsy was found to have prions in his lymphoreticular system (Peden et al., 2004). Lastly, a 73-year-old male patient with hemophilia and no history of neurological disease, who was heterozygous (methionine/valine) at codon 129 and had received more than 9000 units of factor VIII concentrate prepared from plasma pools known to include donations from a vJCD-infected donor, was found at autopsy to have vJCD prions in his spleen (Peden et al., 2010). It is not known whether these latter two pre-clinical patients would have ever developed vJCD through spread to the brain or would have simply survived as carriers and possible reservoirs for vJCD (Garske & Ghani, 2010). A graph of presumed vJCD cases in the U.K. is shown in Fig. 94.8. As Fig. 94.8 shows, the number of cases has been very low over the past several years—at five or fewer per year, with the last death UK in 2016, in the U.K. There is great concern that, however, future cases of vJCD might occur iatrogenically through transfusion of blood products or because many exposed persons, particularly with codon 129 MV or VV polymorphism, might have longer incubation times. These asymptomatic carriers of vJCD might pose the greatest risk for spread of vJCD through transfusion of blood products or invasive procedures. Of great concern is that infected asymptomatic vJCD donors, who eventually became symptomatic, had transmitted the disease about 1.5–3.5 years before they became symptomatic (Health Protection Agency, 2007).

UK

France

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Spain Taiwan Netherlands Portugal Fig. 94.8 Incidence of Death Due To Variant Creutzfeldt-Jakob Disease (vCJD) Worldwide Between the Years 1995 and 2018. vCJD cases (n = 231) are color coded by the countries that diagnosed and reported cases. Not all cases contracted disease in the same country in which they were diagnosed and/or died (see text). (Courtesy National CJD Surveillance Unit, Edinburgh, UK.) Note, vCJD = vJCD.

Prion Properties of Other Neurodegenerative Diseases Numerous neurodegenerative diseases—including Alzheimer disease (AD), MSA, Parkinson disease (PD), dementia with Lewy bodies (DLB), FTD, ALS, and Huntington disease (HD)—have been described to exhibit prion-like features (Krejciova et al., 2019; Scheckel & Aguzzi, 2018). This is because the pathogenic proteins of these neurodegenerative diseases—specifically Aβ-amyloid, tau, synuclein, TDP 43, and huntingtin—tend to exist in the form of aggregated oligomeric or polymeric proteins that are folded into β-sheet structure and stacked into amyloid fibrils (Annus et al., 2016; Prusiner, 1998). As in prion diseases, these amyloid-like misfolded proteins are resistant to proteolysis, aggregate in the brain, and spread in a predictable pattern (Braak et al., 2003, 2006; Brettschneider et al., 2013), which is why these neurodegenerative diseases are sometimes referred as protein misfolding diseases (Knowles et al., 2014). The idea that other neurodegenerative diseases might spread in the brain in a manner similar to prions was further supported when it was shown that α-synuclein pathology was found at autopsy in the healthy fetal graft tissue implanted into brains of patients with PD 11–16 years after dopaminergic neuron transplantation (Kordower et al, 2008a, 2008b). Since then, many in vitro and in vivo studies noted the presence of seeding properties and transcellular spreading abilities in Aβ amyloid, tau, synuclein, TDP 43, and huntingtin proteins (Clavaguera et al, 2013a. 2013b; Frost & Diamond, 2009, 2010; Frost et al., 2009a, 2009b; Hansen et al., 2011; Hasegawa et al., 2017; Holmes et al., 2013; Jeon et al., 2016; Jucker & Walker, 2013; Lasagna-Reeves et al., 2012; Luk et al., 2012; Luks et al., 2009; Masnata et al., 2019; Munch et al., 2011; Olsson et al., 2018; Sanders et al., 2014; Watts et al., 2013). For example, when inoculated intracerebrally and intraperitoneally with brain extracts from Alzheimer disease individuals, transgenic mice that express human amyloid precursor protein showed premature deposition of amyloid plaques and presence of CAA pathology (Eisele et al., 2009, 2010; Kane et al., 2000; Meyer-Luehmann et al., 2006). Injection of human AD brain homogenates into the dentate gyrus of mice successfully induced the aggregation of wild-type murine tau (Audouard et al., 2016). Furthermore, transgenic

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mice that harbor human α-synuclein transgene developed MSA symptoms and somewhat similar pathology when inoculated intracerebrally with brain homogenates of MSA patients (Prusiner et al., 2015; Watts et al., 2013). When studies re-examined brains of hGH iCJD cases in both UK and US cohorts, they found higher than expected frequency of vascular and gray matter amyloid β pathology. Given the young age of these cases, this caused concern of peripheral transmission of amyloid β pathology (Cali et al., 2018; Jaunmuktane et al., 2015; Jucker & Walker, 2015; Tousseyn et al., 2015). Interestingly, the depositions of these proteins in several of the above transmission studies were first found to be adjacent to the inoculation site and gradually involved brain regions that are axonally connected, resembling the spreading nature of prion proteins (Eisele et al., 2009, 2010; Kane et al., 2000; Meyer-Luehmann et al., 2006). Despite possessing the molecular features of seeding, templating, misfolding, and transcellular spreading similar to prion protein, these protein aggregates have yet to be found to show any direct evidence of infectivity between hosts; thus, in the opinion of some, separating themselves from PrPSc. Various terms have been used to describe these other neurodegenerative diseases that display templated misfolding of proteins spreading in the brain, including “prionoid,” “prion-like,” and even simply considering them all prion diseases (Aoyagi et al., 2019; Prusiner, 2012; Scheckel & Aguzzi, 2018). There are a few arguments used to support the terminology “prion” diseases for all of these prion-like disorders. First, despite the definition of “prion” includes the term “infectious,” fewer than 1% of classic PrP prion disease cases are actually infectious, in that they occurred through transmission; more than 99% are sporadic or genetic (Prusiner, 1998). Second, when first identified, viruses were referred to by many different terms because of the great diversity of shapes, sizes, and other characteristics; yet now, the term “viruses” applies to many small infectious agents that replicate only inside the living cells of an organism. Nevertheless, many in the field do not wish to call other prion-like neurodegenerative diseases “prion” diseases because of the implication that they are as infectious or transmissible as PrP prion diseases, which, among other issues, might make it difficult for patients to get standard invasive medical procedures due to infection control concerns. The debate on this nomenclature continues.

Prion Decontamination Decontamination of prions requires methods that will denature proteins, as prions resist normal inactivation methods used to kill viruses and bacteria. Typical methods for reducing the load of or inactivating prions include prolonged moist autoclaving at higher-than-normal temperatures and pressure, with or without denaturing agents (many of which are caustic). Unfortunately, recommended methods for prion decontamination that include very high temperatures with steam and caustic denaturing agents often damage equipment and instrumentation. WHO guidelines state the preferred method is steam sterilization for at least 30 minutes at 132°C in a gravity-displacement sterilizer. If a pre-vacuum sterilizer is used, they note that 18 minutes at 134°C is also effective. Another option is 1N sodium hydroxide or 2% sodium hypochlorite for 1 hour, with 134°C autoclaving for at least 18 minutes. Non-fragile items may be immersed in 1N sodium hydroxide, a caustic solution, for 1 hour at room temperature and then steam-sterilized for 30 minutes at 121°C (Condello et al., 2018; WHO, 2006). Unfortunately, most of the literature on prion infection control is based on non-human prions and using prion-infected brain homogenate, both of which have critical shortcomings. Certain strains of prions, including human prions, are much more difficult to denature than many prions (e.g., mouse or hamster) that have

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been tested in decontamination experiments. Furthermore, many disinfection studies used prion-infected brain homogenate, which is much easier to decontaminate than using small stainless steel wires incubated overnight in prion-infected brain homogenate, which also more closely approximates prions binding to steel surgical equipment. The steel-wire method is an important model because prions bind readily to metal and, thus, become more difficult to remove and denature (Condello et al., 2018; Peretz et al., 2006). Because of the risk of transmission to subsequent patients, when financially feasible, some hospitals dispose of neurosurgical and other surgical equipment potentially exposed to prions (usually by incineration) rather than attempting to decontaminate the equipment for future patient use. Particularly for instruments of intricate design or for which the complete removal of protein cannot be assured, single-use instruments are recommended when possible. Research into improved methods of decontamination of prions is ongoing (Condello et al., 2018; Ward et al., 2018).

Animal Prion Diseases The first known animal prion disease, scrapie, which occurs in sheep and goats, was first described more than 150 years ago. This disease was so named because the sick animals would scrape their skin by rubbing against fences or other objects, probably because of itching. Owing to a phenomenon called the species barrier, scrapie is not directly transmissible to humans. Species barriers prevent or reduce transmission of prions from one species to another, and animal models of prion disease support the idea that scrapie prions do not directly pass to humans (Igel-Egalon et al., 2018). Furthermore, there appear to be no differences in the incidence of human prion disease between countries that have little or no scrapie and those where scrapie is endemic. Unfortunately, in the mid-1980s an outbreak of BSE occurred in the United Kingdom because scrapie-contaminated material was being fed to cattle (Houston & Andreoletti, 2018). Cattle with BSE develop an ataxic illness, weight loss, behavioral changes, and other neurological symptoms progressing to death. More than 280,000 cattle suffered from BSE. Initially, cases were only identified in the United Kingdom, but eventually cases were identified in other countries as well. When cases were identified, entire herds were killed to prevent the disease from spreading further. Fortunately, through proper epidemiological control, including feed bans and cessation of various feeding practices, the incidence of BSE has dropped dramatically now, with only a few, if any, cases occurring each year, some of which might be sporadic cases. Tragically, even though scrapie prions do not pass directly to humans, they were able to overcome the species barrier with humans by passing through cattle. Ingestion of BSE prions unfortunately led to vJCD in the United Kingdom and several other countries (see earlier discussion). The temporal relationship between the BSE epidemic and the rise of vJCD, coupled with data in mice showing the similarity between these conditions, are strong evidence for the link between these two diseases (Bruce et al., 1997; Houston & Andreoletti, 2018; Scott et al., 1999). As of December, 31, 2016, 24 isolated cases of BSE had been reported in North America (three in the United States and 21 in Canada) (Fig. 94.9) (World Organisation for Animal Health—OiE, 2019). Thus, it does not appear that there has been another outbreak, although it is possible that some cases are still getting into the food supply, as not all cattle are being inspected in most countries. Chronic wasting disease (CWD) is a prion disease of mule deer, white-tailed deer, elk, and, more recently, moose. The first clinical cases were recognized in the late 1960s in Colorado, United States,

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USA Canada Fig. 94.9 Bovine Spongiform Encephalopathy (BSE) in North America. This figure illustrates the 26 BSE cases identified in North America, from 1993 through August 2018, of which 7 were atypical BSE cases and 19 were classic BSE cases. The only classic BSE case identified in the United States was imported from Canada. (Courtesy Centers for Disease Control and Prevention. Available at: https://www.cdc.gov/ prions/bse/bse-north-america.html.)

but it was not recognized as a prion disease until 1980. Clinical features of the disease include weight loss, behavioral changes such as depression, and isolation from the herd. Some other features might also include hypersalivation, polydipsia/polyuria, and ataxia. The disease primarily has been reported in the United States and Canada, with the highest concentrations occurring in the Central Mountain region of the United States, especially Colorado and Montana, as well as the Canadian provinces of Saskatchewan and Alberta (Sigurdson, 2008; Williams, 2005). It has also been identified in South Korea, Finland, and Norway (Sigurdson et al., 2018). A map showing the distribution of CWD in North America is in Fig. 94.10. Most concerning aspect of CWD is its ease of horizontal transmission between cervids, which might be due, in part, to the fact that CWD appears to be transmissible through blood, urine, and saliva (Haley et al., 2009). This feature makes it very difficult to prevent spread of the disease in free-ranging cervid populations (Williams, 2005). It still is not clear whether CWD can spread to humans or whether there is a species barrier, but there has been no reported increase in human prion cases in states with the highest

Distribution of Chronic Wasting Disease in North America

CWD in free-ranging populations Known distribution prior to 2000 (free ranging) CWD in captive facilities (depopulated) CWD in captive facilities (current)

Fig. 94.10 Distribution of Chronic Wasting Disease (CWD) in North America. Figure shows the reported distribution of chronic wasting disease in North America as of April 1, 2018. (Courtesy Bryan Richards, US Geological Service (USGS) National Wildlife Health Center. Public domain; https://www.usgs.gov/media/ images/distribution-chronic-wasting-disease-north-america-april-2018.)

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rates of CWD (Sigurdson et al., 2009). Although it has been shown that CWD prions from brains on infected animals can be transmitted to squirrel monkeys by oral or intracerebral inoculation, at least two studies suggest they could not be transmitted to cymologous monkeys, which are closer genetically to humans than squirrel monkeys (Race et al., 2018). Of particular concern, an as-yet unpublished collaboration between Canadian and French scientists, presented at an international prion meeting, suggested that feeding some macaques meat from CWD animals resulted in transmission. To date, there have been no human cases of prion disease linked to CWD, although the Centers for Disease Control and Prevention (CDC) in the US is actively surveilling for new forms of human prion disease that might be linked to CWD.

TREATMENT OF HUMAN PRION DISEASES Currently, there is no known cure for human prion diseases; all cases are uniformly fatal. Some potential mechanisms for treating prion diseases are shown in Fig. 94.11. This include removing or reducing the endogenous substrate PrPC, blocking the interaction of PrPC with PrPSc, removing PrPSc, and blocking its toxicity (Korth & Peters, 2006). Several medicines have been used to treat human prion disease, but only oral flupirtine, quinacrine, and doxycycline have been

tested in randomized double-blinded placebo-controlled trials, and none were effective in prolonging survival in symptomatic patients (Geschwind, 2014; Geschwind et al., 2013; Haik et al., 2014; Korth & Peters, 2006; Stewart et al., 2008). Despite doxycycline not showing benefit in symptomatic patients (Haik et al., 2014), it is being tested in a decade-long, double-blinded study with 25 at-risk members (10 carriers and 15 non-carriers) of a single large Italian family with FFI to assess if it can delay onset in D178N/129M mutation carriers compared with historical controls; the study should be completed by 2023 (Forloni et al., 2015). Intraventricular pentosan polysulfate has been used on a compassionate basis in the United Kingdom, Japan, and a few other countries, but observational data suggest that it does not improve function. The fact that four of the five treated cases in the UK had significantly longer survival than untreated cases might suggest that the drug can prolong survival; it does not, however, appear to affect neuropathological damage or improve function (Newman et al., 2014). An antibody against PrPC, PRN100, is being infused intravenously as an experimental treatment by the UK National Health Service to treat only UK patients with symptomatic prion disease. The first patient, with sJCD, began treatment in October 2018. The goal of this antibody is to block the contact of PrPSc with PrPC and, thereby, prevent propagation of prions. As of May 2019, five patients had begun treatment, but the results have

Fig. 94.11 Schematic drawing of the life of the prion protein (PrP) inside the cell, its conversion to infectious prions, and cell biology-based possibilities of treatment intervention. The cellular PrP (PrPC) is light blue, and the scrapie PrP (PrPSc) is orange. Blue-filled ovals within the plasma membrane are cholesterol-rich, detergent-resistant membrane domains (CR-DRMs). The light blue bar represents a hypothesized conversion-assisting cofactor, sometimes referred to as protein X. For a more detailed explanation, see Korth and Peters (2006). mRNA, Messenger ribonucleic acid; siRNA, small interfering ribonucleic acid. Of note, for Step 2, attempts to treat human prion disease with antibodies targeting PrPC began in London under the Medical Research Council in October 2018 with five symptomatic patients treated with unreported results as of May 2019. Although not shown in this figure, as an addition to Step 1, as of 2019, antisense oligonucleotides (ASOs) are currently being used in clinical practice to treat spinal muscular atrophy (SMA), are being used in treatment trials for Huntington disease, and are actively being studied in animal models of prion disease. (Modified from Korth, C., Peters, P.J., 2006. Emerging pharmacotherapies for Creutzfeldt-Jakob disease. Arch. Neurol. 63 [4], 497–501.)

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CHAPTER 94 Prion Diseases not been reported (Dyer, 2018; Klohn et al., 2012; Medical Research Council Prion Unit, 2019). Several laboratories around the world are actively screening drug libraries and using medicinal chemistry to identify and develop antiprion therapies (Lasmezas & Gabizon, 2018). One of the most promising potential treatments for PrDs is antisense oligonucleotides (ASOs), which are already being used for clinical treatment of spinobulbar muscular atrophy (SMA) in children (Finkel et al., 2017; Mercuri et al., 2018) and in trials for ALS and HD (Kordasiewicz et al., 2012; Ly & Miller, 2018; Rinaldi & Wood, 2017; Tabrizi et al., 2019a, 2019b). The goal of ASOs is to prevent specific proteins from being made; this is done by designing ASOs that bind to the mRNA of interest. When this occurs, the normally single-stranded mRNA becomes double-stranded, which the cell recognizes and degrades, preventing the protein of interest from being translated. ASOs can result in significant knock-down of brain mRNA, in ranges of about 15%–75% in animal models (Kordasiewicz et al., 2012; Rinaldi & Wood, 2017). When inoculated with prions, mice hemizygous for Prnp have significantly longer survival than wild-type mice (Bueler et al., 1994). This suggests that lowering PrPC might prolong survival of symptomatic disease as well as delay onset of pre-symptomatic or at-risk persons (i.e., PRNP mutation carriers or those exposed to prions via blood, surgery, or other methods). Supporting the notion that reduced levels of PrPC would be tolerated in humans is a large genomic data study that reported three individuals who remained healthy despite being hemizygous for PRNP (Minikel et al., 2016), suggesting that partial reduction of PRNP gene dosage can be tolerable. Treatment trials in HD have already demonstrated that intrathecally-delivered ASOs can reduce the level of mutant huntingtin protein in the CSF up to 42% (Tabrizi et al., 2019b). Although it is not yet known how much decrease of huntingtin level is occurring in the brain tissue of these patients with HD, this data is encouraging for the treatment of other proteinopathies, such as prion disease.

Management of Prion Diseases In the absence of any curative treatments, management of prion diseases involves treating symptoms as they arise and comfort care.

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Insofar as there are no approved drugs in any countries for treatment of prion disease, all medications are used off-label for symptomatic treatment. There are no data supporting the use of any medications, including those approved for certain dementias, such as AD and PD. At our center, we have managed hundreds of patients with prion disease and have empirically found certain medications to be helpful. For example, we commonly use selective serotonin reuptake inhibitors (SSRIs), such as escitalopram, to treat depression, anxiety, and mild agitation; atypical antipsychotics (particularly quetiapine as it is less likely to cause parkinsonism) to treat agitation and psychosis; and levetiracetam, clonazepam, or valproic acid to treat myoclonus. One study suggested valproic acid increases PrPC and PrPSc in vitro but had no effect in an in vivo mouse model (Shaked et al., 2000), so one might consider avoiding use of this medicine when disease-modifying treatments become available. We, and others, have published recommendations on the care and ethical issues regarding managing patients with prion disease (Appleby & Yobs, 2018; Bechtel & Geschwind, 2013).

DIFFERENTIAL DIAGNOSIS Other conditions such as AD, Lewy body disease, Hashimoto encephalopathy, and hepatic encephalopathy rarely also have an EEG with PSWCs, typical of sJCD (Geschwind, 2016; Savard et al., 2016). Other rapidly progressive disorders to consider that might present similarly to JCD include paraneoplastic or other autoimmune limbic encephalopathies (Graus et al., 2016; Rosenbloom et al., 2009; Vernino et al., 2007), cancers (particularly lymphoma, either within or outside the nervous system), central nervous system vasculitis, metabolic or toxic disorders (e.g., bismuth intoxication, hepatic encephalopathy, electrolyte imbalance, etc.) (Geschwind, 2016; Rosenbloom et al., 2015), and atypical presentations of more common neurodegenerative conditions such as AD, Lewy body disease, and corticobasal degeneration (Drummond et al., 2017; Geschwind, 2016; Schmidt et al., 2012; Tartaglia et al., 2012). The complete reference list is available online at https://expertconsult. inkling.com/.

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95 Alzheimer Disease and Other Dementias Ronald C. Peterson, Jonathan Graff-Radford

OUTLINE Normal Aging and Mild Cognitive Impairment, 1452 Normal Aging, 1452 Preclinical Stage of Dementia, 1453 Mild Cognitive Impairment, 1453 Subjective Cognitive Impairment, 1455 Dementia, 1455 Dementia Epidemiology, 1455 Diagnostic Approach, 1455 Alzheimer Disease, 1458 Background, 1458 Definition of Alzheimer Disease Over Time, 1458 Alzheimer Epidemiology, 1458 Atypical Alzheimer Disease, 1461 Neuropsychiatric Features of Alzheimer Disease Dementia, 1461 Diagnostic Criteria, 1462 Neuropsychology in Alzheimer Disease Dementia, 1463 Biomarkers in Alzheimer Disease, 1464 Genetics, 1468 Alzheimer Pathophysiology, 1468 Alzheimer Pathology, 1469 Treatment, 1471 Patient Safety, 1472 Neurodegenerative Dementias Associated With Parkinsonism, 1473 Synucleinopathies, 1473 Tauopathies, 1478 Frontotemporal Dementias, 1480 Nomenclature, 1480 Diagnostic Criteria, 1480 Frontotemporal Dementia Epidemiology, 1481 Behavioral Variant Frontotemporal Dementia, 1481 Hippocampal Sclerosis of Aging, 1481 Argyrophilic Grain Disease, 1481

NORMAL AGING AND MILD COGNITIVE IMPAIRMENT Normal Aging A cognitive continuum exists from normal aging through mild cognitive impairment (MCI) to dementia. This continuum is better understood when realizing that it occurs on a background of some degree of cognitive decline with aging. While the theoretical ideal is to age without cognitive change, typically cognitive function declines over time. Research has provided normative data on cognitively normal individuals at each decade of life, but this approach has been criticized because these studies likely

Neuroimaging, 1483 Genetics, 1485 Pathology, 1486 Frontotemporal Dementia Treatment, 1488 Vascular Dementia (Vascular Cognitive Impairment), 1488 History, 1488 Diagnostic Criteria, 1489 Epidemiology, 1490 Vascular Risk Factors, 1490 Subtypes, 1490 Clinical Presentation, 1490 Large-Vessel Stroke, 1490 Cerebral Small-Vessel Disease, 1490 Neuropsychological Testing, 1491 Treatment, 1491 Normal Pressure Hydrocephalus, 1492 Gait Disturbance, 1492 Cognitive Disorder, 1492 Urinary Incontinence, 1492 Assessing Comorbidities, 1492 Neuroimaging, 1492 Confirmatory Diagnostic Tests, 1493 Biomarkers, 1493 Biopsy Studies, 1493 Diagnostic Criteria, 1494 Chronic Traumatic Encephalopathy/Post-Traumatic Dementia, 1494 Other Causes, 1494 Autoimmune or Paraneoplastic Dementia, 1494 Other Non-Degenerative Dementias, 1495 Young-Onset Dementia, 1495 Future Directions, 1496

include individuals who subsequently develop cognitive impairment. Research on normal aging using biomarkers for both Alzheimer disease (AD) and non-AD related pathologies will hopefully improve these methodological issues. Despite the aforementioned limitations, a brief review of cognitive change with age is important. Before age 60, a consistent pattern of cognitive change with age occurs. General knowledge and vocabulary are stable or improve while problem solving, speed of processing and reasoning decline (Salthouse, 2012). Age-related decline occurs primarily in cognitive speed, working memory, and encoding (Hedden and Gabrieli, 2004). The pattern on

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CHAPTER 95 Alzheimer Disease and Other Dementias neuropsychological testing associated with normal aging includes a decline in learning and acquisition performance with delayed recall relatively preserved (Petersen et al., 1992). Recognition performance also is preserved with age. Age-related cognitive decline is heterogeneous as a substantial minority may show minimal decline (Benton et al., 1981). Cognitive reserve refers to different capacities for the brain to maintain cognitive functioning in setting of brain pathology or injury (Stern et al., 2018). Age-related cognitive decline is associated with different neuroanatomical changes compared to cognitive decline from AD. Loss of synaptic density occurs as a function of age independent of Alzheimer pathology (Masliah et al., 1993). While AD is characterized by early damage of the entorhinal cortex and relative preservation of the dentate, age-associated medial temporal lobe changes occur in the dentate with preservation of the entorhinal cortex (Small et al., 2011). Brain volume normally declines with age but at a significantly slower rate than AD patients. In addition to the hippocampus, which declines in volume by 1%–2% a year in normal aging (Du et al., 2006), the prefrontal cortex also undergoes an age-related decrease in volume (Raz et al., 2005).

Preclinical Stage of Dementia Many studies have shown the pathophysiological processes leading to dementia can begin decades prior to cognitive symptoms. An evolving understanding of the preclinical stages of dementia has resulted in significantly increased interest in targeting it as a possible therapeutic time window. In the preclinical phase of dominantly inherited AD, cerebrospinal fluid (CSF) amyloid beta 42 (Aβ42) decreases 25 years before expected symptom onset (Bateman et al., 2012). Recent studies have revealed that in the general population the sequence of biomarkers leading to dementia is more diverse than dominantly inherited AD. In addition to cognitively normal individuals with biomarkers compatible with preclinical AD, the Mayo Clinic Study of Aging identified a group of patients with evidence of neurodegeneration on

TABLE 95.1

fluorodeoxyglucose positron emission tomography (FDG-PET) or magnetic resonance imaging (MRI), but without cerebral amyloid deposition. This group, termed suspected non-Alzheimer pathophysiology (sNAP) did not have imaging evidence consistent with cerebrovascular disease or synucleinopathy as the cause of brain injury (Jack et al., 2012; Knopman et al., 2012b). In general, these sNAP patients have a lower risk of becoming symptomatic after 5 years compared to patients with amyloid or amyloid plus neurodegeneration related biomarkers (Vos et al., 2013). In synuclein-related neurodegenerative disorders, autonomic symptoms, rapid eye movement (REM) sleep behavior disorder, and anosmia can predate cognitive and motor symptoms by many years. Ioflupane dopamine transporter scanning appears to be a promising biomarker in these conditions (Boeve, 2013). Preclinical stages of frontotemporal dementia (FTD) have not been studied as much as AD. The available biomarker data will be reviewed subsequently in this chapter. The 2011 National Institute on Aging (NIA) (Sperling et al., 2011) preclinical AD criteria are summarized in Table 95.1 (Knopman et al., 2013; Vos et al., 2013).

Mild Cognitive Impairment MCI refers to an in-between state of normal cognitive aging and dementia. In MCI, cognitive change is greater than expected for age but independence in the community and activities of daily living are preserved (Petersen, 2004; Petersen et al., 2009). On average, MCI patients perform 1–1.5 standard deviations below matched normative data. In 2018, the American Academy of Neurology published evidence-based guidelines on the concept of MCI, documenting the prevalence of MCI to be 6.7% at 60–64 years, 8.4% between ages 65 and 69, 10.1% between ages 70 and 74, 14.8% between ages 75 and 79, and 25.8% for ages 80–84. The rate of progression from MCI to dementia was between 9% and 20% per year depending on the specific nature of the population (Petersen et al., 2018). In 2004, Petersen published criteria for MCI (Table 95.2; Petersen, 2004). These criteria, proposed at the Key Symposium in Stockholm (Winblad et al., 2004), emphasized the concept as a syndrome between

National Institute on Aging Criteria for Preclinical Alzheimer Disease (AD)

Diagnostic Category Normal AD biomarkers Preclinical AD

1453

Stage 0 (normal AD biomarkers) Stage 1 (asymptomatic amyloidosis) Stage 2 (amyloidosis plus evidence of neural degeneration) Stage 3 (amyloidosis, neurodegeneration, subtle cognitive change) sNAP† (neurodegeneration, no amyloidosis)

Amyloid Beta (Positron Emission Tomography or Cerebrospinal Fluid)

Neuronal Injury*

−

Cognitive Change

% of diagnostic category (Knopman et al., 2013)

5-Year Risk of Dementia (Vos et al., 2013)

−

−

43%

2%

+

−

−

16%

11%

+

+

−

12%

26%

+

+

+

3%

56%

−

+

−

23%

5%

*Biomarkers of neuronal injury include increased cerebrospinal fluid (CSF) tau, hippocampal atrophy, and abnormal fluorodeoxyglucose positron emission tomography (FDG-PET) metabolism. †Suspected non-Alzheimer pathway, not part of 2011 NIA criteria. Data based on studies by Knopman, D.S., Jack, C.R., Jr., Wiste, H.J., Weigand, S.D., Vemuri, P., Lowe, V.J., et al., 2013. Brain injury biomarkers are not dependent on beta-amyloid in normal elderly. Ann. Neurol. 3, 472–480; and Vos, S.J., Xiong, C., Visser, P.J., Jasielec, M.S., Hassenstab, J., Grant, E.A., et al., 2013. Preclinical Alzheimer’s disease and its outcome: a longitudinal cohort study. Lancet Neurol. 2, 957–965. F ECF

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normal aging and dementia. Diagnosing MCI is the initial step, followed by a determination of etiology of the syndrome. In 2011, the NIA and the Alzheimer Association published guidelines for the diagnosis of MCI due to AD (Albert et al., 2011). More

TABLE 95.2

Criteria

Mild Cognitive Impairment

aMCI

naMCI

Cognitive decline with intact ADLs, often corroborated by an informant Memory impairment

Cognitive decline with intact ADLs, often corroborated by an informant

Multidomain aMCI if other domains involved

Nonmemory cognitive impairment (language, attention, executive function, visual-spatial) Multidomain naMCI if more than one other nonmemory domain involved

ADL, Activity of daily living; aMCI, mild cognitive impairment—amnestic; naMCI, mild cognitive impairment—nonamnestic.

recently, the Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) described an analogous concept of “mild neurocognitive disorder.” A comparison of the recent MCI criteria is presented in Fig. 95.1 (Albert et al., 2011; Petersen et al., 2014). The American Academy of Neurology published guidelines recommending clinicians assess patients for MCI (Petersen et al., 2018). The concept of MCI is important because it identifies persons who are at great risk of developing dementia. While the annual risk of developing dementia in the elderly general population is approximately 1%–2%, MCI patients seen in the clinic setting have a 10%–15% annual risk. In population-based studies of MCI the annual risk of developing dementia is slightly lower at 5%–10% (Farias et al., 2009; Petersen et al., 2010; Roberts et al., 2014). The prevalence of MCI in subjects age 70–89 is approximately 16% (Petersen et al., 2010). Identifying MCI patients allows for monitoring of progression, provides opportunity for appropriate counseling, and offers a possible therapeutic window for intervention in the future. Several biomarkers predict the risk of converting from MCI to dementia. On structural MRI, MCI patients with hippocampal volumes on the 25th percentile are 2–3 times more likely to convert to

Mild Cognitive Impairment Cognitive complaint

Not normal for age Not demented Cognitive decline Essentially normal functional activities

MCI

Memory impaired?

Yes

No

Amnestic MCI

MCI Criteria Key Symposium JIM, 2014

Amnestic MCI Single domain

Nonamnestic MCI

Amnestic MCI Multiple domain

DSM-5

Nonamnestic MCI Single domain

Nonamnestic MCI Multiple domains

Mild Neurocognitive Disorder

MCI due to AD No or conflicting Aβ or MRI or FDG-PET or tau

Uncertain

Intermediate

Plus biomarker for Aβ

OR

MRI or FDG-PET or tau

High

Plus biomarker for Aβ

AND

MRI or FDG-PET or tau

Prodromal AD

Plus biomaker for Aβ or tau/Aβ

Fig. 95.1 Comparison of Recent Criteria for Mild Cognitive Impairment (MCI). The criteria outlined in blue were proposed at the Key Symposium. Other criteria include those of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) and MCI due to Alzheimer disease (AD) (Albert et al., 2011). Aβ, Amyloid beta; FDG-PET, fluorodeoxyglucose positron emission tomography; MRI, magnetic resonance imaging. (Reproduced from Petersen, R.C., Caracciolo, B., Brayne, C., Gauthier, S., Jelic, V., Fratiglioni, L., 2014. Mild cognitive impairment: a concept in evolution. J. Intern. Med. 275, 214–228 with permission from Journal of Internal Medicine.) F ECF

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CHAPTER 95 Alzheimer Disease and Other Dementias dementia compared to MCI patients with hippocampal volumes on the 75th percentile (Jack et al., 2010). In CSF, low Aβ 42 and high total tau (t-tau) and phospho tau (p-tau) levels are associated with progression in MCI patients (Mattsson et al., 2009). Other risk factors for conversion include APOE ε4 allele (Petersen et al., 1995, 2005), temporal-parietal hypometabolism on FDG-PET (Chetelat et al., 2003), and amyloid deposition on Aβ PET imaging (Wolk et al., 2009). One criticism of the MCI concept is that a proportion of patients diagnosed with MCI revert to normal. Interestingly, recent longitudinal studies demonstrated that those patients who fluctuate between normal cognition and mild cognitive impairment have a significantly higher risk of developing dementia over time. Therefore, a diagnosis of MCI even with reversion to normal has prognostic value (Lopez, 2013; Roberts et al., 2014). This fluctuation is analogous to labile hypertension and glucose intolerance with respect to the ultimate development of hypertension or diabetes mellitus. Subtyping MCI into amnestic and nonamnestic categories also has predictive value. Amnestic MCI (aMCI), which is more common, refers to memory impairment often noticed by family and even the patient but with intact cognitive skills in other domains (language, executive function, visual-spatial) and preservation of functional capacity. In contrast, nonamnestic MCI (naMCI) patients have declines in nonmemory cognitive domains such as language, executive function, and visual-spatial skills. The vast majority of aMCI patients progress to AD dementia (Petersen et al., 2005). Those with naMCI may progress to dementia with Lewy bodies (DLB) but can also progress to FTD, vascular dementia, and even AD dementia (Ferman et al., 2013b; Molano et al., 2010).

Subjective Cognitive Impairment While restricted insight into memory loss has been a distinguishing feature of individuals with cognitive impairment, recent studies have demonstrated that patients with cognitive complaints, good insight, and normal cognitive testing called subjective cognitive decline (SCD) are three times more likely than controls to develop MCI with AD-related biomarkers (Jessen et al., 2010; van Harten et al., 2018). SCI has been associated with elevated levels of tau regionally in the entorhinal cortex and global elevation of Aβ (Buckley et al., 2017).

DEMENTIA Dementia is an encompassing syndromic term for a decline in cognitive abilities of sufficient severity to interfere with function during daily activities (i.e., shopping, paying bills, cooking, driving, etc.). The term dementia does not imply an underlying etiology, although neurodegenerative diseases represent the most common causes. The decline from a prior higher level of functioning must be present in order to distinguish dementia from a developmental cognitive disorder. The cognitive deficit cannot be due to delirium or altered sensorium, which can be distinguished by the presence of marked fluctuations and acute-to-subacute temporal pattern, although dementia patients are more susceptible to delirium than the general population. The practice guideline on dementia from the American Academy of Neurology (AAN) recommended use of the DSM-IIIR dementia criteria (which were subsequently updated to the DSM-5 criteria). The DSM-5 criteria use the term major neurocognitive disorder to approximate dementia.

Dementia Epidemiology An estimated 35.6 million worldwide were living with dementia in 2010, with a prediction the number would double approximately every

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HS FTD VaD

AD

LBD

Fig. 95.2 Frequency of Different Pathologies in State of Florida Brain Bank. AD, Alzheimer disease; LBD, Lewy body disease; VaD, vascular dementia; HS, hippocampal sclerosis; FTD, frontotemporal dementia. (Based on data from Barker, W.W., Luis, C.A., Kashuba, A., Luis, M., Harwood, D.G., Loewenstein, D., et al., 2002. Relative frequencies of Alzheimer disease, Lewy body, vascular and frontotemporal dementia, and hippocampal sclerosis in the State of Florida Brain Bank. Alzheimer Dis. Assoc. Disord. 16, 203–212.)

20 years (Prince et al., 2013). In the United States, the estimated prevalence of dementia among those 71 and older using an in-home visit is 13.9%. A sharp increase in dementia prevalence occurs with age (Plassman et al., 2007). However, data from the Rotterdam study indicate the incidence of dementia may be declining (Schrijvers et al., 2012). This has been replicated in the UK (Matthews et al., 2013) and Rochester, MN (Rocca et al., 2011). One possible explanation is that this decrease is related to improved treatment of vascular risk factors. Dementia can result from numerous causes, including brain injury (cerebrovascular disease or trauma) or infectious and metabolic diseases, but the most common causes are neurodegenerative diseases. Fig. 95.2 represents frequency of the predominant pathologies in a large dementia brain bank (Barker et al., 2002). However, it is clear that while each patient has a predominant pathology, the majority of patients have multiple pathologies at autopsy. In fact, only 30% had AD pathology without other pathologies. Similarly, in the Rush Memory and Aging Project, over 50% of autopsied subjects with dementia had multiple pathological diagnoses (Schneider et al., 2007). In a longitudinal clinicpathological study of aging, AD was the most common underlying pathology (65%) but occurred without other pathologies rarely (9%). On an individual level, AD pathology accounted for approximately 50% of cognitive decline on average, highlighting the importance of pathological heterogeneity in agerelated cognitive decline (Boyle et al., 2018). In fact, even among patients diagnosed with AD-dementia, multiple pathologies are the rule rather than the exception (Schneider et al., 2007, 2009). With age, amyloid accumulation plateaus (Jack et al., 2017), tau, TAR DNAbinding protein 43 (TDP-43), and cerebrovascular pathologies continue to accumulate (Josephs et al., 2014; Schneider et al., 2007, 2009).

Diagnostic Approach In 2001, the AAN published evidence-based guidelines for the diagnosis of dementia (Knopman et al., 2001).

History The history is the most important component of the dementia diagnosis. Ideally, the history should be taken from not only the patient but also an individual who knows the patient well as lack of awareness

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TABLE 95.3

Neurological Diseases and Their Treatment

Key Parts of the History

Cognitive Symptoms

Motor Symptoms

Autonomic Symptoms

Sleep

Behavioral

Impaired recent memory (repetitive questions/statements, forgets appointments, loses items easily) Language difficulty (trouble understanding others, trouble getting words out, trouble finding words, uses incorrect words) Visual spatial difficulty (getting lost more easily, trouble reading, difficulty recognizing familiar people) Executive/attentional dysfunction (poor judgment, difficulty problem solving, difficulty maintaining focus, trouble with calculations)

Presence of tremor or myoclonus

Bowel/bladder symptoms

Presence of REM sleep behavior disorder

Trouble swallowing/ slurred speech

Presence of orthostasis

Excessive daytime sleepiness

Change in personality, socially inappropriate behavior Loss of empathy/interest in hobbies, family

Change in gait/falls

Sexual dysfunction (erectile dysfunction)

Muscle cramps atrophy, fasciculations

Change in sweating

Evidence of sleep apnea (snoring, stopped breathing during sleep) Evidence of stridor

Compulsive behaviors, change in dietary preference Disheveled, decreased interest in hygiene

REM, Rapid eye movement.

of impairment commonly accompanies dementia. This individual can provide invaluable information regarding impairment in activities of daily living (ADLs). Other key elements of the history include identifying the presenting symptom, mode of onset, duration of symptoms, and rate of progression. Neurodegenerative causes of dementia typically present with an insidious onset and slow rate of progression, while the sudden onset of symptoms should raise suspicion for stroke, medication effect, infection, autoimmune process, or psychosocial stressors. Patients may have a subacute onset over weeks or months. The dementias presenting with this course will be discussed in Chapter 94. Thorough evaluation of patients referred for cognitive symptoms to a memory clinic can identify a potentially reversible or partially reversible disorder in up to 9% of cases (Clarfield, 2003) and a treatable coexisting disorder in up to 23% (Hejl et al., 2002). Several key components of the dementia history are reviewed in Table 95.3. Background information such as age, level of education, occupation, social stressors, and cultural background can influence the presentation of dementia and should be taken into consideration. As a general framework, when an older patient presents with a progressive amnestic disorder with subsequent decline in other cognitive domains, AD dementia is the most common diagnosis. Alternatively, if the initial presentation is one of a change in language, personality, or behavior with relatively spared memory, FTD is the most likely consideration. The presence of parkinsonism, hallucinations, fluctuations, and REM sleep behavior disorder with dementia are most suggestive of DLB. Vascular cognitive impairment (VCI) (Corriveau et al., 2016) can be temporally related to a stroke or develop gradually with prominent cognitive slowing and executive dysfunction with cerebral small-vessel white matter disease. Often vascular disease occurs together with other causes of dementia as a comorbid component of the clinical picture. In the setting of subacute dementia, consider Creutzfeldt-Jakob disease, autoimmune dementia, and their differential diagnosis. Medical history. The past medical history can provide clues to the diagnosis or identify contributors to the cognitive decline. A careful head injury history is important because significant head trauma is a risk factor for dementia (Guo et al., 2000). Repeated head injuries may suggest chronic traumatic encephalopathy (CTE) such as can occur in contact sports or the military (McKee et al., 2013). Histories of stroke, hypertension, diabetes, high cholesterol, atrial fibrillation, smoking, or other vascular risk factors are important clues to vascular disease contributing to dementia. A history of cancer or autoimmune disease in the setting of a subacute cognitive decline may point to a paraneoplastic disorder or autoimmune dementia. A history of

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seizures, meningitis, or encephalitis, chemotherapy, brain radiation, sleep apnea, and other sleep disorders, depression and other psychiatric illness, and medication use may all be informative. Family history. Knowledge about genetic causes and risk factors has rapidly increased in the last few decades. Thus a careful family history is essential. Identify not only first degree relatives but other relatives with dementia. It is also important to ask about Parkinson disease, amyotrophic lateral sclerosis (ALS), and psychiatric disease. Patients with one phenotype may have relatives with another. For example, one patient may have FTD and a relative may have ALS from the same gene mutation. Medications. A thorough review of medications is essential as medication side effects exacerbate an underlying cognitive impairment or even mimic a dementia. A temporal association or worsening with starting a medication should be taken seriously and prompt consideration of a medication taper. While numerous medications are associated with cognitive side effects, the most common include anticholinergic agents (often present in medications for incontinence or antihistamines), benzodiazepines, zolpidem and other sedatives, opioids, and muscle relaxants. Table 95.4 is a partial list of medications that can be associated with cognitive symptoms. Neuropsychiatric history. A thorough neuropsychiatric history provides important information by identifying potentially treatable symptoms and narrowing the differential diagnosis. According to the AAN guidelines, depression should be screened for in all dementia patients because it occurs frequently and is treatable (Knopman et al., 2001). While depression can mimic dementia, depression is also a risk factor for and occurs frequently with AD and DLB (Boot et al., 2013; Ownby et al., 2006). Traditional teaching suggested that patients with dementia have consistent memory deficits and executive dysfunction of which they are unaware or minimize, while depressed patients are more likely to complain about cognitive impairment and perform variably on cognitive testing due to attention deficits and poor effort on testing (although in practice, distinguishing the two is difficult due to the significant overlap). However, more recent work on the MCI stage of dementia due to AD has demonstrated that early neuropsychiatric features such as apathy, agitation, and dysphoria may be presenting features of a neurodegenerative process (Geda et al., 2014). Important neuropsychiatric symptoms to review include change in mood (depression, mania), change in personality, and presence of delusions, obsessive behaviors, or hallucinations. The presence of certain neuropsychiatric features may narrow the differential diagnosis. For example, personality changes in behavioral variant FTD

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TABLE 95.4

Partial List of Medications Which Can Cause Cognitive Impairment

Sleep aids, cold medications, and antihistamines with an anticholinergic component: Diphenhydramine Acetaminophen/Dextromethorphan/Doxylamine succinate, Ibuprofen/Diphenhydramine

Antihypertensives Beta-blockers Antidepressants Amitriptyline (anticholinergic property) Imipramine (anticholinergic property)

Opiates Oxycodone Morphine Hydrocodone Fentanyl Propoxyphene Methadone Benzodiazepines Alprazolam Clonazepam Lorazepam Diazepam Temazepam

(bvFTD) or hallucinations or delusions in DLB. The Neuropsychiatric Inventory (NPI) can be used to screen for common neuropsychiatric manifestations of dementia (Cummings, 1997).

Cognitive Assessment Many useful cognitive screening instruments have been developed. Common well validated instruments include the Mini-Mental State Exam (MMSE) (Folstein et al., 1975), the Blessed Orientation Memory Concentration Test (Katzman et al., 1983), the Kokmen Short Test of Mental Status (STMS) (Kokmen et al., 1991), and the Montreal Cognitive Assessment (MOCA) (Nasreddine et al., 2005). Detailed cognitive testing by a neuropsychologist can be very helpful. The neuropsychologist provides an in-depth cognitive evaluation by administering a standardized battery of tests. These tests evaluate important cognitive domains such as attention and concentration, memory, language, visuospatial abilities, and executive function. They also gauge the psychiatric contributions to the clinical picture. Patients with different dementias have different strengths and weaknesses on these tests. The pattern of performance helps determine if the person is impaired, the severity of impairment, and the likely brain areas that are damaged. Neuropsychology can also be helpful in following a patient’s progression over time.

General Neurological Examination A general neurological exam is a key part of the evaluation of dementia. While the general neurological exam is typically normal in early AD, abnormalities on exam may indicate other neurodegenerative processes. The presence of parkinsonism may suggest DLB or another parkinsonian dementia. Focal findings on exam such as asymmetric

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Anticonvulsants Lamotrigine Phenobarbital Phenytoin Levetiracetam Topiramate Zonisamide Anticholinergics Tolterodine Oxybutynin Antipsychotics Quetiapine Olanzapine Risperidone Aripiprazole Hypnotics Zolpidem Eszopiclone

Anticholinergics Benztropine Meclizine Scopolamine

Antibiotics Metronidazole Cefepime

Mood stabilizer Lithium

Muscle relaxants Baclofen Cardiac Digoxin

Immunosuppressants Tacrolimus Cyclosporine

reflexes or other lateralizing signs may suggest a vascular component to the dementia. A coexisting peripheral neuropathy may suggest a metabolic disturbance. Fasciculations can be seen in patients with suspected FTD to suggesting coexisting motor neuron disease. A language screening exam and testing for apraxia should also be performed. The presence of a gait abnormality may indicate normal pressure hydrocephalus (NPH), parkinsonism, or vascular disease.

Laboratory Evaluation The AAN practice parameter recommends routine assessment for vitamin B12 deficiency and thyroid hormone abnormalities because these conditions are common, and can affect cognitive function. Treatment of vitamin B12 deficiency and hypothyroidism may not completely reverse cognitive symptoms, but recognition of these conditions is important. Other routine lab tests include a complete blood cell count, electrolyte panel, glucose, liver function tests, and creatinine. Screening for syphilis should be done based on clinical suspicion (Knopman et al., 2001). Special circumstances, including age less than 65 years, seizures, rapidly progressive dementia, history of cancer or autoimmune disease, suspicion of central nervous system (CNS) infection, constitutional symptoms, history of drug abuse or immunosuppression, systemic infection, suspicion of vasculitis, or other atypical features, can guide further laboratory evaluation, including CSF examination. In neurodegenerative disease, the cell count, protein, and glucose concentrations in the CSF are within normal limits and specific markers of AD pathology; for example, Aβ42 total and phospho-tau, may be useful. The AAN practice parameter recommends against electroencephalogram (EEG) in the standard evaluation of dementia (Knopman et al., 2001). However, EEG may be very useful in a patient with a history of

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seizures, assessment of rapidly progressive dementia, a history of spells, or suspicion of transient epileptic amnesia (Butler et al., 2007).

Neuroimaging Structural neuroimaging modalities including computed tomography (CT) and MRI can identify potentially treatable causes of dementia including subdural hematoma, hydrocephalus, and intracranial neoplasm. The AAN practice parameter paper recommends screening with either CT or MRI to identify these conditions (Knopman et al., 2001). In a study evaluating the usefulness of the AAN dementia guidelines, 3% of dementia patients had a surgically treatable finding on neuroimaging (NPH, subdural hematoma, neoplasm). Neuroimaging changed management in 15% of cases and clinical diagnoses in 19%–28% (Chui and Zhang, 1997). In the recent “Imaging Dementia-Evidence for Amyloid” Scanning (IDEAS) study, the use of amyloid PET among Medicare beneficiaries with cognitive impairment of unclear etiology led to a change in diagnosis and clinical management in a significant proportion of the participants (Rabinovici et al., 2019).

DSM-5 Recently, the DSM-5 was released, updating the prior criteria for dementia. DSM-5 introduces the terms “mild neurocognitive disorder,” which is similar to MCI, and “major neurocognitive disorder,” which is analogous to dementia. Major neurocognitive disorder represents a significant cognitive decline in at least one cognitive domain that interferes with daily function that is recognized by the individual, informant, or clinician and documented by neuropsychological testing. Mild neurocognitive disorder represents a cognitive decline which does not impair daily activities (American Psychiatric Association, 2013). DSM-5 recommends a two-tiered approach: (1) syndrome characterization as outlined above and (2) an etiological determination.

ALZHEIMER DISEASE Background In 1906 Alois Alzheimer, a German psychiatrist, reported the case of a woman in her 50s with paranoia and memory loss followed by aphasia whom he evaluated in a psychiatric unit. She eventually lost the ability to perform motor tasks. At autopsy, gross inspection revealed an atrophied brain with vascular changes. Microscopic sections prepared with Bielschowsky stain revealed the hallmark AD inclusions which would later be known as amyloid plaques and neurofibrillary tangles (NFTs). Although the patient had early onset of symptoms, Alzheimer’s case summarizes many of the key clinical features of AD dementia.

Definition of Alzheimer Disease Over Time In 1984, the National Institute on Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association criteria were created conceptualizing Alzheimer disease as a clinicopathological entity for over 30 years (McKhann et al., 1984a). With advancing technology allowing in vivo detection of amyloid with PET and CSF as well as measurement of neurodegeneration, in 2011 revised AD criteria were proposed by the National Institute on Aging-Alzheimer’s Association. Individuals were characterized by their clinical state (normal, MCI, and dementia) with biomarkers of amyloid and neurodegeneration providing the likelihood that their clinical state was due to Alzheimer disease. For example, if amyloid and neurodegeneration biomarkers were present in conjunction with the clinical syndrome of dementia, the diagnosis of dementia due to AD with high likelihood could be made (McKhann et al., 2011). But the diagnoses of MCI and dementia due to AD were still clinical-pathological conditions.

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More recently, tau PET imaging and improvement in CSF assays has allowed detection of both hallmark AD proteins in vivo. This advance of being able to detect both amyloid and tau in conjunction with data from clinical trials, which suggested that almost a quarter of individuals enrolled in a trial targeting amyloid were considered amyloid negative (Siemers et al., 2016), led to a new research framework proposing that AD should be defined biologically by the presence of both amyloid and tau either with biomarkers during life or pathologically with a separation of the clinical syndrome from the disease definition. The advantages of this framework include the ability to classify individuals earlier in the disease process, prevention of individuals with an amnestic dementia being misclassified as AD dementia if they have an alternative pathology, and the ability for individuals with an atypical phenotype (nonamnestic) to be classified as AD. In this research framework, each individual would be characterized by 3 biomarker groupings: (1) β-amyloid deposition, (2) pathological tau, and (3) neurodegeneration [AT(N)]. In this research framework, neuritic plaques may be identified by decreased CSF Aβ42 or amyloid PET positivity and neurofibrillary tangles identified by a positive tau PET or elevated phospho-tau protein in the CSF (Jack et al., 2018a). The presence of an amyloid biomarker alone without tau would be referred to as Alzheimer pathological change and the absence of amyloid as non-Alzheimer pathological change. The authors cautioned that this framework is for research at this point in time and should not be used in routine clinical practice. This framework provides a universal terminology to allow comparison between research studies, avoiding misclassification and potential erroneous enrollment in randomized clinical trials of individuals with an amnestic dementia syndrome not due to Alzheimer pathology such as hippocampal sclerosis (Botha et al., 2018a). A cognitive staging scheme can be applied to an individual’s biomarker status (Jack et al., 2018a). This history of Alzheimer disease definition was reviewed in the 2018 Wartenberg lecture (Petersen, 2018). Table 95.5 provides proposed cognitive stages applied to the new AD biomarker framework.

Alzheimer Epidemiology Prevalence

According to the Alzheimer’s Association in 2018, 5.7 million Americans have AD dementia (2018) which represents 70% of dementia in the United States (not autopsy confirmed) (Plassman et al., 2007). The prevalence of Alzheimer dementia increases with age from 3% of people between the ages of 65 and 74 to 32% of people age 85 and older (Alzheimer’s disease facts and figures 2018). While MCI is more common in men, the prevalence of AD dementia is higher in women. This in part can be explained by a longer life span in women than men. The lifetime risk of developing Alzheimer dementia from the age of 45 is approximately 10% for men and 20% for women (Alzheimer’s disease facts and figures 2018). By 2060, the prevalence will increase to an estimated 15 million individuals in the United States (Brookmeyer et al., 2018).

Incidence Age is the most important risk factor for AD dementia. The incidence of AD dementia increases with age: 2 new cases per 1000 for individuals age 65 to 74, 11 new cases per 1000 people age 75 to 84, and 37 new cases per 1000 people age 85 and older (Alzheimer’s disease facts and figures 2018).

Societal Cost and Future Projections Anticipated increases in cost to society for AD dementia are notsustainable. The total payments in 2018 for all individuals with dementia are estimated to be $277 billion (Alzheimer’s disease facts and figures

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TABLE 95.5 A–T–(N)– A+T– (N) A+T+ (N)– A+T+ (N)+ A+T– (N)+

A–T+ (N)– A–T– (N)+ A–T+ (N)+

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Cognitive Stage

Cognitively Unimpaired

Mild Cognitive Impairment (MCI)

Dementia

Normal Alzheimer disease (AD) biomarkers, cognitively unimpaired Preclinical Alzheimer pathological change

Normal AD biomarkers with MCI

Normal AD biomarkers with dementia

Alzheimer pathological change with MCI

Preclinical Alzheimer disease

Alzheimer disease with MCI (Prodromal AD)

Alzheimer pathological change with dementia Alzheimer disease with dementia

Alzheimer and concomitant suspected non-Alzheimer pathological change, cognitively unimpaired

Alzheimer and concomitant suspected non-Alzheimer pathological change with MCI Non-Alzheimer pathological change, cognitively unimpaired Non-Alzheimer pathological change with MCI

Alzheimer and concomitant suspected non-Alzheimer pathological change with dementia Non-Alzheimer pathological change with dementia

A, Amyloid status; T, tau status; N, neurodegeneration status. Adapted from Jack, C.R., Jr., Bennett, D.A., Blennow, K., Carrillo, M.C., Dunn, B., Haeberlein, S.B., et al., 2018a. NIA-AA Research Framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 4, 535–562.

2018). The Alzheimer Association estimates that by 2050 annual costs for AD dementia will reach approximately $1.2 trillion (Thies and Bleiler, 2013). Therefore, the burden on society will continue to be enormous unless a prevention or treatment is developed. The Health and Retirement Study has reported that AD is the costliest chronic disease in the United States exceeding those of cancer and heart disease (Hurd et al., 2013).

Risk Factors In addition to age and female gender, many other risk factors for AD dementia have been reported. Hypertension. After controlling for confounders, systolic blood pressure (>160 mm Hg) and elevated cholesterol increase risk for AD dementia later in life (Kivipelto et al., 2001). In the Honolulu-Asia Aging Study, the use of beta-blockers for hypertension was associated with less cognitive decline, especially among diabetics (Gelber et al., 2013). In the Ginkgo Evaluation of Memory Study, the use of a diuretic blood pressure medication, angiotensin-1 receptor blocker, or angiotensin-converting enzyme inhibitor was associated with reduced risk of AD dementia in those with normal cognition at baseline (Yasar et al., 2013). The relationship between hypertension and dementia is complicated. Counterintuitively, some studies have shown that low blood pressure is more commonly seen in demented patients than high blood pressure (Guo et al., 1996). A parsimonious explanation of this apparent discrepancy is that the association between hypertension and cognitive decline is age dependent. Mid-life hypertension and late-life hypotension are associated with AD dementia (Qiu et al., 2005). The relative risk of mid-life hypertension and dementia is 1.61 and it has been estimated that decreasing the prevalence of mid-life hypertension by 10% could result in a worldwide decrease of 160,000 AD dementia cases (Barnes and Yaffe, 2011). The recent SPRINT-MIND trial demonstrated that treating systolic blood pressure to a goal of less than 120 mm Hg compared to a goal of less than 140 mm Hg reduced the risk of mild cognitive impairment by approximately 19%, but the study did not meet its primary endpoint of showing a reduction in the risk of dementia (Williamson et al., 2019). Diabetes and elevated glucose. Type 2 diabetes is associated with hyperinsulinemia. Both insulin and Aβ are substrates for insulin-degrading enzyme. Therefore, hyperinsulinemia may result in accumulation of Aβ through competing with Aβ for insulin-degrading enzyme (Qiu and Folstein, 2006). However, at autopsy, type 2 diabetes

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is associated with vascular brain disease not increased AD pathology (Arvanitakis et al., 2006). Nonetheless, a meta-analysis estimated the relative risk of dementia related to diabetes was 1.39 (Lu et al., 2009). It has been estimated that a 10% decrease in diabetes prevalence may decrease the number of worldwide dementia cases by 81,000. Recently, a study has demonstrated that elevated glucose in the absence of diabetes also increases the risk of dementia (Crane et al., 2013). Head injury. A meta-analysis of 15 case-control studies demonstrated an increased risk of AD dementia with prior head injury in men (Fleminger et al., 2003). The mechanism is unclear, but after severe head injury, levels of Aβ42 in the CSF decrease, which also occurs in preclinical AD (Franz et al., 2003). The presence of the APOE4 allele may confer a higher risk of dementia after head injury (Koponen et al., 2004). In a population-based study, MCI subjects but not normal control subjects with history of head trauma had elevated brain Aβ deposition (Mielke et al., 2014). Sleep. The glymphatic system of the brain allows clearance of waste products. In mice, it has been shown that during sleep there is an increase in the interstitial space allowing for increased rate of clearance of β-amyloid (Xie et al., 2013b). Emerging evidence suggests that impaired sleep may alter β-amyloid dynamics in humans (Lucey et al., 2018; Shokri-Kojori et al., 2018). This is an active area of ongoing research. Others. Other risk factors associated with an increased risk of AD include smoking (Anstey et al., 2007), cerebrovascular disease (Pendlebury and Rothwell, 2009), anemia (Hong et al., 2013), and obesity (Profenno et al., 2010).

Protective Factors Education/leisure activities/early-life cognitive abilities. In 1990, a study performed in Shanghai demonstrated an association between a lower educational attainment and dementia risk (Zhang et al., 1990). Subsequently, several other studies have demonstrated an association between low educational attainment and increased dementia risk (Qiu et al., 2001; Stern et al., 1994). In addition to education, participation in certain leisure activities, including reading, dancing, playing board games, and playing musical instruments, is associated with a decreased dementia risk (Verghese et al., 2003). These studies and others have led to the development of the cognitive reserve hypothesis. Which attempts to explain why those with

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certain life experiences, including higher educational attainment and increased leisure activity participation, are more resistant to neurodegenerative changes (Stern, 2012). Early-life cognitive abilities also may play an important role in dementia risk. In the nun study, autobiographical essays from nuns at a mean age of 22 were evaluated for idea density and grammatical complexity. Those with low idea density and grammatical complexity had lower cognitive scores later in life, and, in a small sample of nuns who came to autopsy, those with low early-life linguistic ability had AD pathology while those with linguistic talent did not have AD pathology (Snowdon et al., 1996). Similarly in 1932, participants in the 1921 Scottish birth cohort took a test of intelligence at age 11. Lower mental ability at age 11 was associated with an increased risk of dementia (Whalley et al., 2000). Exercise. A Cochrane review of 11 studies of exercise in elderly non-demented participants concluded that exercise enhanced cognitive function (Angevaren et al., 2008). In addition, Yaffe and colleagues (Yaffe et al., 2001) reported that women with higher baseline levels of self-reported physical activity were less likely to decline cognitively. Similar findings were found in the nurses’ health study (Weuve et al., 2004) and a population-based study (Geda et al., 2010). In addition to epidemiological studies, a single-blind prospective study of physical activity intervention in participants with subjective cognitive impairment but not dementia demonstrated modest but significant improvement in cognition at 18 months follow-up (Lautenschlager et al., 2008). The mechanism of how exercise can improve cognition is unclear, but exercise and improvement in aerobic fitness correlate with increased hippocampal volumes (Erickson et al., 2011). Even in autosomal dominant AD, self-reported exercise of greater than 150 minutes per week was associated with lower amyloid load compared to those who exercised less than 150 minutes per week (Brown et al., 2017). Diet. In a nested case-control study from the Cardiovascular Health Study, consumption of 1–6 alcoholic beverages per week was associated with decreased odds of dementia relative to abstinence (Mukamal et al., 2003). In contrast, heavy drinking (>3/day) was not associated with a lower AD dementia risk (Luchsinger et al., 2004). In fact, it is well described that alcoholic patients can develop dementia for multifactorial reasons. Korsakoff syndrome related to thiamine deficiency is primarily an amnestic disorder. Other neuropsychological features of alcoholics with dementia include impaired letter fluency, fine motor control, and delayed recall with relative preservation of recognition (Saxton et al., 2000). Dietary fat intake has been associated with AD dementia risk. While intake of saturated fats and trans-unsaturated fats is associated with a higher risk, intake of unsaturated, unhydrogenated fats may be protective against AD dementia (Morris et al., 2003a, 2003b). Weekly fish consumption and increased intake of omega-3 fatty acid may also be associated with decreased AD dementia risk. Similarly, adherence to the Mediterranean diet, which recommends fish intake, is associated with decreased risk of AD and decreased risk of converting from MCI to AD dementia (Scarmeas et al., 2006, 2009). Cognitive outcome data from a clinical trial in which a Mediterranean diet was compared to a control diet demonstrated that a Mediterranean diet supplemented with olive oil or nuts was associated with better cognition than a control diet (Livingston et al., 2017).

Alzheimer Clinical Features AD dementia survival is shorter than predicted based on US population estimates, with a median survival from diagnosis of 4.2 years for men and 5.7 years for women (Larson et al., 2004).

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Early Presentation Typical AD dementia initially presents with an episodic memory impairment reflecting the selective vulnerability of the medial temporal lobe to AD pathology. Episodic memory relates to our ability to remember information specific to a time and place when that memory was formed (e.g., “What did you eat for dinner? What did you do on a trip?”). Recent episodic memory is particularly impaired in early AD.

Pattern of Progression While episodic memory is the hallmark of early AD, subsequent cognitive decline is heterogeneous as the pathology spreads to the association cortices. While individual presentations vary significantly, Feldman and Woodward have described the typical symptom progression in AD dementia: Mild AD (recent memory impairment, repetitive questions, loss of interest in hobbies, anomia, impaired instrumental ADLs), moderate AD (aphasia, executive dysfunction, impaired basic ADLs), severe AD (agitation, complete loss of independence, sleep disturbance) (Feldman and Woodward, 2005).

Common Clinical Features Semantic memory dysfunction can be an early feature of AD but occurs after episodic memory involvement. Semantic memory is factual knowledge not linked to time or space context. Examples include naming or recalling animals, objects and tools, or landmarks. The preservation of semantic memory in a subset of early AD cases indicates that transentorhinal dysfunction is inadequate to disrupt semantic memory, which likely requires extension of pathology into the temporal neocortex (Hodges and Patterson, 1995). A category fluency test (asking the subject to generate as many items as possible from a given category such as fruits, animals, or vegetables) is commonly used as a brief test of semantic knowledge. This not only tests the ability to remember the names of objects but the ability to search one’s mind for a category of objects. This test is often impaired early in the course of the disease and also tests executive function. Executive function (planning, organization, problem solving, set switching) decline occurs in mild AD (Greene et al., 1995). The executive dysfunction in AD dementia is mild until later in the disease course compared to bvFTD. Language disturbance often occurs in the mild-moderate stage of AD dementia. Initial complaints often include word-finding difficulty. In time, other features of aphasia may develop, and in the late states, language output can be limited. Decline in visuospatial skills is common, often manifesting early with the complaint of becoming lost or being disorientated in unfamiliar places. Apraxia often occurs later in the course of typical AD, although it may be an early feature in atypical AD. Strikingly, several abilities are preserved until very late in the development of AD dementia. For example, AD dementia patients have preserved motor learning (procedural) (Eslinger and Damasio, 1986), motor, and sensory skills. A useful way to think of the clinical picture of AD dementia is to look at the pattern of both deficits and strengths the patient exhibits. Patients with AD dementia have episodic memory loss and develop anomia, executive dysfunction, and visuospatial difficulty in the setting of preserved ability to walk, see, hear, and feel. AD dementia is also characterized by the juxtaposition of “knowing how” (procedural memory) and “not knowing what” (declarative memory). The clinical picture of deficits and preserved abilities is explained by the anatomical distribution of the NFT pathology. Arnold et al. (1991) demonstrated that tangle burden is greatest in the medial temporal lobe but spares the primary sensory and motor cortices until very late in the

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course, which is why AD dementia patients can see, hear, and move but not remember. Early AD is characterized by an isolated memory impairment resulting from significant pathology in the entorhinal cortex and hippocampus, which serves to disconnect the medial temporal lobe from other cortices. The spread of pathology to other association cortices results in accumulation of other symptoms: semantic memory involvement from spread to the anterior temporal lobes, executive dysfunction from spread to the frontal lobes, and visual-spatial dysfunction from spread to the occipitotemporal lobes. In contrast, the primary motor and sensory cortices are only affected late in the course. The preserved basal ganglia and cerebellum are involved in the procedural/motor learning (or knowing how).

Atypical Alzheimer Disease Occasionally, AD can present with focal cortical syndromes without memory loss initially. The three most commonly described atypical presentations are posterior cortical atrophy (PCA), logopenic aphasia (LPA), and frontal variant of AD.

Posterior Cortical Atrophy In 1988, Benson used the term posterior cortical atrophy to describe five cases with progressive dementia involving visual-spatial function, alexia, and partial Balint and Gerstmann syndromes with relatively preserved memory (Benson et al., 1988). Later, autopsy series of PCA revealed Alzheimer pathology as the most common underlying etiology. While AD is the most common pathology, other pathologies in clinically diagnosed PCA cases include corticobasal degeneration and prion disease. PCA patients are often initially referred to optometry or ophthalmology for difficulty seeing, which may manifest as driving impairment or trouble reading. Not uncommonly, PCA patients undergo procedures such as cataract removal without significant benefit, or alternatively, they may be told there is nothing wrong with their eyes prior to definitive diagnosis. The mean age of onset of PCA is approximately 60 (Tang-Wai et al., 2004). Compared to typical AD, insight is preserved (Mendez et al., 2002). In a large series of 40 PCA cases, complete or partial Balint syndrome (optic ataxia, oculomotor apraxia, simultanagnosia) was present at diagnosis in 88% of patients, complete or partial Gerstmann (left-right confusion, finger agnosia, agraphia, acalculia) was present in 62%, and visual field loss was present in 48%. Simultanagnosia is characterized by only being able to see one object at a time while viewing a scene. Ishihara plates used to assess color perception and complex scenes are good screening tools for the presence of simultanagnosia. Other important signs and symptoms include ideomotor apraxia, alexia, prosopagnosia, hemineglect (sensory or visual), achromatopsia, and dressing apraxia (Tang-Wai et al., 2004). PCA is associated with the APOE ε4 allele (Carrasquillo et al., 2014). Structural MRI reveals parieto-occipital atrophy and FDG-PET demonstrates associated parieto-occipital hypometabolism (Figs. 95.3 and 95.4, respectively). The distribution of amyloid is similar between PCA and typical AD (Rosenbloom et al., 2011). In contrast, PCA patients have significantly more tau deposition in the occipital lobe compared to typical AD (see Fig. 95.4), corresponding to their clinical symptoms (Hof et al., 1990). Adaptive equipment for the blind or those with low sight can be helpful. No randomized controlled trial supports the use of any drug therapies in PCA, although acetylcholinesterase inhibitors are commonly used since the most common underlying pathology is AD. Recent consensus criteria (Table 95.6) for the diagnosis of PCA have been published emphasizing PCA as a clinicoradiological syndrome (Crutch et al., 2017). The new classification recognizes that PCA can present in a “pure” form or overlap with other degenerative diseases such as corticobasal syndrome.

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Fig. 95.3 T2 fluid-attenuated inversion recovery magnetic resonance imaging scans in a patient with posterior cortical atrophy revealing significant parietal and occipital atrophy.

Logopenic Primary Progressive Aphasia LPA is one of the primary progressive aphasias. The distinguishing features of LPA include impaired naming, repetition, and word retrieval with phonological errors. Motor speech and grammar are spared. Gorno-Tempini et al. (2008) have suggested impairment in the phonological loop, which stores and rehearses verbal memory as the basis of the clinical presentation. In a study by Mesulam et al. (2008), 64% of logopenic patients had AD pathology at autopsy, and these patients had greater tangle burden in the left hemisphere language areas and fewer tangles in the entorhinal cortex when compared to typical AD pathology. In a large multicenter study, amyloid pathology was present in 86% of those with LPA compared to 20% of those with nonfluent/agrammatic PPA and 16% of those with semantic variant PPA (Bergeron et al., 2018). Phonological errors may be the strongest predictor of underlying AD pathology (Leyton et al., 2014). Structural MRI reveals left temporal-parietal atrophy. FDG-PET scans reveal temporal-parietal hypometabolism and tau PET demonstrates left greater than right temporal and parietal tau deposition (Fig. 95.5, A and B).

Behavioral/Frontal or Dysexecutive Variant Alzheimer Disease Rarely, patients with pathologically confirmed AD present with early impairment on tests of frontal lobe function including verbal fluency and Trails A. These patients may have behavioral and personality changes similar to patients with FTD. However, those with behavioral presentation of AD develop apathy as the most common behavioral feature, in contrast to hyperorality and perseverative/compulsive behaviors seen more commonly in bvFTD (Ossenkoppele et al., 2015). Interestingly, the NFT burden in these patients is increased in the frontal lobes (Johnson et al., 1999).

Others Other focal presentations with underlying AD pathology include corticobasal syndrome and, rarely, progressive agrammatic aphasia or semantic variant primary progressive aphasia, which are typically due to FTLD pathology (Alladi et al., 2007).

Neuropsychiatric Features of Alzheimer Disease Dementia In a study using the Neuropsychiatric Inventory in AD, apathy (72%) was the most common neuropsychiatric symptom, followed by

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B Fig. 95.4 A, Top row: Fluorodeoxyglucose-positron emission tomography (PET) statistical stereotactic surface projection map (Cortex ID) in patient with posterior cortical atrophy demonstrating marked left greater than right occipital-parietal hypometabolism. B, Bottom rows: Tau PET in posterior cortical atrophy demonstrating posterior tau deposition.

agitation (60%) and anxiety (48%) (Mega et al., 1996). Identification of delusions is important because it often precedes physically aggressive behavior (Gilley et al., 1997). Common delusions in AD include paranoia and infidelity. Identification of neuropsychiatric features is important because these symptoms result in significant caregiver burden and can be targeted for treatment (Kaufer et al., 1998).

Diagnostic Criteria For many years, the most commonly used criteria for the diagnosis of AD were the National Institute of Aging and Stroke–Alzheimer’s Disease and Related Disorders Association criteria (McKhann et al., 1984b). However, over the ensuing years, it became apparent that the pathophysiological

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underpinning of AD began many years before the symptoms of dementia presented themselves. Therefore, in 2011, the National Institute on Aging–Alzheimer’s Association (NIA–AA) published revised criteria for the AD process. In this exercise, a distinction was drawn between the clinical symptoms of AD and the underlying pathophysiology. That is, prior to this point, AD was defined as a clinical–pathological entity, but that caused confusion in the field (Petersen, 2018). Therefore, the NIA– AA research criteria characterized the AD clinical spectrum in three phases: dementia, MCI, and preclinical. The dementia due to AD phase was quite similar to what had been defined in 1984 but was made more specific and suggested that biomarkers for AD may be useful in the future when they are validated. The new criteria, however, also recognized a

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TABLE 95.6

Syndrome

A similar condition, sNAP MCI has been described (Knopman et al., 2013). Fig. 95.6 compares the newest research diagnostic criteria for AD (Dubois et al., 2014; McKhann et al., 2011) and reports the NIA– AA criteria, including the 2018 proposed research framework, which divorces the pathology from the clinical stage. This proposed framework is a significant departure from the 1984 and 2011 proposals since AD could only be called a disease if there was biomarker or autopsy evidence for the presence of amyloid (neuritic plaques) and tau (neurofibrillary tangles) independent of clinical state. One implication of this proposal is that a clinically unimpaired person could be labeled as having AD if there was biomarker evidence for amyloid and tau. Fig. 95.1 reports the NIA–AA criteria for MCI due to AD. The International Working Group has also incorporated biomarkers into updated criteria in 2007 (Dubois et al., 2007) and 2014 (Dubois et al., 2014).

Posterior Cortical Atrophy

Clinical Features Insidious onset Gradual progression Prominent early disturbance of visual ± other posterior cognitive functions Cognitive Features At least three of the following must be present as early or presenting features: Space perception deficit Simultanagnosia Object perception deficit Constructional dyspraxia Environmental agnosia Oculomotor apraxia Dressing apraxia Optic ataxia Alexia Left/right disorientation Acalculia Limb apraxia (not limb-kinetic) Apperceptive prosopagnosia Agraphia Homonymous visual field defect Finger agnosia All of the following must be evident: Relatively spared anterograde memory function Relatively spared speech and nonvisual language functions Relatively spared executive functions Relatively spared behavior and personality Neuroimaging: Predominant occipito-parietal or occipito-temporal atrophy on magnetic resonance imaging/hypometabolism on positron emission tomography/ hypoperfusion single-photon emission computed tomography

Neuropsychology in Alzheimer Disease Dementia

Adapted from Crutch, S.J., Schott, J.M., Rabinovici, G.D., Murray, M., Snowden, J.S., van der Flier, W.M., et al., 2017. Consensus classification of posterior cortical atrophy. Alzheimers Dement. 13, 870–884..

milder symptomatic stage of the AD process which was termed MCI due to AD (Albert et al., 2011). This stage recognized the growing literature on MCI that had been generated in the previous decade, documenting the existence of a clinical phase of the disease by which people may be mildly impaired from a cognitive perspective, usually with a memory disorder, but were otherwise intact in other cognitive domains and were functionally intact (Petersen et al., 2018). The most novel phase of the disease process was termed preclinical AD. In this phase, subjects were cognitively and functionally normal but harbored the underlying pathophysiological features of AD, such as amyloid deposition. This phase of the disease was meant to generate research on the preclinical aspects of the disease process to allow intervention when disease-modifying therapies become available. Subsequent research has demonstrated that these research criteria are reasonably accurate and data regarding the validation of the biomarkers are accumulating (Jack et al., 2012; Landau et al., 2012). The role of biomarkers has been documented using both neuroimaging and cerebrospinal fluid measures (Jack et al., 2012; Vos et al., 2013). Recent work has revealed a group of preclinical subjects without the typical AD biomarker profile (i.e., no evidence of Aβ deposition on PET or in the CSF) but evidence of neurodegeneration by FDGPET or MRI, termed suspected non-Alzheimer disease pathophysiology or sNAP given the absence of Aβ deposition (Knopman et al., 2012b).

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Neuropsychology provides a more detailed understanding of cognitive constructs, thereby allowing identification of what cognitive functions are deficient or preserved. The pattern of neuropsychometric testing abnormalities can assist in predicting underlying anatomy and in the differential diagnosis of dementia. Testing is particularly helpful early in the course. Neuropsychology uses well-developed standards based on normative data that improve clinical utility and predictive value. The NIA workgroup consensus criteria of MCI due to AD (Albert et al., 2011) recommend episodic memory evaluation to assist in predicting those with MCI at high risk of converting to AD dementia. Memory testing alone is insufficient, and simple bedside testing cognitive screens can be insensitive to early changes of neurodegeneration. The preservation versus impairment in memory subcomponent testing allows for differentiation among disorders. In brief, learning or encoding refers to the transfer of to-be-learned material from short-term sensory stores into consolidated traces in recent memory involving numerous integrated networks. Free recall pertains to the retrieval of that material without any cues or aids and recognition refers to the identification of the material from among several candidates. A classical memory test such as a verbal memory test consists of reading a list of words over multiple trials. An improvement in encoding over the learning trials (i.e., an increase in number of correct words per trial) is found in normal learning. An individual with an encoding problem may demonstrate a flat learning curve (i.e., the same number of words per trial). Despite the flat learning curve, an encoding problem might lead to preserved free recall and recognition of words with cues. A retrieval deficit is manifest when the person is unable to perform free recall of the material but is able to recall the items when retrieval cues are given. For example, if the person remembers the word “sweater” and is unable to free recall it but can recall it when cued, “It is an item of clothing,” then the person was demonstrating a retrieval failure since the word was encoded but not recalled without cues. With a retention or consolidation problem, the individual generally encodes normally with improvement in number of words learned over trials, but with delayed recall has significant difficulty recalling words and does not benefit from recognition cuing. Encoding problems may correspond to attentional deficits or a failure of medial temporal lobe structures such as the hippocampus to facilitate consolidation of the material. This pattern of poor learning and consolidation is commonly seen in AD. In contrast, a relatively pure retrieval problem would be more characteristic of parkinsonian disorders, vascular cognitive impairment, or other disorders not involving the medial temporal lobe. Other neuropsychometric tests can provide discriminating information. For example, category and letter fluency tests may also provide useful diagnostic pattern in AD. Typically, fluency for semantic categories (e.g., fruits, vegetables, and animals) is impaired relative to letter fluency performance (e.g., words beginning with a certain letter). This discrepancy in verbal fluency performance

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B Fig. 95.5 A, Top row: T2 fluid-attenuated inversion recovery magnetic resonance imaging scans in a patient with logopenic primary progressive aphasia revealing significant left parietal and temporal atrophy (red arrows). Bottom row: Fluorodeoxyglucose-positron emission tomography (PET) statistical stereotactic surface projection map (Cortex ID) in patient with logopenic aphasia demonstrating left temporal-parietal hypometabolism. B, Tau PET in logopenic primary progressive aphasia demonstrating left greater than right temporal and parietal tau deposition.

tends to reflect temporal lobe involvement in AD pathology and the relative preservation of subcortical circuitry. Confrontation naming of common objects is also impaired in early AD. Executive function tasks may also be impaired in early AD as evidenced by tasks requiring set-shifting and sequencing, including Trail Making Test Part B (Albert, 1996). Tests of visual spatial function including figure copying can also be impaired early in AD spectrum disorders.

Biomarkers in Alzheimer Disease Cerebrospinal Fluid Biomarkers

The combination of reduction in the CSF Aβ42 and elevation in the CSF tau protein has a sensitivity of 85% and specificity of 86% for the

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diagnosis of AD dementia (Hulstaert et al., 1999). More recent studies using Aβ42 and tau or phosphorylated tau suggest these biomarkers can improve diagnosis in difficult cases and predict conversion from MCI to AD dementia (Hansson et al., 2006; Mattsson et al., 2009; Shaw et al., 2009). The current research framework includes elevated phosphorylated tau as evidence of pathological tau accumulation while the less specific total tau is used as a neurodegenerative biomarker (Jack et al., 2018a). While these biomarkers can provide important information, normal CSF Aβ42 and tau have been reported in autopsy-proven AD dementia patients (Brunnstrom et al., 2010). Recent data suggest that novel CSF markers, for example, neurofilament light protein, may be good index of neurodegeneration (Mielke et al., 2019).

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Alzheimer disease 1984 NINCDS-ADRDA criteria Clinical-pathological definition

2011 NIA-AA criteria Clinical syndrome with biomarkers for amyloid and neurodegeneration

2014 IWG-2 The presence of dementia not required; therefore, both MCI and dementia are grouped together. Separate criteria for atypical AD and mixed AD

2018 NIA-AA framework Alzheimer’s disease as a biological entity defined by positive biomarkers for amyloid and tau clinical spectra independent Fig. 95.6 Timeline of Criteria and Research Frameworks for Alzheimer Disease (AD). The International Working Group 2 (IWG-2) (Dubois et al., 2014) criteria do not require the presence of dementia: therefore, both mild cognitive impairment (MCI) and dementia are grouped together. IWG-2 includes separate criteria for atypical AD and mixed AD. The National Institute on Aging and the Alzheimer Association (NIA-AA) criteria (McKhann et al., 2011): Dementia due to AD criteria is separated into three subgroups, uncertain, intermediate, and high, representing the likelihood that the dementia syndrome is due to underlying AD pathology. Amnestic presentation refers to decline in learning and recall. Nonamnestic presentation refers to decline in language, visuospatial function, or executive function. Both sets of criteria include exclusionary criteria such as the presence of other types of dementia or systemic medical issues that better account for cognitive decline. In the 2018 research framework, the AD is defined purely on biological grounds requiring the presence of an amyloid and tau biomarker separate from clinical status.

Neuroimaging Biomarkers Various neuroimaging biomarkers are sensitive to different stages and markers of AD. Structural imaging. The AAN practice parameter recommends that a neuroimaging examination, either CT or MRI, be performed at the time of the initial dementia assessment (Knopman et al., 2001). While this recommendation was primarily suggested to exclude reversible and treatable causes of dementias, MRI provides much higher resolution than CT and has proven very useful in the differential diagnosis of dementia and as a biomarker of neurodegeneration in AD dementia. Medial temporal lobe atrophy of the hippocampus and entorhinal cortex with concomitant dilatation of the temporal horns is an early characteristic of AD dementia (Fig. 95.7) and can predict conversion from normal cognition to MCI and MCI to AD dementia (Jack et al., 2000). Reduction in hippocampal volumes correlates with NFT pathology at autopsy and cognitive decline (Jack et al., 2002). In aMCI, atrophy is limited to the medial temporal lobe structures while with AD onset, atrophy spreads to the lateral temporal and parietal cortices. This change corresponds with Braak staging, which is why structural MRI serves as a biomarker of neurodegeneration (Braak and Braak, 1991).

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Fig. 95.7 Longitudinal coronal T1 magnetic resonance imaging in a patient that progressed from normal cognition to amnestic mild cognitive impairment (aMCI) to dementia due to Alzheimer disease (AD). Note progressive hippocampal and cortical atrophy. Top image: Normal cognition age 75. Bottom left image: aMCI age 81. Bottom right image: Dementia due to AD age 86.

The utility of volumetric measurements of the entorhinal cortex, while promising, is controversial. Although medial temporal lobe structures become atrophic in early AD and correlate with episodic memory performance, later in the disease atrophy rates are greater in the temporal, parietal, and frontal cortices and are associated with deterioration in other cognitive domains including language, praxis, and visuospatial (Frisoni et al., 2010). Medial temporal lobe atrophy is not specific for AD and can be seen in other degenerative and vascular processes. In particular neurodegenerative hippocampal sclerosis of aging can have a similar imaging appearance to Alzheimer dementia (Botha et al., 2018b). During the dementia stage, significant global atrophy occurs typically most significantly in a temporal-parietal distribution with coinciding ventriculomegaly. The presence of white matter hyperintensities observed by FLAIR or T2 MRI also appears to contribute to cognitive impairment in AD (Provenzano et al., 2013). Cerebral amyloid angiopathy. Hypointense signal on MRI gradient-echo sequences represents hemosiderin deposition reflective of cerebral microbleeds. Newer techniques, such as susceptibilityweighted imaging, are more sensitive for these findings. In the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort, cerebral microbleeds were present in approximately 33% of cases and increased with Aβ load as measured by amyloid PET (Kantarci et al., 2013). When cerebral microbleeds occur in a lobar distribution in elderly patients, they often represent cerebral amyloid angiopathy (CAA). In a population-based study, β-amyloid load on PET was associated with lobar but not with deep cerebral microbleeds (Graff-Radford et al., 2019). Identification of coexisting CAA and AD has clinical importance because patients with AD and CAA have worse cognition

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Fig. 95.8 Fluorodeoxyglucose-positron emission tomography statistical stereotactic surface projection map (Cortex ID) showing marked hypometabolism involving the temporal-parietal junction and posterior cingulate gyri which is relatively symmetric. Relative preservation of the frontal and occipital lobes consistent with Alzheimer disease dementia.

and higher mean tangle and plaque rates than patients with just AD changes alone (Arvanitakis et al., 2011; Pfeifer et al., 2002). Specific cognitive correlates of CAA include decreased perceptual speed and episodic memory (Arvanitakis et al., 2011). CAA preferentially involves the occipital lobe. Functional imaging. Functional brain imaging using singlephoton emission computed tomography (SPECT) and FDG-PET can suggest disease specific patterns. While functional imaging studies have not been endorsed by criteria for MCI or AD due to dementia (Albert et al., 2011; McKhann et al., 2011), their value is recognized in selected cases. Especially when the structural imaging scan is not informative, functional imaging modalities may provide additional useful information (Reiman et al., 1996; Sanchez-Juan et al., 2014). Decreased blood flow in a temporal-parietal distribution seen on SPECT correlates with hypometabolism seen on FDG-PET and is suggestive of AD. In aMCI, hypometabolism is primarily in the hippocampus and posterior cingulate. In AD dementia, the hypometabolism includes these regions as well as the temporal-parietal regions (Mosconi et al., 2008). Recent studies have indicated that FDG-PET can be used as an aid in the diagnosis of AD dementia, in particular in differentiating AD from FTD (Foster et al., 2007; Rabinovici et al., 2011), which has led to the Centers for Medicare and Medicaid Services approving reimbursement for evaluating this differential diagnosis. Several studies have validated the use of FDG-PET as a biomarker in AD, resulting in its inclusion as a biomarker in the most recent AD criteria (McKhann et al., 2011). In MCI ADNI participants, FDG-PET predicted conversion to AD dementia (Landau et al., 2010). Of particular interest, FDG-PET in cognitive normal homozygous carriers for APOE ε4 demonstrates hypometabolism in the posterior in the cingulate, temporal, and parietal cortices (Reiman et al., 1996). Fig. 95.8 demonstrates an FDG-PET in a patient with typical AD dementia. Amyloid imaging. The development of Pittsburgh Compound B (PiB) has allowed measurement of amyloid burden in living subjects (Klunk et al., 2004). While not currently recommended for routine clinical use, this imaging modality is already being used in clinical trials for identifying preclinical AD, MCI due to AD, and monitoring effectiveness of amyloid-targeted therapies. Appropriate-use criteria have been published which make recommendations regarding the clinical setting in which amyloid PET could be considered (Johnson et al., 2013). The deposition of amyloid as measured by PiB-PET occurs

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Fig. 95.9 Top Row: Amyloid Pittsburgh Compound B (PiB)-Positron Emission Tomography Imaging. A, PiB retention is not present. B, Significant PiB retention. Bottom Row: Tau PET in Typical amnestic AD. C, Coronal view of Tau signal in medial temporal lobe. D, Axial view of Tau PET signal in the bilateral temporal lobes (Courtesy Dr. Val Lowe.)

primarily in the frontal and temporal-parietal regions (see Fig. 95.9 for examples of PiB-PET imaging). Since its discovery, numerous studies have demonstrated possible clinical utilities. PiB-PET outperformed FDG-PET in discriminating FTD from AD (Rabinovici et al., 2011). PiB binding cross-sectionally correlates with cognitive function (Jack et al., 2008). Longitudinally, however, once, symptomatic, the deposition of β-amyloid plateaus demonstrating that PiB utility may be greatest in the preclinical stages (Engler et al., 2006). In a population-based study of cognitively normal individuals over age 70, approximately one-third have significant β-amyloid load (Kantarci et al., 2012b). The prevalence of a positive amyloid PET scan among cognitively unimpaired individuals in the general population

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CHAPTER 95 Alzheimer Disease and Other Dementias increased from 2.7% in individuals between ages 50 and 59 years to 41% in those individuals between ages 80 and 89 years (Roberts et al., 2018). The high rate of amyloid-positive scans in the cognitively normal population along with the absence of any disease-modifying therapy would suggest amyloid imaging in cognitively normal elderly individuals should be reserved for research purposes until disease-modifying therapy is available. Several F-18 analog amyloid tracers have been developed and approved for clinical use by the Food and Drug Administration (FDA) florbetapir, flutemetamol, and florbetaben. The F-18 agents provide comparable results to PiB imaging, but a longer half-life allows for transportation to clinical centers. Florbetapir performs well compared to autopsy confirmation (Clark et al., 2011). In the ADNI study, Aβ deposition, as measured with florbetapir, correlated with cognitive decline in cognitive normal and MCI participants. In the cognitive normal group this decline sometimes occurred in the absence of FDG abnormality (Landau et al., 2012). Multiple studies have demonstrated the prognostic importance of amyloid PET. The incident risk of developing mild cognitive impairment increased greater than twofold among cognitively unimpaired individuals who were amyloid PET positive compared to those who were amyloid PET negative (Roberts et al., 2018). Task-free functional magnetic resonance imaging. Functional MRI (fMRI) measures the blood-oxygen-level dependent (BOLD) signal, essentially relying on the fact that neuronal activation in a region produces associated increases in blood flow to that same region. Dementia caused by neurodegeneration is caused by the disruption of specific, large-scale neural networks (Seeley et al., 2009). fMRI is one technique to study these neural networks. The default mode network (DMN) refers to connected regions of brain that are active when an individual is at rest or not focused on the external environment (Raichle et al., 2001). In AD, the DMN is selectively targeted. The core regions of the brain activated in this default state include the medial prefrontal cortex, inferior parietal lobule, posterior cingulate gyrus, hippocampal formation, and lateral temporal cortex. These changes on fMRI occur early in the disease process. In cognitively normal APOE ε4 subjects, there is a decrease in connectivity relative to controls (Machulda et al., 2011). These changes occur in the absence of brain amyloidosis, as measured by amyloid PET and Aβ42 levels in the CSF (Sheline et al., 2010). Therefore, fMRI changes may be a very early marker of the pathophysiology of AD. While current use of fMRI in dementia is limited to research, it has provided substantial knowledge about degenerative disease and is actively being investigated as a biomarker. Tau imaging. Recently, several tau imaging tracers have been developed The FDA approved Tauvid (flortaucipir F18) for patients being evaluated for AD. Since tau comprises the other hallmark of the AD pathological process, neurofibrillary tangles, the ability to image it in vivo would be extremely useful. Tau is also implicated in a variety of other disorders and the ability to characterize this protein would be advantageous in diagnosis and following putative treatments. The presence of tau PET signal in the inferior temporal cortex is closely linked to clinical symptoms (Johnson et al., 2016). Tau PET reliably distinguishes AD dementia from non-AD dementias (Ossenkoppele et al., 2018). Since flortaucipir binds to AD-type tau (3R,4R), it is not surprising that tau-PET levels in the temporal pole of tau mutation (microtubule-associated protein tau [MAPT]) cases were lower than in AD dementia cases, with the exception of tau mutation cases, whose MAPT mutation occurs outside of exon 10 (V337M and R406W) and, therefore, develop AD-like tau and have tau-PET signal close to the AD dementia levels (Jones et al., 2018a). Many issues exist regarding these tracers, such as specificity for tau and various tau isoforms, but it is a promising technique. For example, in semantic

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Aβ Neurodegeneration Cognitive symptoms

Stage 1 Stage 2 Stage 3 MCI Fig. 95.10 Hypothetical model for the sequence of biomarkers and pathological events in the development of Alzheimer disease. Aβ, Amyloid beta; MCI, mild cognitive impairment. (Modified with permission from Jack, C.R. Jr., Knopman, D.S., Jagust, W.J., et al., 2010. Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol. 9, 119–128.)

variant primary progressive aphasia, which is most often associated with TAR DNA-binding protein (TDP)-43-positive inclusions, tauPET signal has been seen in areas of atrophy, possibly reflecting offtarget binding (Josephs et al., 2018; Makaretz et al., 2018). Tau PET has allowed investigation into how patterns develop with age. In cognitively unimpaired individuals in the preclinical stage of AD, in addition to the expected medial temporal tau involvement, tau is present in extra-medial temporal regions and extra-temporal regions arguing against a region-region spread of tau pathology that has been previously proposed (Lowe et al., 2018) (see Fig. 95.9 bottom row for examples of tau-PET imaging).

Longitudinal Tracking of Biomarkers The advent of biomarkers for tracking the progression of AD has vastly increased our knowledge about its temporal progression and will play a key role in clinical trial design and execution. Several key biomarker studies in conjunction with data of unselected autopsies published over a short period of time have provided evidence that the pathophysiological processes underlying AD start decades before cognitive decline. This knowledge has shifted the focus of disease therapies to the presymptomatic or early symptomatic phases of the disease. One influential hypothetical model for the sequence of these biomarkers was first proposed by Cliff Jack in 2010 (Jack et al., 2010) and revised in 2013 (Jack and Holtzman, 2013). This model represents the pathophysiological processes underlying AD, and is summarized in Fig. 95.10. The Dominantly Inherited Alzheimer Network (DIAN) study has provided important information regarding the timing of biomarkers in autosomal dominant AD largely consistent with the model described above (Bateman et al., 2012). This sequence can be summarized by the following: CSF Aβ42 declines over two decades before clinical symptoms; Aβ-PET abnormalities begin about 15 years before symptoms; brain volume loss and increased CSF tau also occur 15 years before symptoms; FDG-PET abnormalities occur 10 years before symptoms (Bateman et al., 2012). While this sequence is predictable for dominantly inherited AD, the Mayo Clinic Study of Aging has demonstrated that a substantial proportion of cognitively normal subjects have neurodegeneration biomarkers but not amyloid biomarkers, as was noted earlier in this chapter (Jack et al., 2012; Knopman et al., 2012a). In preclinical AD, 42% of incident Aβ-PET positive cases also have positive neurodegeneration

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biomarkers first. This suggests that at least two biomarker profile pathways to preclinical AD exist, and some of the cases labeled sNAP are on the AD pathway but with a different biomarker progression (Jack et al., 2013). In the same framework, progression in MCI to dementia has also been characterized and a similar group of MCI sNAP subjects have been identified, implying that neurodegenerative pathologies other than AD may be operating in some MCI subjects, and while most progress to AD dementia, some do not (Petersen et al., 2013). Recently, longitudinal tau-PET studies have demonstrated the rate of accumulation of tau over time. Cognitively unimpaired individuals accumulate tau at a rate of 0.5% per year compared to cognitive impaired individuals who accumulate at a rate of 3% per year (Jack et al., 2018b).

Late-Onset Genes

In a large twin study from Sweden based on 392 pairs of twins, the genetic component of AD was estimated to be 58%–79% (Gatz et al., 2006). Family history of AD can provide important risk information. The lifetime risk of AD dementia in first-degree relatives is approximately 39% and this risk increases to 54% by age 80 if both parents have AD dementia (Lautenschlager et al., 1996).

Apolipoprotein E (APOE) is the most important genetic risk factor for late-onset AD (Corder et al., 1993). APOE has three isoforms (E4 associated with high risk, E3 associated with neutral risk, and E2 which is protective). About 20% of all late-onset AD is thought to be related to APOE ε4 (Slooter et al., 1998). APOE ε4 affects AD risk and age of onset in a dose-dependent way; for example, E4 homozygotes have a mean age of onset of 68 with a lifetime AD risk of 91%; in E4 heterozygotes, the mean age of onset is 76 with a 47% lifetime risk (Liu et al., 2013). In contrast, E4 noncarriers have a mean age of onset of 84 with an approximately 20% lifetime frequency (Corder et al., 1993; Liu et al., 2013). Trem2 variants have recently been identified as rare risk variants for AD dementia (Guerreiro et al., 2013b). The odds ratio is similar to APOE ε4 but it is rare, which is why it was not seen in previous genome-wide association studies. Its population-attributable risk is lower than APOE ε4 due to its lower frequency. Many other risk loci have been associated with AD risk, but their overall impact is thought to be small. These include CD33 molecule, ATP-binding cassette, subfamily A, member 7 (ABCA7), sortilin-related receptor L (SORL1), clusterin (CLU), phosphatidylinositol binding clathrin assembly protein (PICALM), as well as many others (Guerreiro et al., 2013a).

Early-Onset Genes

Genetic Testing

Three rare, early-onset, fully penetrant gene mutations have been described to cause Alzheimer dementia. While mutations in these genes are rare, studying them has been instrumental in our understanding of AD. All three increase brain Aβ levels and form an important part of the amyloid hypothesis for AD (discussed later). This provided the basis for several animal models and biomarker development including development of CSF and PET Aβ. Amyloid precursor protein chromosome 21. Mutations in amyloid precursor protein (APP) were the first mutation to be described to cause AD. Chromosome 21 became a chromosome of interest for AD, since patients with trisomy 21 (Down syndrome) develop AD pathology after age 40. Investigators looked at the brains of patients with AD dementia and Down syndrome and found Aβ in both. Since Aβ is the product of APP (located on chromosome 21), APP became a candidate gene (Glenner and Wong, 1984; Goate et al., 1991; Goldgaber et al., 1987; St George-Hyslop et al., 1987). All APP mutations that cause AD change the Aβ42 to Aβ40 ratio. Recently, certain mutations in APP have been described to be protective against AD (Jonsson et al., 2012) by decreasing the production of Aβ. The mean age of onset for APP mutation families is approximately 50. In addition to early age of onset, the clinical presentation of APP mutations carriers may be distinguished from sporadic AD by the presence of myoclonus, seizures, early dyscalculia, cerebral white matter changes, and even corticospinal tract signs (Rossor et al., 1993). Presenilin 1 chromosome 14. The majority of early-onset familial AD cases are mapped to chromosome 14 (Rossor et al., 1993). In 1995, mutations on chromosome 14 were found in PSEN1 in autosomal dominant AD families (Sherrington et al., 1995). Interestingly, presenilin is part of the γ secretase complex that cleaves APP (Wolfe et al., 1999). Clinical features of PSEN1 families can include significant aphasia in addition to myoclonus and seizures (Lampe et al., 1994). Presenilin 2 chromosome 1. PSEN2 was discovered shortly thereafter (Rogaev et al., 1995). PSEN 2 mutations are the rarest of the autosomal dominant mutations. PSEN2 is part of the γ secretase complex that cleaves APP. Most of these individuals are descendants of families from the Volga River region of Russia. Similar to the other familial early-onset mutations, PSEN2 families have a higher rate of seizures than in sporadic AD (Jayadev et al., 2010).

Genetic testing for APP, PSEN1, PSEN2, and APOE is commercially available in Clinical Laboratory Improvement Amendments (CLIA) laboratories. Routine genetic testing is not recommended by the practice parameter of the AAN, but if patients have testing, genetic counseling prior to testing is essential. Testing may have significant implications for patients and families in terms of family planning, financial costs, and risk of depression. Genetic testing currently does not change treatment of the patient but may provide opportunities to participate in research studies such as DIAN.

Genetics

Alzheimer Genetics

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Alzheimer Pathophysiology All three early-onset AD genes (APP, PSEN1, PSEN2) play a role in Aβ metabolism which has provided the foundation for the amyloid hypothesis of AD. The basic hypothesis is that abnormal Aβ metabolism altering the Aβ42/Aβ40 ratio in the brain causes Aβ oligomer formation and aggregation to form fibrils, which form the amyloid plaque. This oligomer formation and aggregation results in a cascade of events, including tau protein tangle formation, increased inflammatory response, and oxidative injury, to cause neurotoxicity and neurodegeneration. More recent work has focused on the pathogenicity of soluble Aβ oligomers with converging basic scientific evidence that they play a major role in neurotoxicity. For example, human Aβ oligomers injected into the hippocampus of rats inhibit long-term potentiation (Walsh et al., 2002) and result in synaptic dysfunction which impairs memory formation (Walsh et al., 2002). Aβ is derived from APP through proteolytic processing. Aβ is produced normally in the body but under normal circumstances it is removed efficiently by a number of mechanisms. These include breakdown by extracellular proteases, such as insulin-degrading enzyme, and receptor-mediated endocytosis followed by lysosomal degradation and drainage through the cerebral vasculature and into the CSF via the glymphatic system (Xie et al., 2013a).

Amyloid Hypothesis The amyloid hypothesis proposes that AD can result from too much Aβ production or a change in ratio with more Aβ42 than Aβ40 produced, or impaired clearance of Aβ. Understanding APP processing is central to the amyloid hypothesis (Hardy and Higgins, 1992).

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Fig. 95.11 Amyloid Precursor Protein Processing. Aβ, Amyloid Beta; AICD, APP intracellular domain; APP, amyloid precursor protein; sAPPα, soluble APP α.

APP is a type 1 protein with the amino terminal in the extracellular space. APP is cleaved by three enzymes (α, β, and γ secretase) (Selkoe and Schenk, 2003) and can undergo processing either through the amyloidogenic pathway (γ and β secretases) which produces Aβ, or the nonamyloidogenic pathway (α secretase) (Fig. 95.11). In the amyloidogenic pathway, APP is first cleaved by β secretase. This cleavage produces a β C-terminal fragment, which stays on the membrane and soluble APP Aβ. This β C-terminal fragment is then cleaved by γ secretase in the transmembrane region producing APP intracellular domain (AICD) and Aβ peptide, which is then released into extracellular space. PSEN 1 and 2 are part of the γ secretase complex (Iwatsubo, 2004). Other components of the γ secretase complex include nicastrin, APH-1. This aforementioned cleavage occurs by sequential events eventually producing β-amyloid fragments, either Aβ1-42 (about 10%) or Aβ1-40 (about 90%). Aβ can aggregate and these aggregates may form oligomers which may be toxic. Aβ1-42 has a greater tendency to aggregate and is found in greater concentration in plaques, while Aβ1-40 is the predominant form in vascular amyloid deposits. In the nonamyloidogenic pathway, APP cleavage is mediated by α secretase. This cleavage is in the middle of the β-amyloid peptide above the surface of the membrane, thereby preventing the formation of Aβ. This cleavage generates soluble APP α (sAPPα) and α C-terminal fragments, which can also undergo cleavage by γ secretase, producing a nontoxic peptide called P3. APOE functions primarily in the transport of lipids/cholesterol from astrocytes to neurons. The presence of the APOE ε4 allele is associated with decreased CSF Aβ42 and increased brain Aβ burden seen on Aβ (Morris et al., 2010). Despite these biomarker changes, the mechanisms of E4 leading to AD are numerous and include both Aβrelated and Aβ-unrelated mechanisms. Aβ-dependent mechanisms include interfering with cerebral Aβ clearance and promoting Aβ aggregation. Aβ-independent mechanisms include promoting abnormal lipid transport, thereby altering synaptic plasticity and the inflammatory response (Liu et al., 2013).

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Accumulating evidence suggests that a common mechanism across neurodegenerative diseases may include the trans-synaptic spread of tau and other misfolded proteins to anatomically connected regions in a prion-like manner where the protein is released and taken up by the anatomically related neuron (Walker et al., 2013). Recent efforts have been made to investigate how large-scale neural networks may be involved in the pathophysiology of AD and other neurodegenerative disorders. It has long been known that systems of connected neurons are selectively vulnerable to neurodegenerative disease, but the pathophysiology behind this association is debated. In contrast to disease models that emphasize the molecular misfolding of proteins spreading within connected systems, complex systems models emphasize the causal role of dynamic functional activity within brain systems interacting with molecular physiology (Jones et al., 2016).

Alzheimer Pathology Alzheimer disease is defined by two pathological findings: extracellular plaques composed primarily of amyloid and intraneuronal neurofibrillary tangles composed primarily of hyperphosphorylated tau. Both involve abnormal conformational changes in proteins. Proteolytic events are critical in APP processing that leads to Aβ. In neurofibrillary pathology, phosphorylation of tau is a critical event. Macroscopically, AD is characterized by diffuse brain atrophy including significantly decreased weight at autopsy. Some areas are preferentially affected, including multimodal association areas, while others, like primary motor, somatosensory, auditory, and visual cortices, are relatively spared. The limbic areas including hippocampi and cingulate gyrus are severely affected. Substantia nigra (unlike in parkinsonian disorders) is relatively spared while locus coeruleus is severely affected. Work from Braak looking at autopsies of young adults suggests the earliest place neurofibrillary tangle pathology occurs is in the locus ceruleus, with tangles occurring in the third or fourth decades without involvement of tangles in the limbic areas or the presence of amyloid plaques (Braak et al., 2011). Fig. 95.12 summarizes typical examples of Alzheimer pathology.

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D Fig. 95.12 Alzheimer Disease Pathology. Bielschowsky stain of CA1 of the hippocampus (A) and temporal cortex (B) demonstrating neurofibrillary tangles and amyloid plaques. C, Tau stain of CA1 of the hippocampus demonstrating neurofibrillary tangles. D, Aβ stain of the parietal cortex demonstrating plaques. (Courtesy Dr. Joseph Parisi.)

Amyloid Plaques Aβ deposition in the brain occurs in a sequential manner starting in the cortex, followed sequentially by the hippocampus, basal ganglia, thalamus, and basal forebrain before in the final stages reaching the brainstem and cerebellum (Thal et al., 2002). Plaques are complicated heterogeneous lesions composed of extracellular protein deposits and certain cellular components. Aβ derived from APP is the sine qua non of plaques, which are in turn the defining pathological finding in AD. Despite the strong association of Aβ with plaques, in reality plaques contain many other components. Other associated components of the plaque include APOE, alpha-1 antitrypsin, complement factors, and immunoglobulins. Plaques can be divided into diffuse (Aβ mainly) and neuritic plaques (includes damaged tau containing axons and dendrites, i.e., neurites). Cell components seen in plaques include neurites, microglia, and astrocytes. The typical neuritic plaque has a dense core of Aβ and less compact rim consisting of neurites, microglia, and astrogliosis at the periphery. Diffuse plaques have less diagnostic specificity and can be seen in a variety of different disorders. They contain Aβ but do not stain with tau-containing neurites and are not associated with synaptic loss, reactive astrocytes, or microglia.

Neurofibrillary Tangles The major component of the NFT is tau within neurons and their cell processes. First, pretangles form in the neuron cytoplasm, often

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concentrated around the membrane. Then, tau is organized into fibrils as NFTs. When the cell dies, the tangle may be situated extracellularly. Normal tau is a microtubule-associated protein and is not visible within the brain. In NFTs, tau has become hyperphosphorylated and abnormally conformed. This tau can be detected with immunostains that bind abnormally conformed tau. Braak and Braak (1991) have described a fairly predictable spread of NFT pathology through the brain occurring in six stages which can be reduced to three, consisting of transentorhinal (stages I, II), limbic (III, IV), and isocortical (V, VI) stages. Braak staging has recently been modified to include brainstem regions preceding medial temporal involvement (Braak et al., 2011). Several other associated pathological findings may be seen with AD. CAA, often present in leptomeningeal vessels, capillaries, small arterioles, and middle-sized arteries, is seen in over 80% of AD cases. In contrast to cerebral plaques consisting primarily of Aβ42, CAA’s major component is Aβ40. Granulovacuolar bodies, typically found in the hippocampus, are small dense granules within the vacuole and can be labeled with acid phosphatase, tubulin, ubiquitin, and neurofilament. Hirano bodies (eosinophilic rod bodies), also typically found in the hippocampus, are often in neuronal processes and contain actin and actin-binding proteins. The significance of granulovacuolar bodies and Hirano bodies is incompletely understood.

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Clinicopathological Correlations Numerous studies have shown that dementia duration and severity correlate better with NFTs compared to amyloid plaques (Arriagada et al., 1992; Grober et al., 1999).

Cholinergic Loss Studies of subjects with advanced AD demonstrated depleted cholinergic neurons in the basal forebrain. This finding served as the basis for the cholinergic hypothesis, which postulated that memory loss in AD was caused by a cholinergic deficit. This hypothesis led to the development and approval of acetylcholinesterase inhibitors for AD. In one study (DeKosky et al., 2002), the loss of choline acetyltransferase (ChAT) and cholinergic neurons did not occur until late in the AD course.

Neuropathological Criteria The pathological criteria for AD are based not only on the presence of the pathological lesions but also the severity and location of the lesions. Original criteria (Khachaturian, 1985) were only plaque based and included all types of plaques. In 1991, modifications were then made by the Consortium to Establish a Registry for Alzheimer Disease (CERAD) (Mirra et al., 1991). These criteria emphasized the importance of neuritic plaques over diffuse plaques but lacked specificity because NFTs were not included. In 1997, the NIA and the Reagan Institute criteria were developed which included both neurofibrillary pathology and neuritic plaques and included probability statements (low, intermediate, or high likelihood AD) based on Braak stage and severity of plaques (none, sparse, moderate, or frequent). Most recently, the 2012 criteria incorporated evaluation of coexisting pathologies and the recognition that AD pathological changes can occur without cognitive decline (Montine et al., 2012). The separation of the clinical symptoms from the pathological features of AD was an important advancement for the field. Alzheimer disease is no longer considered a “clinical-pathological” entity; rather there are two continua, clinical and pathophysiological.

TAR DNA-Binding Protein 43 TDP 43 deposition was originally thought to be specific for frontotemporal lobar degeneration. Recent studies, however, have shown that TDP-43 pathology occurs in AD and may play an important role in neurodegeneration and clinical features (Josephs et al., 2014; Wilson et al., 2013).

Alzheimer Pathology in Aging and Mild Cognitive Impairment Plaques can be found in cognitively normal individuals. This has been termed “pathological aging,” although there is significant evidence that these individuals may have preclinical AD (Dickson et al., 1992). The plaques seen in “pathological aging,” unlike neuritic AD plaques, lack tau immunoreactivity. NFTs can also be seen with aging but are typically restricted to the medial temporal lobe and brainstem in cognitively normal individuals. In addition, cognitively normal individuals with tau in the entorhinal cortex will have neurons surrounding the tau, in contrast to AD where tau will be associated with significant neuronal loss. Not surprisingly, autopsies of patients with MCI typically fall in a transition pathological state between aging and AD dementia, most commonly Braak stage II or III (Petersen et al., 2006).

Hippocampal-Sparing Alzheimer Disease While progression of tangles from the medial temporal to association cortex is typical, there is a subgroup of individuals with a high burden of cortical tau pathology with relative sparing of the hippocampus. This is termed hippocampal-sparing AD. Despite the difference in tau

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pathology between sites, the amyloid burden is similar. Hippocampal sparing occurs in approximately 10% of cases (Murray et al., 2011). It occurs more often in men and is an early-onset disease with a more aggressive course. These patients are often clinically diagnosed with frontotemporal dementia, posterior cortical atrophy, or logopenic aphasia.

Treatment

Acetylcholinesterase Inhibitors Acetylcholinesterase inhibitors (AChEIs) are recommended by AAN practice parameter for the treatment of dementia (Doody et al., 2001). The mechanism of action of AChEIs is to improve cholinergic functioning in the brains of patients with AD by increasing the concentration of acetylcholine through inhibition of acetylcholinesterase. Tacrine was the first AChEI approved for use in AD but was limited by four times a day dosing and strict hepatic function monitoring requirements due to a risk of toxicity. These limitations in combination with the development of newer drugs resulted in its disappearance from the market place. Donepezil, a reversible AChEI that can be administered with a single daily dose and does not require laboratory monitoring, was the next AChEI approved by the FDA. Donepezil is initiated at 5 mg per day for 28 days and if tolerated can be increased to 10 mg daily. Initial donepezil studies were 12–24 weeks in duration and demonstrated improvement on neuropsychological testing and clinician evaluation (Burns et al., 1999; Rogers and Friedhoff, 1996; Rogers et al., 1998). Double-blind placebo-controlled trials of up to 1 year demonstrated sustained medication benefit (Winblad et al., 2001). Common side effects include vivid dreaming, diarrhea, and nausea. Education to patients and caregivers about cholinergic mediated gastrointestinal side effects which often attenuate with time can lead to improved drug compliance. Giving the medication in the morning instead of the evening may decrease the vivid dreams. While not common, serious side effects may include provoking bradycardia and heart block in patients with cardiac conduction disorders. Recently, a 23-mg preparation of donepezil became available with inconclusive results as to its effectiveness (Doody et al., 2012). Rivastigmine is another AChEI with FDA approval. Rivastigmine is initiated at 1.5 mg twice daily, which can be increased by 1.5 mg twice daily every 2 weeks to a maximum of 6 mg twice daily. The side effects of rivastigmine mirror those of donepezil, although gastrointestinal side effects may be more common (Rosler et al., 1999). Rivastigmine has been formulated in a patch form and has demonstrated similar efficacy with decreased side effects (Winblad et al., 2007). Galantamine is a reversible AChEI. Galantamine is dosed twice daily, and should be titrated over 4 weeks. Dosing is initiated at 4 mg twice daily, with increases every 2 weeks to 8 mg twice daily and eventually 12 mg twice daily if tolerated. Galantamine is available in a sustained release formulation. The side-effect profile is similar to donepezil and rivastigmine; however, the FDA recommends caution when using galantamine for MCI due to concerns about an increase in cardiac-related deaths in clinical trials evaluating its use in MCI.

N-Methyl-D-Aspartate Receptor Antagonist Memantine is an N-methyl-d-aspartate (NMDA) receptor antagonist. It also blocks the 5-hydroxytryptamine-3 receptor. Memantine was approved by the FDA for the treatment of moderate to severe AD and can be used in conjunction with AChEIs (Tariot et al., 2004) or on its own (Reisberg et al., 2003). Side effects are rare, although confusion and dizziness have been reported.

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Vitamin E In a large double-blind, randomized, placebo-controlled, multicenter trial, high-dose vitamin E (2000 IU a day) and selegiline delayed the progression of moderate AD to severe AD dementia. In contrast, high-dose vitamin E failed to delay progression of MCI to AD dementia (Petersen et al., 2005). This negative trial in concert with a meta-analysis which suggested an increase in all-cause mortality with high-dose vitamin E (Miller et al., 2005) resulted in a decreased enthusiasm for vitamin E in AD dementia. More recently, a large double-blind, placebo-controlled, randomized trial involving patients with mild-to-moderate AD dementia demonstrated less decline with high-dose vitamin E in the primary outcome of the Alzheimer’s Disease Cooperative Study/Activities of Daily Living, which translated to a delay in progression of about 19% per year without an increase in mortality (Dysken et al., 2014). Further research into the safety of high-dose vitamin E in a dementia population will be needed before it can be recommended routinely.

Estrogen Replacement Therapy Epidemiological evidence has recognized that postmenopausal women who take estrogen replacement may be at decreased risk of AD. Randomized controlled trials showed no effect of estrogen on AD risk (Henderson et al., 2000; Mulnard et al., 2000), but there are issues pertaining to the time in life the estrogen was administered, e.g., around menopause or later in life.

Antiinflammatory Medications Converging basic science and epidemiological data suggested that antiinflammatory therapy may decrease the risk of developing AD. Clinical studies using prednisone (Aisen et al., 2000) and nonsteroidal antiinflammatory drugs (NSAIDs) (Aisen et al., 2003) have been negative.

Treatment of Noncognitive Symptoms in Alzheimer Disease Noncognitive side symptoms of AD play a major role in caregiver burden. Medical conditions such as urinary tract infections can present with confusion or agitation in dementia patients and should be excluded prior to considering other therapies. If possible, nonpharmacological treatment is preferred over pharmacological intervention to minimize undesirable side effects. Simple nonpharmacological approaches to neuropsychiatric problems include avoiding prior triggers, limiting changes to the environment, regular exercise, and shifting attention. Other techniques include aromatherapy and music therapy. “Sun-downing,” the phenomenon of increased confusion or agitation late in the day, can be particularly problematic. This can occur in the hospital, in the nursing home, or at home. Nonpharmacological interventions during waking hours include maximizing patient activity, exposing the patient to light, and discouraging daytime napping. Prior to sleep, extra noise should be minimized. Depression commonly accompanies AD. Selective serotonin reuptake inhibitors (SSRIs) are preferable to tricyclic antidepressants because the anticholinergic side effects of tricyclics can exacerbate cognitive decline. Agitation, psychosis, and aggressive behavior are also commonly seen in AD. Traditionally, these behaviors were treated with atypical antipsychotics (risperidone, olanzapine, quetiapine), which have a better side-effect profile than typical antipsychotics such as haloperidol. In 2006, a double-blind, placebo-controlled trial of atypical antipsychotics in Alzheimer patients demonstrated no significant difference in Clinical Global Impression of Change at 12 weeks, although patients in the placebo group stopped medication due to lack of efficacy more than those on olanzapine or quetiapine (Schneider et al., 2006). In addition to the limited effectiveness in randomized clinical trials, these medications are not approved by the FDA

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for behavioral disturbance in dementia and have been associated with increased mortality in dementia patients. In a meta-analysis of randomized placebo-controlled trials, the use of atypical antipsychotics in dementia was associated with an odds ratio of 1.54 for increased mortality (Schneider et al., 2005). The FDA has issued a black box warning for the use of these medications in dementia. After informing the patient and families of the increased risk of death, there is a minority of dementia patients in whom the benefits may outweigh the risks. In these cases, antipsychotics should be used at the lowest effective dose for the shortest period of time necessary. The Citalopram for Agitation in Alzheimer Disease Study demonstrated that the SSRI citalopram given at 30 mg daily improved agitation in AD dementia patients compared to placebo but was associated with prolonged QTc, which led the authors to conclude that it could not be routinely recommended for the treatment of agitation (Porsteinsson et al., 2014).

Patient Safety Driving

In 2010, the AAN published a practice parameter on the evaluation and management of driving in dementia patients. This practice parameter reports that useful indicators of impaired driving performance include a Clinical Dementia Rating Scale (CDR) of 0.5 or above, MMSE score of ≤ 24, caregiving rating driving safety as unsafe, recent history of crashes or traffic violation, or aggressive or impulsive personalities (Iverson et al., 2010). Patients with MCI or mild dementia and no other risk factors for impaired driving may benefit from a driving-risk management strategy that includes regular roadside driving tests, while those with dementia and several risk factors for impaired driving should surrender driving privilege (Iverson et al., 2010).

Medication Supervision Given the cognitive impairment, medication errors are common when demented patients manage their own medications. The caregiver and patient should be educated to develop an organized system to prevent any medication errors.

Other Safety Issues Dementia patients with a propensity to wander can obtain an identity bracelet through the Alzheimer Association. The safety of the home living situation should be reviewed with the patient and caregiver, including support system need for adaptive equipment at home. While patients may live at home with a spouse for many years, assisted living and nursing homes may need to be considered based on level of care needed, behavioral disturbance, and caregiver burden. During the early stages of cognitive impairment, the healthcare provider should advise the patient to designate a healthcare durable power of attorney. Also, the healthcare provider should recommend the family help oversee finances to minimize errors and prevent any exploitation.

The Future Treatment of Alzheimer Disease To date, there have been no medications found definitely to modify the course of disease in AD. A wide array of studies, including those directed at inflammation, hormonal therapy, homocysteine, direct immunization against Aβ, passive immunization against Aβ, β, and γ secretase inhibitors, and those directed against tau, have been negative. There are ongoing anti amyloid and anti-tau medications still being studied. However, with all of the present failures, researchers have proposed that doctors may have to intervene earlier to modify AD. The biomarker studies in AD may provide such an opportunity. Biomarker studies indicate that AD pathogenesis starts many years before the symptoms occur. At this time, secondary prevention studies are beginning in this pre-symptomatic window. Ongoing studies

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CHAPTER 95 Alzheimer Disease and Other Dementias include the Anti-Amyloid in Asymptomatic Alzheimer Disease (A4) study, the DIAN study, the Alzheimer’s Prevention Initiative studies on the Columbian autosomal dominant kindred, and the APOE ε4 study as well. The A4 study is a 3-year, double-blind study evaluating solanezumab in cognitively normal persons who are florbetapir positive. The DIAN study is evaluating solanezumab and gantenerumab versus placebo in unaffected carriers of dominantly inherited gene mutation. Amyloid trials. After early negative trials with amyloid therapy, it was felt that two possible reasons for failure were that participants were enrolled based on clinical diagnosis rather than biomarker status and that the amyloid intervention may have taken place too late in the disease course. The EXPEDITION 3 trial of solanezumab in mild cognitive impairment or dementia in individuals with a positive Aβ biomarker did not reach its primary endpoint of cognitive improvement even though it restricted its criteria to individuals with early disease and required biomarker positivity for entry (Honig et al., 2018). Verubecestat, a β-secretase inhibitor, was tested in mild-tomoderate Alzheimer dementia and reduced CSF Aβ42 and amyloid PET levels. Verubecestat did not reduce cognitive decline, and the treated groups had a greater decline in hippocampal volume compared to placebo (Egan et al., 2018). Two Aβ antibodies have demonstrated efficacy in lowering brain amyloid but whether they can influence cognitive decline remains to be seen (Sevigny et al., 2016). A recent trial using one of these Aβ antibodies, aducanumab, was prematurely stopped due to lack of efficacy in participants with MCI due to AD and mild AD dementia but subsequent analysis of the full data set reignited interest in Aducanumab and it continues to be investigated. Some have viewed these results as indicating that Aβ-based therapies should be tried earlier in the disease course while others have taken these negative trials as impetus to try other non-Aβ-based therapeutic approaches.

NEURODEGENERATIVE DEMENTIAS ASSOCIATED WITH PARKINSONISM The neurodegenerative dementias associated with parkinsonism can be classified based on the molecular pathology found at autopsy: dementia (PDD), and multisystem atrophy (MSA); and Guam dementia Parkinson complex, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), and familial FTD with parkinsonism. Table 95.7 summarizes key clinical features of parkinsonian syndromes.

Synucleinopathies

Dementia With Lewy Bodies In 1961, Okazaki described two male patients with dementia who were admitted to the hospital and subsequently died and went to autopsy. One of the patients had been hallucinating for over 1 year. Autopsy of both patients revealed Lewy bodies in the cerebral cortex, brainstem, and spinal cord. Okazaki recognized the clinical presentation with distinctive pathological findings represented a unique disease entity (Okazaki et al., 1961). Lewy bodies are difficult to recognize with standard histological sections. Immunohistochemistry with ubiquitin in the 1980s led to a greater recognition of the disorder. A major breakthrough occurred in 1997, when mutations in alpha-synuclein were shown to be a cause of autosomal dominant Parkinson disease (Polymeropoulos et al., 1997). The same year it was shown that Lewy

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TABLE 95.7 Clinical Features of Selected Parkinsonian Dementias Subtype

Key Clinical Findings

Dementia with Lewy bodies

Fluctuations/hypersomnolence Parkinsonism Visual hallucinations REM sleep behavior disorder Progressive supra- Supranuclear gaze palsy nuclear palsy Axial rigidity Gait disorder/frequent falls Bulbar symptoms Corticobasal Asymmetric apraxia, dystonia, myoclonus syndrome Cortical sensory findings, alien hand/limb Rigidity MSA-C/P Ataxia, parkinsonism, long tract signs, autonomic dysfunction

MSA-C/P, Multiple system atrophy—cerebellar/parkinsonian type; REM, rapid eye movement.

bodies were immunoreactive for alpha-synuclein (Spillantini et al., 1997), significantly improving recognition of Lewy bodies, leading to improved understanding of the clinical characteristics associated with Lewy body pathology. Prodromal dementia with Lewy bodies. Prior to cognitive decline, DLB patients often experience several clinical symptoms common to disorders with underlying synuclein pathology. DLB patients may variably report loss of smell, autonomic dysfunction, and REM sleep behavior disorder (RBD) prior to the onset of cognitive symptoms. In a series of patients with RBD who subsequently developed DLB, the mean age of onset of RBD was 61.5 while the age of cognitive decline was 68.1 (Boeve et al., 1998). More recently it has been reported that RBD can precede other symptoms of synucleinopathies by 50 years (Claassen et al., 2010), or can occur after cognitive decline has started. Similar to RBD, autonomic symptoms can precede DLB by many years (Kaufmann et al., 2004).

Mild cognitive impairment due to dementia with Lewy bodies.

In a large series of MCI patients, those with naMCI were much more likely to develop DLB, with over 80% having either attention or visualspatial dysfunction (Ferman et al., 2013b). In an autopsy series of MCI patients with underlying DLB or AD pathology, MCI-DLB patients were distinguished from MCI-AD patients by the presence of more parkinsonism, hallucinations or episodes of delirium, and relatively preserved memory testing (Jicha et al., 2010). Epidemiology. DLB is the second most common cause of degenerative dementia. In autopsy series, DLB accounts for approximately 20% of dementia cases. Similarly, DLB accounted for approximately 20% of patients referred for dementia to specialty clinics in Norway (Aarsland et al., 2008). The population-based incidence of DLB in France was estimated at 112 per 100,000 person-years (Perez et al., 2010). The majority of DLB patients are male (around 70%) with average age of onset of approximately 72.5 years old (Boot et al., 2013). Compared to AD, DLB patients are more likely to have a history of depression and a positive family history of Parkinson disease (Boot et al., 2013). The prognosis is different between DLB and AD. DLB patients have a shorter survival compared to AD patients (Williams et al., 2006) and are admitted to nursing homes 2 years earlier in the disease course (Rongve et al., 2014). Clinical features. Consortium consensus criteria for the diagnosis DLB were published in 2005 and updated in 2017 (McKeith

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Consensus Diagnostic Criteria for Dementia With Lewy Bodies

Symptom/Sign

Cardinal Manifestations

Frequency

Dementia (required criteria)

Attentional, frontal-executive, and visuospatial deficits, often worse than in AD dementia; episodic memory relatively better than in AD dementia

100%

Probable DLB (a) Presence of 2 or more core clinical features (with or without indicative biomarker) (b) One core clinical feature plus at least one indicative biomarker Possible DLB (a) Presence of 1 core clinical feature (no indicative biomarker) (b) Presence of 1 or more indicative biomarkers but no core clinical features Core Features Fluctuating cognition Visual hallucinations Parkinsonian motor signs

Variable timing of altered level of attention or arousal; distinct from sundowning Recurrent; typically involve animate subjects; variable degree of insight Spontaneous; rigidity and bradykinesia most common; action tremor more common than resting tremor Loss of atonia during REM sleep; individuals appear to act out dreams; may be combative or violent

REM sleep behavior disorder

60%–89% 50%–75% 50%–90% 25%–76%

Indicative Biomarkers 1. Reduced dopamine transporter uptake (SPECT or PET) 2. Low uptake iodine-123-MIBG myocardial scintigraphy 3. Confirmation of REM sleep without atonia on polysomnography Supportive Clinical Features 1. Neuroleptic sensitivity 2. Postural instability 3. Repeated falls 4. Syncope 5. Autonomic dysfunction 6. Excessive daytime sleepiness 7. Hyposmia 8. Hallucinations (non-auditory) 9. Delusions 10. Apathy, anxiety, and depression Supportive Biomarkers 1. Preservation of medial temporal lobe volume on CT/MRI 2. Generalized low uptake on SPECT/PET perfusion/metabolism scan with reduced occipital activity and/or the cingulate island sign on FDG-PET imaging 3. Prominent posterior slow-wave activity on EEG with periodic fluctuations in the pre-alpha/theta range CT, Computed tomography; EEG, electroencephalogram; FDG, fluorodeoxyglucose; MIBG, metaiodobenzylguanidine; MRI, magnetic resonance imaging; PET, positron emission tomography; REM, rapid eye movement; SPECT, single-photon emission computed tomography. Modified from McKeith I.G., Boeve, B.F., Dickson, D.W., Halliday, G., Taylor, J.P., Weintraub, D., et al., 2017. Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium. Neurology. 89, 88–100.,

et al., 2005, 2017; Table 95.8). The major change was elevation of RBD to a core clinical feature. The cardinal features of DLB can present in any order but typically RBD precedes cognitive changes followed shortly thereafter by parkinsonism and hallucinations (Fields et al., 2011). DLB patients are also notably susceptible to delirium, which frequently occurs if they are hospitalized. DLB can rarely present as a rapidly progressive dementia (Fields et al., 2011). Parkinsonism. Parkinsonism is present in approximately 50% of DLB patients at diagnosis, but up to 25% in autopsy series do not develop parkinsonism (McKeith et al., 2004). The absence of parkinsonism is one of the major reasons for misdiagnosis (McKeith et al., 2000). Parkinsonian features of DLB tend to be symmetrical with action tremor greater than rest tremor. Parkinsonian features more severe in DLB than Parkinson disease (PD) include difficulty getting up from a chair, gait difficulty, impaired facial expression, and rigidity (Aarsland et al., 2001). While DLB patients respond to l-dopa therapy,

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the proportion that does not respond to l-dopa is higher than in PD patients (Bonelli et al., 2004). Cognitive fluctuations. Fluctuations have been reported to occur in up to 89% of DLB patients (Del Ser et al., 2000; McKeith et al., 2004). Cognitive fluctuations in DLB resemble delirium but do not have any provoking cause. Fluctuations are difficult to characterize and several fluctuations scales have been developed. Fluctuations in DLB can lead to variable performance on cognitive tests. Despite the difficulty in quantifying them, fluctuations can distinguish DLB from AD. One study found that the presence of at least 3 of 4 characteristic fluctuation features (staring into space, disorganized speech, drowsiness, and napping during the day despite getting adequate sleep) occurred in 63% of DLB patients, 12% of AD patients, and 0.5% of normal elderly persons, but asking specifically if the patient fluctuates did not distinguish DLB from AD (Ferman et al., 2004). Another fluctuations battery found the following four features distinguished DLB from

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CHAPTER 95 Alzheimer Disease and Other Dementias PDD, vascular dementia, and AD, with sensitivity ranging from 78.6% to 80.3% and specificity ranging from 73.9% to 79.3%: 1. Significant differences in daytime functioning; 2. Somnolence; 3. Drowsiness; and 4. Daytime altered levels of consciousness (Lee et al., 2014). Hallucinations. Hallucinations in DLB are often detailed, vivid visual images of people and animals. Children and insects are also common themes. Hallucinations tend to cluster in the evening, and patient insight is variable. Hallucinations occur in 63% of autopsyconfirmed DLB patients and are much more likely to be due to DLB when they occur in the first 5 years of the dementia (Ferman et al., 2013a). Rapid eye movement sleep behavior disorder. RBD refers to loss of the normal REM sleep with atonia. RBD can be screened for by asking “Does the patient act out his or her dreams while sleeping?” Polysomnogram is the gold standard for diagnosing RBD. In an autopsy series of patients with RBD, 141 of 172 had Lewy body disease of any kind (DLB, PDD, or PD) while 19 of 172 had MSA, demonstrating the relationship between synuclein pathology and the presence of RBD (Boeve et al., 2013). In autopsy-confirmed DLB patients, approximately 76% have RBD (Ferman et al., 2011). Patients who have DLB with RBD differ from those without RBD. DLB with RBD patients are more likely to be male, have earlier parkinsonism and hallucinations, and lower Braak tangle staging than those without RBD (Dugger et al., 2012). RBD improves the diagnosis of DLB. The odds ratio of DLB compared to other causes of dementia improves from 2 to 6 when RBD is added to visual hallucinations, parkinsonism, and fluctuations (Ferman et al., 2011). Other sleep disorders are often comorbid, including obstructive sleep apnea and periodic limb movements of sleep. Neuroleptic sensitivity. DLB patients experience greater neuroleptic sensitivity than AD patients. Of DLB patients who receive dopamine-blocking antipsychotics (e.g., haloperidol and risperidone), approximately 80% will experience an adverse reaction, with 50% experiencing a severe reaction (McKeith et al., 1992). Symptoms include worsening motor symptoms, confusion, and agitation. Autonomic dysfunction. Autonomic symptoms are common in DLB. The most common symptoms are orthostatic hypotension, urinary incontinence, and erectile dysfunction (Thaisetthawatkul et al., 2004). Other neuropsychiatric symptoms. Delusions occur in approximately 70% of DLB patients, with 40% developing misidentification syndromes (Ballard et al., 1999). Depression, anxiety, and apathy are also frequently seen. Falls. Falls are more common in DLB than AD. Falls may be related to a combination of parkinsonism and autonomic symptoms. Neuropsychology. The neuropsychological profile is helpful in distinguishing DLB from AD. Compared to AD dementia patients, DLB patients perform worse on tests of visual spatial ability (Mori et al., 2000) and attention but better on tests of naming and verbal memory (Ferman et al., 1999). Laboratory studies. No proven blood or CSF tests for DLB exist, although serum and CSF biomarkers are actively under development. Genetics. The genetics of DLB remain obscure. Genes implicated in PD and AD are also implicated in DLB and PDD. In a Belgian kindred with familial DLB, chromosome 2q35-q36 was mapped as the region of interest (Meeus et al., 2010). Duplications in the α-synuclein (SNCA) gene (Kasuga et al., 2010) and mutations in the leucine-rich repeat kinase 2 (LRRK2) gene on chromosome 12 also cause DLB (Qing et al., 2009). In a multicenter study, glucocerebrosidase (GBA1) mutations were associated with DLB with an odds ratio of 8.28 (Nalls et al., 2013). GBA1 carriers had an earlier age of onset and worse

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parkinsonism. In all likelihood, there are multiple genes involved, with most undiscovered. Neuroimaging in dementia with Lewy bodies. The pathological overlap of AD and DLB results in significant overlap of the imaging biomarkers. A multimodal imaging approach (MRI, PiB-PET, FDGPET) is additive in its ability to distinguish AD from DLB (Kantarci et al., 2012c). Structural magnetic resonance imaging. Compared to AD, DLB patients have relatively preserved hippocampal volumes and less global atrophy although there is significant overlap. In DLB patients, lower hippocampal volumes correlate with higher Braak tangle stage (Kantarci et al., 2012a), indicating greater coexisting AD pathology. The posterior mesopontine region is also significantly smaller in DLB compared to AD (Kantarci et al., 2012a; Whitwell et al., 2007). The presence of hippocampal atrophy among DLB patients is associated with a shorter survival time compared to DLB patients with normal hippocampal volumes (Graff-Radford et al., 2016).

Amyloid imaging in dementia with Lewy bodies. Approximately 50%–80% of DLB patients are amyloid-positive on PiBPET scans although at lower levels than AD patients and the pattern of deposition is similar to AD (Edison et al., 2008; Kantarci et al., 2012c). Therefore, amyloid PET should not be used to distinguish DLB from AD.

Fluorodeoxyglucose positron emission tomography in dementia with Lewy bodies. The FDG-PET pattern of DLB is very characteristic, involving parietal-occipital hypometabolism. In an autopsy-confirmed series, occipital hypometabolism distinguished DLB from AD dementia with a sensitivity of 90% and specificity of 87% (Minoshima et al., 2001), but it is important to understand that cases of atypical AD and late AD may show significant occipital hypometabolism. Since occipital hypometabolism does not occur in all cases, this limits its clinical utility. More recently, the relative preservation of the posterior cingulate metabolism relative to the precuneus and cuneus metabolism, termed the “cingulate island,” has been shown to have the highest specificity in distinguishing DLB from AD (Graff-Radford et al., 2014; Lim et al., 2009). Fig. 95.13 demonstrates imaging features of DLB. Dopamine transporter (DaT) scan. Dopamine transporter imaging with [123I]-FP-CIT SPECT differentiates DLB from other dementias with 78% sensitivity and 90% specificity (McKeith et al., 2007). In DLB patients, there is significantly decreased nigrostriatal uptake compared to AD, particularly in the putamen. The 4th consortium criteria for DLB recognized reduced dopamine transporter uptake in basal ganglia demonstrated by SPECT or PET as an indicative biomarker of the diagnosis of DLB (McKeith et al., 2017). Fig. 95.13 demonstrates a dopamine transporter scan in DLB. In an autopsy series, approximately 10% of patients with LBD pathology had a normal dopamine transporter scan with [123I]-FP-CIT SPECT (Thomas et al., 2017). Myocardial iodine-131-meta-iodobenzylguanidine. Myocardial iodine-131-meta-iodobenzylguanidine (MIBG) imaging can also help distinguish DLB from other dementias and is considered an indicative biomarker in the DLB criteria (McKeith et al., 2017; Yoshita et al., 2006). MIBG imaging measures postganglionic sympathetic cardiac innervation, which is reduced in DLB compared to AD. Pathology. α-Synuclein is the primary protein in Lewy bodies. The presence of Lewy bodies and Lewy neurites in limbic and cortical regions distinguishes DLB from PD, where Lewy bodies are limited to the brainstem. Lewy bodies in the cortex are more difficult to identify. In 2003, Braak proposed a staging scheme for synuclein pathology where the earliest region involved was the dorsal motor nucleus of the medulla followed by the pons, midbrain (nigra), basal forebrain, and then cortical

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A

B

Right Lateral

Left Lateral

Anterior

Posterior

Right Medial

Left Medial

Superior

Inferior

Fig. 95.13 A, Left: Fluorodeoxyglucose positron emission tomography (FDG-PET) in dementia with Lewy bodies (DLB) patient demonstrating relative preservation of posterior cingulate (arrow) (e.g., cingulate island sign). Middle: Dopamine transporter single-photon emission computed tomography (DaT-SPECT) imaging with iodine123-ioflupane in patient with DLB. There is markedly decreased striatal accumulation bilaterally, left greater than right. Right: Normal dopamine transporter imaging. B, FDG-PET statistical stereotactic surface projection map (Cortex ID) showing occipital hypometabolism in a DLB patient. (DaT imaging courtesy Dr. Bradley Boeve.)

areas, particularly frontal and temporal. Another early region involved is the olfactory bulb. Synuclein is also present in the striatum of DLB patients, although this was not included in Braak’s staging scheme. Synuclein pathology in the spinal cord affects the intermediolateral cell column and less often Onuf’s nucleus. There is significant pathological overlap between AD and DLB. The majority of DLB patients have amyloid plaques at autopsy. Most of the plaques in DLB tend to be diffuse without associated tau neuritic pathology. Interestingly, plaques may increase Lewy body density, suggesting a possible interaction between amyloid and synuclein. In the consortium criteria for DLB, the relative amount of Lewy body pathology to AD pathology is taken into account to determine the likelihood of the patient presenting with a clinical syndrome of DLB. Fig. 95.14 summarizes the pathological features of DLB. Treatment. A systematic approach to DLB patients aids in maximizing function. Cognitive symptoms, motor symptoms (parkinsonism, falls), neuropsychiatric symptoms, autonomic symptoms, and sleep disorders should all be addressed. Discontinuing medications which can exacerbate cognitive or motor symptoms is an important part of the management of DLB patients. These medications include those with anticholinergica properties, antipsychotic medications with antidopaminergic properties, and benzodiazepines.

Cognitive symptoms

Acetylcholinesterase inhibitor drugs. Compared to AD, DLB patients have a greater loss of cholinergic function. The loss of cholinergic function with comparatively intact structural integrity has provided the rationale to suggest that DLB patients may respond better to AChEIs than AD dementia patients. In 2000, a double-blind, randomized, controlled multicenter trial demonstrated that DLB subjects receiving rivastigmine

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improved significantly in neuropsychiatric features and a four-item DLBspecific subset of the NPI composed of delusions, hallucinations, apathy, and depression subscales (McKeith et al., 2007). In another randomized, double-blind, placebo controlled trial, donepezil 5 or 10 mg improved MMSE scores, caregiver burden, and behavioral symptoms in DLB patients relative to placebo (Mori et al., 2012a). DLB patients without imaging markers of coexisting AD pathology (hippocampal atrophy, PiB-PET positivity) are more likely to improve with AChEIs compared to those with imaging markers of AD pathology (Graff-Radford et al., 2012).

Parkinsonism Dopaminergic therapy. Parkinsonism in DLB is l-dopa responsive, although less so than PD. To minimize the risk of inducing or exacerbating neuropsychiatric symptoms such as hallucinations, l-dopa/carbidopa should be introduced at a low dose and titrated slowly. Many medications may exacerbate various symptoms of DLB and should be avoided where possible. Specifically, dopamine agonists are more likely to exacerbate hallucinations and behavioral disorders. Selegiline may also exacerbate psychosis, and anticholinergics such as benztropine and trihexyphenidyl can cause confusion. Neuropsychiatric features. Depression and anxiety can be treated with SSRIs. As previously noted, it is important to avoid anticholinergic agents when selecting an antidepressant. Hallucinations and delusions that do not bother the patient may not require treatment. First-line therapy for hallucinations and delusions in DLB should be AChEIs, which have been shown to improve delusions and hallucinations (McKeith et al., 2000c).

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Fig. 95.14 Dementia With Lewy Bodies Pathology. Hematoxylin and eosin (H&E) stain of anterior cingulate cortex (A) and temporal cortex (B) demonstrating Lewy bodies. Alpha-synuclein stain of anterior cingulate cortex (C) and temporal cortex (D) demonstrating Lewy bodies. (Courtesy Dr. Joseph Parisi.)

Typical antipsychotics are contraindicated in DLB due to severe sensitivity and association with increased mortality. Atypical antipsychotics (risperidone, olanzapine, and quetiapine) are associated with increased mortality in dementia and their use should be avoided if possible (Schneider et al., 2005). Pimavanserin was approved to treat Parkinson psychosis by the FDA and has not been approved for use in DLB. It also carries a black box warning that elderly patients with dementia treated with antipsychotics are at increased risk of death. When the benefits of antipsychotics are felt to outweigh the risks, quetiapine and clozapine are often used to minimize the risk of worsening parkinsonism. The use of clozapine is limited because of the risk of agranulocytosis requiring routine blood monitoring. Antipsychotics should be used at the lowest effective dose for the shortest interval necessary, due to side effects. Autonomic symptoms. Since autonomic symptoms vary significantly among patients, an individualized approach is necessary. Constipation can be treated by increasing water and fiber intake initially followed by over-the-counter therapies such as psyllium powder and rarely prescription therapies. Orthostasis can initially be treated by lifestyle modifications and limiting drugs that lower blood pressure. As dysautonomia worsens, pharmacological interventions with midodrine or fludrocortisone may become necessary. In appropriate patients, erectile dysfunction can be managed with phosphodiesterase inhibitors.

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Sleep disorders. RBD is the most common sleep disorder in DLB, but other sleep disorders are common and can be treated. Therefore, patients should be screened for sleep apnea because treatment can improve daytime alertness. Treatment of RBD should be individualized to see if the patient is at risk of harming themselves or their bed partner. Nonpharmacological treatments include removal of sharp objects from around the bed, creating barriers between bed partners, or even bed alarms. Melatonin can improve RBD and is well tolerated. Clonazepam is often used as a second-line option at low doses, but this should be monitored carefully as benzodiazepines are typically avoided in dementia and may increase fall risk. Parkinson Disease Dementia PDD is distinguished from DLB by the presence of parkinsonism preceding cognitive decline for at least 1 year. About 80% of PD patients will develop dementia (Aarsland and Kurz, 2010). The clinical features of PDD are otherwise similar to DLB and some authorities have questioned whether they are distinct entities or different presentations of the spectrum of Lewy body diseases. There are some pathological differences between PDD and DLB. For example, PDD patients have greater substantia nigra neuronal loss. In addition to treatment of motor symptoms, a recent multicenter placebo-controlled study of the AChEI rivastigmine in PDD showed an improvement in cognitive, neuropsychiatric, and functional features,

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leading to FDA approval (Emre et al., 2004). An MCI stage of PDD is recognized, and similar criteria to MCI due to AD have been suggested (Litvan et al., 2012).

Multiple System Atrophy Multiple system atrophy was known as striatonigral degeneration, olivopontocerebellar atrophy (OPCA), and Shy-Drager syndrome. Current consensus criteria (Gilman et al., 2008) recognize two types of MSA: MSA-P (l-dopa nonresponsive parkinsonism) and MSA-C (cerebellar ataxia). Approximately 58% of European patients with MSA have MSA-P (Geser et al., 2006) while MSA-C is more common in the Japanese population (84%) (Yabe et al., 2006). Mean age of onset is 54 (Ben-Shlomo et al., 1997) with mean survival from symptom onset of 5.7 years (Bjornsdottir et al., 2013). The average annual incidence rate of MSA is 3 per 100,000 person-years (Bower et al., 1997). The prevalence is estimated at 4.4 cases per 100,000 (Schrag et al., 1999). Patients with pure autonomic failure may evolve into MSA. A prospective study of pure autonomic failure found that about one-third of patients later met clinical criteria for a synucleinopathy, including MSA within 4 years of follow-up (Kaufmann et al., 2017). Clinical characteristics include autonomic dysfunction with any combination of parkinsonism and/or ataxia. Autonomic symptoms may manifest as cardiovascular in the form of orthostatic hypotension, urogenital or gastrointestinal dysfunction. Erectile dysfunction is common among male MSA patients. RBD is strongly associated with MSA, reflecting the underlying synuclein pathology. In MSA-C, ataxia progresses faster than in other degenerative ataxias (Klockgether et al., 1998). The parkinsonism in MSA-P typically lacks the classic rest tremor and l-dopa responsiveness seen in PD and progresses more rapidly than in PD (Seppi et al., 2005). Other key symptoms associated with MSA include pyramidal signs, stridor, dysarthria, oculomotor dysfunction, pseudobulbar affect, myoclonus, orofacial dystonia, and dysphagia (Gilman et al., 2008). Significant cognitive deficits at diagnosis are rare in MSA. In the 2nd consensus statement on the diagnosis of multiple system atrophy, the presence of dementia was considered a red flag against the diagnosis of MSA (Gilman et al., 2008), although in one clinical series, dementia was diagnosed in 10 of 58 MSA patients with 3 of 58 presenting with cognitive symptoms (Kitayama et al., 2009). Neuropsychological testing can often detect executive deficits and slowed processing speed. Common neuropsychiatric symptoms include depression and anxiety. Evaluation. Autonomic dysfunction can be detected by supine and standing blood pressure, with the drop of 30 mm Hg systolic or 15 mm Hg diastolic required in order to meet diagnostic criteria for probable MSA. Autonomic reflex screen testing may demonstrate the orthostatic blood pressure drop and other signs of adrenergic or cardiovagal failure. Thermoregulatory sweat testing demonstrates anhidrosis in a central pattern. Elevated postvoid residual volumes are often seen in patients with urological symptoms. Neuroimaging. The imaging features differ between the types of MSA. In MSA-C, atrophy of the pons, cerebellum, or middle cerebellar peduncles is characteristic. On T2-weighted MRI, hyperintensity can be seen in the pons (“hot cross bun sign”), middle cerebellar peduncles, and cerebellum. Putaminal abnormalities are more commonly seen in MSA-P with T2-hyperintensity of the lateral putaminal rim or hypointensity of the posterior putamen. FDG-PET findings in MSA include hypometabolism of the basal ganglia and cerebellum (Eckert et al., 2005). Genetics. Recently, mutations in CoQ2 were shown to be associated with MSA in Japanese cases (2013), but this mutation was not confirmed in other populations.

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Pathology. The gross pathology of MSA-P demonstrates degeneration of the putamen and lateral substantia nigra. The hallmark lesion of MSA is glial cytoplasmic inclusions that consist of filamentous inclusions of synuclein in oligodendroglia. These can be located in the cortex, subcortical areas, cerebellum, spinal cord, and dorsal root ganglia. Treatment. Treatment is symptomatic, with autonomic dysfunction being most disabling. Early in the course, lifestyle modifications can be effective, including increasing salt and fluid intake, sleeping with the head of the bed elevated, learning physical maneuvers, and wearing compression garments. Later, pharmacological intervention may become necessary with fludrocortisone, midodrine, pyridostigmine, or droxidopa often providing a measure of symptomatic relief although they may cause supine hypertension. Raising the head of the bed can help mitigate the supine hypertension. A subset of MSA-P patients may respond to l-dopa, but the benefit is often transient and limited, with treatment exacerbating orthostatic hypotension. Physical and occupational therapy can be helpful with gait instability and safety evaluation. Referral to a sleep medicine specialist for evaluation of respiratory stridor should be considered as stridor carries a poor prognosis (Silber and Levine, 2000). Dysphagia should also be monitored.

Tauopathies

Corticobasal Degeneration/Corticobasal Syndrome In the 1960s, Rebeiz reported three patients with an asymmetrical akinetic rigid syndrome and apraxia with unique pathological features which was called corticodentatonigral degeneration with neuronal achromasia (Rebeiz et al., 1968). Later the name changed to corticobasal ganglionic degeneration or corticobasal degeneration. The clinical syndrome of progressive asymmetric rigidity and apraxia became synonymous with corticobasal degeneration. Subsequent autopsy series revealed patients with this characteristic clinical syndrome had heterogeneous pathology including CBD, PSP pathology, AD pathology, or Creutzfeldt-Jakob disease (CJD) (Boeve et al., 1999). Currently, corticobasal syndrome (CBS) refers to a clinical syndrome characterized by asymmetric rigidity, apraxia, and alien limb phenomenon variably associated with cortical sensory loss, myoclonus, dystonia, and parkinsonism. This syndrome can be caused by several pathologies. The term CBD refers to the distinct pathological entity which can present with a variety of clinical syndromes. While CBD is the most common pathological substrate of CBS, this pathology only accounts for approximately 50% of cases of CBS (Boeve et al., 2003). In the most recent criteria for the diagnosis of CBD, four clinical phenotypes are recognized (corticobasal syndrome, frontal behavioral-spatial syndrome, nonfluent/agrammatic variant of PPA, and PSP-syndrome) (Armstrong et al., 2013). The mean age of symptom onset is approximately 64 years, with average disease duration of 6.6 years (Armstrong et al., 2013). CBS has an incidence rate per year of approximately 0.02 cases per 100,000 persons (Winter et al., 2010). The key features of CBS are a progressive, asymmetric apraxia and rigidity. Cortical features variably associated with CBS include cortical sensory loss, alien limb syndrome, mirror movements, cognitive impairment, and myoclonus. Motor features associated with CBS include bradykinesia, dystonia, tremor, and poor l-dopa response. Additionally, the hand can form a characteristic fist. Common neuropsychiatric features include depression, disinhibition, and obsessive-compulsive features. Capgras and hallucinations are quite rare in CBS relative to other neurodegenerative diseases (Geda et al., 2007). Most patients with underlying CBD pathology present with cognitive or behavioral symptoms, with a significant portion presenting as bvFTD (Lee et al., 2011b).

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B Fig. 95.15 Corticobasal Degeneration Pathology. A, Tau-positive astrocytic plaque with pleomorphic neuronal inclusions and neurites with tau staining. B, Balloon neuron on hematoxylin and eosin (H&E). (Images courtesy Dr. Joseph Parisi.)

Neuropsychological testing demonstrates prominent deficits in executive functions, language, and visual-spatial functions, with relative sparing of episodic memory at presentation (Murray et al., 2007). Structural MRI in CBS often shows asymmetrical frontoparietal atrophy corresponding to the side contralateral to the affected limb. FDG-PET imaging demonstrates focal asymmetric hypometabolism in the posterior frontal, anterior parietal region. Pathology. The gross pathology of CBD includes atrophy of the superior frontal gyrus, thinning of the corpus callosum, and loss of pigment of the substantia nigra. CBD is a four-repeat (four microtubule-binding domains) tauopathy. The pathology in CBD occurs in both the cortex and white matter. Tau accumulates in certain regions including cortex, basal ganglia, basal nucleus of Meynert, thalamus, and brainstem (Dickson et al., 2002). Rebeiz described swollen achromatic neurons, now known as ballooned neurons, which are present in CBD but not specific (Rebeiz et al., 1968). The hallmark of CBD is the astrocytic plaque. These plaques are tau positive without amyloid. Research criteria for the pathological diagnosis of CBD also include tau-reactive gray- and white matter threadlike lesions (Dickson et al., 2002). Fig. 95.15 summarizes the key pathology of CBD. The clinical presentation is determined by the distribution of tau. In autopsy-proven CBD patients, tau deposition in the motor and somatosensory cortex was associated with a CBS presentation while tau deposition in limbic regions and the hindbrain was associated with PSP syndrome (Kouri et al., 2011). The tau genotype consists of two haplotypes, H1 and H2. In typical populations approximately 60% are homozygous for H1/H1, but in PSP and CBD over 80% are H1/H1, indicating that being H1 is a risk factor for CBD (Houlden et al., 2001). Interestingly, some MAPT gene mutations can cause CBD pathology. Treatment. No disease-modifying therapy is available for CBD/ CBS; therefore, treatment is symptomatic. A minority of patients will have a modest response of rigidity and bradykinesia to dopaminergic therapy. If myoclonus is problematic, clonazepam, levetiracetam, and gabapentin can be considered. Physical and occupational therapy are important to prevent falls, provide adaptive equipment, and maximize function with appropriate exercises.

Progressive Supranuclear Palsy The nomenclature of PSP is confusing. PSP syndrome (PSP-S) refers to the classical clinical presentation, while PSP pathology refers to pathological substrate. The classical clinical presentation of PSP-S is

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characterized by unexplained falls, symmetric predominantly axial rigidity, bradykinesia, poor l-dopa responsiveness, and impaired vertical gaze, especially downgaze. This typical presentation is also called Richardson syndrome. Other clinical features include eyelid apraxia, dysphagia, abnormal neck posturing, pseudobulbar affect, long tract signs, and impaired saccadic pursuits. Five clinical presentations associated with PSP pathology have been described: 1. PSP-S (described above). 2. PSP-parkinsonism (characterized by limb and axial rigidity, tremor, l-dopa responsiveness). 3. PSP-pure akinesia with gait freezing (early gait disorder with subsequent freezing, early micrographia, phonation difficulties, lack of l-dopa response, or early eye movement abnormalities). 4. PSP-corticobasal syndrome (CBS as previously described). 5. PSP-progressive nonfluent aphasia/apraxia of speech (language and/or speech disorder characterized by agrammatism and/or speech apraxia) (Williams and Lees, 2009). In 2017, new criteria for PSP were published by the Movement Disorder Society recognizing four functional domains (ocular motor dysfunction, postural instability, akinesia, and cognitive dysfunction) which can predict PSP. Patients can be categorized as probable, possible, or suggestive of PSP based on degree of certainty (Hoglinger et al., 2017). Neuropsychiatric features of PSP-S include prominent apathy, disinhibition, depression, and anxiety (Litvan et al., 1996). Bradyphrenia can be prominent and PSP can mimic bvFTD. The annual incidence rate of PSP-S is 5.3 per 100,000 person-years (Bower et al., 1997). The prevalence is approximately 6.4 per 100,000 (Schrag et al., 1999). The disease duration is approximately 7 years. Most patients die from complications related to dysphagia. Neuropsychological profile includes prominent executive dysfunction. Language and speech difficulties can be present or even dominate the clinical presentation. Structural MRI demonstrates midbrain atrophy and has been called the “hummingbird sign” (Kato et al., 2003). A small midbrain to pons ratio may also predict PSP (Massey et al., 2013). Enlargement of the third ventricle is also described in PSP. The FDG-PET scan reveals frontal-subcortical hypometabolism. Midbrain hypometabolism is also described and has been called the “pimple sign” (Botha et al., 2014). Of patients clinically diagnosed with PSP-S, 76% will have PSP at autopsy, with CBD, MSA, and DLB accounting for most of the other pathologies (Josephs and Dickson, 2003). PSP-S caused by CBD differs from PSP-S caused by PSP pathology. PSP-S with underlying CBD

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D Fig. 95.16 Progressive Supranuclear Palsy Pathology. A, Hematoxylin and eosin (H&E) stain demonstrating globose neurofibrillary tangle. B, Bielschowsky stain demonstrating globose neurofibrillary tangle. C, Tau stain demonstrating globose neurofibrillary tangle. D, Neurofilament stain demonstrating ballooned neuron. (Courtesy Dr. Joseph Parisi.)

pathology is more associated with cognitive behavioral dysfunction and tends to have less subthalamic nucleus neuronal loss but more neuronal loss in the medial aspect of the substantia nigra and degeneration of the anterior part of the corpus callosum (Kouri et al., 2011). Gross pathological findings with PSP pathology include midbrain, superior cerebellar peduncle, and subthalamic nucleus atrophy. PSP is a four-repeat tauopathy characterized by globose tangles in the globus pallidus, substantia nigra, and subthalamic nucleus. The pathology also affects motor cortex, striatum, pontine nuclei, inferior olive, and dentate nucleus. Tufted astrocytes are also present. The neuronal loss in PSP correlates with NFTs rather than the astrocytic pathology. Fig. 95.16 summarizes the key pathological features of PSP. No disease-modifying treatment is available for PSP. Subgroups of PSP (PSP-parkinsonism) patients respond to l-dopa therapy. SSRIs can be used for depression, anxiety, and pseudobulbar affect.

In 1892, Arnold Pick described a patient with progressive aphasia associated with frontal and temporal lobar atrophy. This was the first description of FTD. In 1911, Alois Alzheimer described the pathological hallmark of this disorder, a rounded inclusion now called a Pick

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Nomenclature FTD is an encompassing term that refers to a group of clinical syndromes that are characterized by degeneration of the frontal and temporal lobes, while frontotemporal lobar degeneration (FTLD) is an encompassing term for the spectrum of pathologies associated with FTD.

Diagnostic Criteria

FRONTOTEMPORAL DEMENTIAS

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body (Alzheimer, 1911). Only later was it recognized that only a small proportion of FTD cases have Pick bodies at autopsy. In 1982, Mesulam reported six patients with “slowly progressive aphasia,” and later introduced the term primary progressive aphasia (PPA) (Mesulam, 1982, 1987). Brun and Gustafson in Sweden (Gustafson et al., 1990) and Neary and Snowden in the UK (Neary et al., 1988) termed the group of disorders “frontal lobe dementia of the non-Alzheimer type,” and “dementia of the frontal type,” respectively.

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In 1998, consensus criteria were published that recognized three clinical variants of FTD that correlate with FTLD pathologically: FTD, progressive nonfluent aphasia (PNFA), and semantic dementia (Neary et al., 1998). More recently updated criteria have been proposed to further characterize FTD variants including bvFTD (Rascovsky et al.,

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CHAPTER 95 Alzheimer Disease and Other Dementias 2011) and the PPA variants (Gorno-Tempini et al., 2011). Currently, three clinical variants of FTD are recognized: bvFTD, semantic dementia or semantic variant PPA (svPPA), and PNFA.

Frontotemporal Dementia Epidemiology In a UK-based study of dementia patients aged 45 to 64, the prevalence of FTD and AD was the same (15 per 100,000) (Ratnavalli et al., 2002). In a population-based study in Rochester, MN, the incidence rates (number of new cases per 100,000 person-years) of FTD were 2.2 for ages 40–49, 3.3 for ages 50–59, and 8.9 for ages 60–69 (Knopman et al., 2004). While FTD is an early onset dementia, 30% of FTD patients are estimated to be over the age of 65 (Knopman and Roberts, 2011). Median survival from symptom onset among FTD patients is approximately 6 years but FTD with motor neuron disease (FTD-MND) patients have a significantly shorter survival of approximately 3 years (Hodges et al., 2003).

Behavioral Variant Frontotemporal Dementia Clinical Presentation

The characteristic clinical features of bvFTD include a change in personality and behavior such as disinhibition, and executive dysfunction such as poor planning, loss of judgment, difficulty with organization and loss of insight. In bvFTD, patients exhibit social isolation, peculiar affiliations, antisocial behavior, compulsions, and drug or alcohol abuse. A change in dietary preference, particularly an increased interest in sweets, may occur, although indiscriminate overeating can also occur. Other features include apathy, decreased pain response, utilization behaviors, and obsessive compulsive and perseverative behaviors. Patients often lack empathy and insight. They may show little concern for friends or family members. Language deficits occur but are not the presenting feature. The most recent criteria for bvFTD are listed in Table 95.9A (Rascovsky et al., 2011). Differentiating features are summarized in Table 95.9B. Parkinsonian features are often mild. Motor neuron disease more commonly occurs with bvFTD than PPA. Early in the disease course neuropsychological testing can be completely normal. Typically, neuropsychological testing demonstrates less episodic memory impairment than patients with semantic dementia or dementia due to AD (Hodges et al., 1999). Executive function deficits are characteristic but may be absent. Semantic memory is spared in bvFTD relative to semantic variant PPA and AD dementia (Rogers et al., 2006). Hodges described a disorder he termed bvFTD phenocopy describing patients who met bvFTD criteria but had no major imaging findings of FTD and remained clinically stable over time. This disorder may represent lifelong personality quirks and unusual behaviors or, alternatively, a subset may represent a slowly progressive bvFTD secondary to a C9ORF72 mutation (Khan et al., 2012).

Primary Progressive Aphasias The primary progressive aphasias refer to a group of disorders where neurodegeneration targets the language network. Two variants of PPA are under the FTD umbrella: PNFA and semantic dementia or svPPA. The logopenic variant is most frequently caused by AD pathology and is not considered a type of FTD. Criteria were published for the classification of the PPA variants (Gorno-Tempini et al., 2011).

Nonfluent/agrammatic variant primary progressive aphasia.

Agrammatic primary progressive aphasia is characterized by nonfluent, hesitant speech. Agrammatism occurs and is characterized by telegraphic speech, misuse of pronouns, and errors in sentence construction. Word and object knowledge is relatively spared. Early in the course, agrammatism may only be evident in writing samples. The Northwestern Anagram Test which focuses on grammar can be

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considered to aid in the diagnosis (Weintraub et al., 2009). Apraxia of speech often co-occurs and accounts for some of the appearance of nonfluency. Comprehension for complex sentences can be impaired. Behavioral symptoms often co-occur but are not the presenting feature. Over time, patients often develop a parkinsonian syndrome. Semantic variant primary progressive aphasia. svPPA is a fluent aphasia characterized by a prominent anomia with loss of single word meaning. Nouns are particularly difficult to comprehend. Patients will replace a specific word with a more general word such as “it” for “telephone.” In most patients repetition is relatively spared, and grammar remains intact. The commonest age range of presentation in svPPA is between 66 and 70 years of age (Hodges and Patterson, 2007). Surface dyslexia occurs in svPPA, where irregularly pronounced words such as “colonel” and “pint” are pronounced phonetically. svPPA patients also may develop loss of visual object meaning and prosopagnosia (difficulty recognizing familiar faces) when the right temporal lobe is more affected than the left. Testing for prosopagnosia can be accomplished by showing pictures of famous celebrities and asking the patient to identify the famous face (Tiger Woods) among distractor (non-famous) faces. To test person knowledge, a follow-up question of asking who, in fact, Tiger Woods is can also be helpful. A svPPA patient may not know he is a golfer or in professional sports. Over time, svPPA patients commonly develop coexisting behavioral issues which overlap with bvFTD. svPPA patients are more likely to develop food fads and seek social attention, while bvFTD patients are more likely to overeat and become withdrawn (Snowden et al., 2001). Additionally, patients with svPPA tend not to have parkinsonism, a family history of dementia, or associated motor neuron disease. Some patients present with nonverbal semantic deficits, typically right greater than left temporal involvement, do not meet root criteria for PPA, and the term semantic dementia may continue to be most appropriate.

Amnestic Syndromes Occasionally, elderly patients with FTLD pathology can present with an amnestic syndrome resembling AD.

HIPPOCAMPAL SCLEROSIS OF AGING Hippocampal sclerosis refers to loss of neurons and gliosis in the subiculum and CA1 of the hippocampus which is accompanied with TDP-43 pathology. Patients present typically over the age of 75 with a progressive amnestic course (Pao et al., 2011). In the elderly, hippocampal sclerosis is seen in approximately 13% of autopsy cases. It may occur as a co-pathology with AD or in isolation (Nag et al., 2015). While clinical features of hippocampal sclerosis and AD dementia overlap, the presence of focal medial temporal and posterior cingulate hypometabolism is a promising biomarker to distinguish hippocampal sclerosis from AD dementia (Botha et al., 2018).

Argyrophilic Grain Disease Argyrophilic grain (AG) disease is a 4-repeat tauopathy. Patients with AG may have an unusually long course of aMCI (Petersen et al., 2006) or present with an FTD syndrome.

Frontotemporal Dementia With Motor Neuron Disease FTD-MND represents approximately 10%–15% of FTDs. Identification of MND in FTD patients is important because of the decreased survival compared to FTD patients ( 0.3). 4. Above-mentioned symptoms cannot be completely explained by other neurological or non-neurological disease. 5. Preceding diseases possibly causing ventricular dilation are not obvious, including subarachnoid hemorrhage, meningitis, head injury, congenital hydrocephalus, and aqueductal stenosis. Possible iNPH Supportive Features (a) Small stride, shuffle, instability during walking, and increased instability with turning. (b) Symptoms progress slowly; however, sometimes an undulating course, including temporal discontinuation of development and exacerbation, is observed. (c) Gait disorder is the most prevalent feature, followed by cognitive impairment and urinary incontinence. (d) Cognitive impairment is detected on cognitive tests. (e) Sylvian fissures and basal cisterns are usually enlarged. (f) Other neurological diseases such as Parkinson disease, Alzheimer disease, and cerebrovascular disease may coexist; however, all such diseases should be mild. (g) Periventricular changes are not essential. (h) Measurement of CSF is useful for differentiation from other dementias. Probable iNPH (Meets All of the Following Three Features)

Definite iNPH

Improvement of symptoms after the shunt procedure 1. Meets criteria for possible iNPH. 2. CSF pressure 100 mg/dL) (Flanagan et al., 2010). Autoimmune dementias must be kept in the differential diagnosis of rapidly progressive dementias because they

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BOX 95.1

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Partial List of Non-Degenerative Dementias

Vascular Vasculitis (primary or secondary) Chronic subdural hematoma

Carbon monoxide poisoning Drugs (see prior table for list of drugs that can affect cognition) Structural Causes Primary or metastatic neoplasm Hydrocephalus

Infectious Causes Syphilis Chronic meningitis CJD and other prion disease Whipple PML Sequelae of herpes encephalitis HIV/AIDS-associated dementia Neuro brucellosis CNS tuberculosis Parasitic infections (e.g., cysticercosis) Lyme disease Subacute sclerosing panencephalitis

Immune/Inflammatory Autoimmune dementia Multiple sclerosis Sarcoidosis Collagen vascular diseases (e.g., systemic lupus erythematosus, Sjögren syndrome) Behçet Neoplastic Slow-growing neoplasm (e.g., meningioma, pituitary tumors) Gliomatosis cerebri Radiation effect Paraneoplastic syndromes Lymphoma

Toxic/Metabolic Causes Hypothyroidism Liver disease Kidney disease Vitamin B12 deficiency Thiamine deficiency Vitamin E deficiency Marchiafava-Bignami disease Deficiency of nicotinic acid (pellagra) Heavy metal toxicity Parathyroid hormone dysfunction Adrenal and pituitary disorders

Psychiatric Depression Inherited Disorders Leukodystrophies (e.g., metachromatic leukodystrophy, adrenoleukodystrophy) Krabbe disease Storage disorders: Gaucher disease, Niemann-Pick disease, cerebrotendinous xanthomatosis, and polysaccharidoses, neuronal ceroid lipofuscinoses Wilson disease

AIDS, acquired immunodeficiency syndrome; CJD, Creutzfeldt-Jakob disease; CNS, central nervous system; HIV, human immunodeficiency; PML, progressive multifocal leukoencephalopathy.

can mimic CJD and cause an elevated 14-3-3 protein in the CSF, as well as demonstrate cortical diffusion-weighted imaging abnormalities on MRI (called cortical ribboning) (Geschwind et al., 2008b). In addition to autoimmune dementias associated with specific autoantibodies, patients with autoimmune conditions such as systemic lupus erythematosus (SLE) or Sjögren syndrome can present with cognitive decline. Neuropsychiatric symptoms occur in up to 90% of SLE patients, with cognitive dysfunction (approximately 80%) and mood disorder (43%) being quite common (Ainiala et al., 2001). Sjögren syndrome can be associated with a vasculitis and meningoencephalitis. Dementia and more subtle cognitive dysfunction may also occur.

diseases causing rapidly progressive dementia include FTD-MND, 4R tauopathy, and DLB (Josephs et al., 2009). In a retrospective review of brain biopsies referred to the US National Prion Disease Pathology Surveillance Center for rapidly progressive dementia, 71 out of 1106 had a potentially treatable condition (26 immune related, 25 neoplastic related, 14 infectious, and 6 metabolic [most commonly Wernicke]) (Chitravas et al., 2011). Chapter 94 reviews this subject in more detail. A partial list of causes of rapidly progressive dementia is listed in Box 95.2.

Other Non-Degenerative Dementias

Young-onset dementia has a wide differential diagnosis. Definitions vary but typically age of onset before 45 is used to distinguish it from early-onset dementia. At the Mayo Clinic, the most common causes were neurodegenerative (31.1%), autoimmune or inflammatory (21.3%), and metabolic (10.6%), with a substantial proportion remaining unknown (18.7%). Among the neurodegenerative diseases FTD and Huntington disease were most common (Kelley et al., 2008). When the age range is extended to 65, AD dementia becomes the most common neurodegenerative cause (Janssen et al., 2003). Given the number of potentially treatable etiologies, young-onset dementia requires a thorough work-up. The nine most common causes in the papers from Kelley et al. 2008 and Harvey et al. 2003 are listed in Table 95.12.

Rapidly Progressive Dementias

Rapidly progressive dementias typically present over weeks to months, but may still be considered up to 1–2 years after symptom onset (Paterson et al., 2012). A thorough work-up is important to identify treatable causes before they are irreversible. At the University of California-San Francisco, which is the referral center for rapidly progressive dementia, of 178 rapidly progressive dementia cases, approximately 75% of cases were prion disorders, 14.6% neurodegenerative diseases, and 8.4% autoimmune in etiology (Geschwind et al., 2008a). Four cases were infectious with viral encephalitis and three were cancer-associated encephalopathies without paraneoplastic antibodies. At the Mayo Clinic, the most common neurodegenerative

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YOUNG-ONSET DEMENTIA

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Partial Differential Diagnoses of Rapidly Progressive Dementias

BOX 95.2

Prion diseases Autoimmune/paraneoplastic disorders Infections: Viral encephalitis, Whipple disease, fungal meningitis, human immunodeficiency virus-related, Lyme disease, syphilis, tuberculosis Neurodegenerative diseases presenting with rapid time course Central nervous system (CNS) vasculitis and other vasculopathies (e.g., Susac syndrome, Abeta-related angiitis) Neurosarcoidosis Neoplastic: CNS lymphoma, gliomatosis, metastatic disease Toxic/metabolic conditions: Vitamin B1 (thiamine) deficiency, vitamin B12 deficiency, alcohol related, uremia, hepatic failure, drug toxicity (e.g., lithium, methotrexate) Wilson disease Nonconvulsive status epilepticus Subdural hematoma Primary or secondary hydrocephalus

Future Directions It has become apparent in recent years that the most common neuropathology underlying cognitive changes in aging is multifactorial. As has been discussed above, age is the primary risk factor for virtually all of the degenerative and vascular diseases. In the early-onset cases, 65 years and younger, a single or a few pathological entities are more

TABLE 95.12

common, but when a person is older, most individuals will have a combination of contributing pathologies present, including amyloid, tau, alpha-synuclein, TDP-43, and vascular disease. The proportion of each of these will vary in each person and there are likely many factors contributing to this combination, genetic and lifestyle among them. A challenge for the field lies in our ability to identify these factors in life as early as possible with the goal of prevention. Biomarkers have taken on a huge role in this regard and progress is being made. As is depicted in Fig. 95.28, ideally we would like to identify a biomarker for each pathological entity and develop therapies for each component (Petersen et al., 2018). This would result in combination therapy for each person tailored to that person’s unique biomarker profile. If these therapies were shown to be preventive, early intervention would be the key. Due to the personal, societal, and economic burden of these diseases, attempts at prevention or delaying onset and slowing progression are essential. If a biomarker’s proof of concept could be demonstrated with imaging and CSF measures, extension to involve blood-based biomarkers would be a major step forward. Ultimately, one could imagine a person having a blood panel drawn that would give the person and the physician a profile of biomarkers for a variety of neurodegenerative and vascular processes to direct individual therapy programs. While actual prevention may not be feasible, a delay and slowing of the underlying processes would produce huge benefits. A great deal of research is underway pursuing this approach. The complete reference list is available online at https://expertconsult. inkling.com.

Young-Onset Dementia

Nine Most Common Causes of Dementia (Ages 17–45) According to Kelley et al. (2008)

Nine Most Common Causes of Dementia (Ages 30–65) According to Harvey et al. (2003)

Frontotemporal dementia Huntington disease Multiple sclerosis Autoimmune encephalopathy (dementia) Neuropsychiatric lupus Mitochondrial disease Storage disease Prion disease Vasculitis

Alzheimer dementia Vascular dementia Frontotemporal dementia Alcohol-related dementia Dementia with Lewy Bodies Huntington disease Multiple sclerosis Dementia due to Down syndrome CBD/prion disease/Parkinson dementia

CBD, corticobasal degeneration.

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CHAPTER 95 Alzheimer Disease and Other Dementias

Rx?

PET/CSF

Rx?

Rx? Aβ

?CSF

PET/CSF

TDP-43 Hippocampal sclerosis

Tau Clinical spectrum

Pathology Biomarker Therapy

CN - MCI -dementia

Alpha synuclein

Other

Vascular disease

?CSF

?

Rx?

Rx?

MRI

Rx?

Petersen, Neurology, 2018, 91: 395-402 ©2014 MFMER I slide-29

Fig. 95.28 Clinical spectrum of cognitively unimpaired–mild cognitive impairment–dementia with its multiple potential etiologies. The contribution of Alzheimer disease (AD) is expressed by β-amyloid (Aβ) and tau. However, the other protein abnormalities, including TDP-43 and β-synuclein, as well as vascular disease may also contribute to cognitive impairment. Biomarkers for TDP-43, alpha-synuclein and other are under development. Treatments may be developed for each pathological entity.

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96 Parkinson Disease and Other Movement Disorders Joseph Jankovic

OUTLINE Movement Disorders and the Basal Ganglia, 1498 Basal Ganglia Anatomy, 1499 Functional Organization of the Basal Ganglia and Other Pathways, 1499 Biochemistry, 1501 Mechanisms of Neurodegeneration, 1502 Parkinsonian Disorders, 1504 Parkinson Disease, 1504 Multiple System Atrophy, 1512 Progressive Supranuclear Palsy, 1513 Corticobasal Degeneration, 1515 Dementia with Lewy Bodies, 1515 Frontotemporal Degeneration with Parkinsonism, 1516 Parkinsonism-Dementia Complex of Guam, 1516 Guadeloupean Parkinsonism, 1516 Vascular Parkinsonism, 1516 Bilateral Striatopallidodentate Calcification (Fahr Disease), 1517 Postencephalitic Parkinsonism, 1517 Drug-Induced Parkinsonism, 1517 Toxin-Induced Parkinsonism, 1517 Tremor, 1517 Physiological Tremor, 1517 Essential Tremor, 1517 Primary Writing Tremor, 1519 Orthostatic Tremor, 1519 Neuropathic Tremor, 1519 Cerebellar Tremor, 1519 Hereditary Geniospasm (Chin Tremor), 1520 Fragile X Premutation, 1520 Chorea, 1520 Huntington Disease, 1520 Dentatorubral-Pallidoluysian Atrophy, 1523 Neuroacanthocytosis and McLeod Syndrome, 1523

Sydenham Chorea and Other Autoimmune Choreas, 1523 Other Choreic Disorders, 1524 Ballism, 1524 Dystonia, 1525 Childhood-Onset Generalized Primary Dystonia, 1525 Adult-Onset Primary Focal and Segmental Dystonia, 1526 X-linked Dystonia-Parkinsonism (Lubag), 1527 Dopa-Responsive Dystonia, 1527 Myoclonus Dystonia (DYT11), 1527 Rapid-Onset Dystonia Parkinsonism (DYT12), 1527 Wilson Disease (Hepatolenticular Degeneration), 1527 Neurodegeneration with Brain Iron Accumulation, 1528 Post-traumatic Dystonia and Peripherally Induced Movement Disorders, 1528 Paroxysmal Movement Disorders, 1529 Tics, 1529 Tourette Syndrome, 1529 Myoclonus, 1531 Essential Myoclonus, 1531 Posthypoxic Myoclonus (Lance-Adams Syndrome), 1531 Startle and Hyperekplexia, 1531 Palatal Myoclonus, 1531 Spinal Myoclonus, 1532 Toxin- and Drug-Induced Myoclonus, 1532 Tardive Dyskinesia, 1532 Classic Tardive Stereotypy, 1532 Tardive Dystonia, 1532 Stereotypies, 1533 Miscellaneous Movement Disorders, 1533 Hemifacial Spasm, 1533 Painful Legs–Moving Toes Syndrome, 1534 Stiff Person Syndrome, 1534 Functional (Psychogenic) Movement Disorders, 1534

MOVEMENT DISORDERS AND THE BASAL GANGLIA

implied but not proven. Clinicopathological studies relate the signs of Parkinson disease (PD) to deficient dopaminergic neurotransmission in the striatum consequent to the death of dopaminergic neurons in the substantia nigra pars compacta (SNc). Choreic movements in Huntington disease (HD) are linked to the death of medium spiny neurons in the caudate and putamen. Hemiballism (HB) is typically associated with structural lesions in the contralateral subthalamic nucleus (STN) or its afferent or efferent connections. Changes in basal ganglia neurotransmission are well described in many movement disorders, and deepening understanding of basal ganglia neurotransmission has yielded promising symptomatic therapies in many such conditions.

Neurologists often equate movement disorders with disease or dysfunction of the basal ganglia, so no review of movement disorders would be complete without a discussion of these subcortical structures and their connections. In some movement disorders such as parkinsonism, chorea, and ballism, the link to the basal ganglia is supported by clinicopathological, biochemical, functional neuroimaging, and electrophysiological data, whereas in other movement disorders such as tremor, dystonia, and tics, dysfunction of the basal ganglia is

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CHAPTER 96 Parkinson Disease and Other Movement Disorders Functional neuroimaging studies with specific radiopharmaceutical agents demonstrate abnormal function of basal ganglia structures, and intraoperative electrophysiology studies demonstrate abnormalities in neuronal firing rates and patterns, particularly in the STN and globus pallidus (GP) of patients with PD, dystonia, chorea, and other movement disorders. Animal models including the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD, excitotoxic and transgenic models of HD, and the STN lesion model of HB confirm the central role of disordered basal ganglia function in these conditions. In other movement disorders such as dystonia, the link with basal ganglia function is more complex. For example, although secondary dystonias may result from structural lesions in the contralateral putamen, other sites of pathology include the thalamus, rostral brainstem, and cerebellum. Functional neuroimaging studies in patients with dystonia show abnormal activation of the lenticular nucleus, but neuroimaging and physiological studies provide support for additional involvement of the cortex, brainstem, and cerebellum. In other movement disorders such as essential tremor (ET), restless legs syndrome (RLS), stiff person syndrome (SPS), hemifacial spasm (HFS), spinal myoclonus, and painful legs–moving toes syndrome (PLMTS), the dysfunction appears to lie outside the basal ganglia, such as in the brainstem, cerebellum, spinal cord, or even in the peripheral nervous system.

Basal Ganglia Anatomy There is no clear consensus on which structures should be included in the basal ganglia. For the purposes of this discussion, we consider those structures in the striatopallidal circuits involved in modulation of the thalamocortical projection: the caudate nucleus, the putamen, the external segment of the GP (GPe), and the internal segment of the GP (GPi). In addition, the SNc, the substantia nigra pars reticulata (SNr), and the STN are included in the basal ganglia (Ellens et al., 2013). The substantia nigra (SN), a melanin-containing (pigmented) nucleus, normally contains about 500,000 dopaminergic neurons. Several transcriptional regulators, including Nurr1, Lmx1a, Lmx1b, Msx1, and Pitx3, are responsible for the development and maintenance of midbrain dopaminergic neurons (Le et al., 2009). The caudate nucleus is a curved structure that traverses the deep hemisphere at the lateral edge of each lateral ventricle. Its diameter is largest at its head, tapering to a small tail. It is continuous with the putamen at the head and tail. The caudate and putamen together are called the striatum, and they form the major target for projections from the cerebral cortex and the SN. The putamen and the GP together form a wedge-shaped structure called the lenticular nucleus. The GP is divided into two parts, the GPe and the GPi. The GPi is structurally and functionally homologous with the SNr. The SNr and SNc extend the length of the midbrain ventral to the red nucleus and dorsal to the cerebral peduncles. The STN is a small lens-shaped structure at the border between the cerebrum and the brainstem. The basal ganglia and its relation to the thalamus and overlying cortex are illustrated in Fig. 96.1.

Functional Organization of the Basal Ganglia and Other Pathways Afferent projections to the striatum arise from nearly all areas of the cerebral cortex, the intralaminar nuclei of the thalamus, mesencephalic SN, and from the brainstem locus coeruleus and raphe nuclei. There is also a projection from the cerebral cortex to the STN (Eisenstein et al., 2014). The major efferent projections are from the GPi and SNr to the thalamus and brainstem nuclei such as the pedunculopontine nucleus (PPN). The GPi and SNr project to ventral anterior and ventrolateral thalamic nuclei. The GPi also projects to the centromedian thalamic nuclei, and the SNr projects to the mediodorsal thalamic nuclei and

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Area 4 and 6

All areas of cerebral cortex

Area 6 SMA

C, P GPe

VA

T

GPi

I, CM

VL STN

SC SNc

Afferent connections Intrinsic connections Efferent connections SNr Fig. 96.1 Schematic drawing of interconnections between the basal ganglia and its afferent and efferent connections. CM, Centromedian nucleus of thalamus; C,P, caudate, putamen (striatum); GPe, lateral (external) globus pallidus; GPi, medial (internal) globus pallidus; SC, superior colliculus; SMA, supplementary motor area; STN, subthalamic nucleus; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata; T, thalamus; VA, ventral anterior; VL, ventrolateral.

superior colliculi. The ventral anterior and ventrolateral thalamic nuclei then project to the motor and premotor cortex. Throughout, these projections are somatotopically organized (Rodriguez-Oroz et al., 2009). The basal ganglia has dense internuclear connections (see Fig. 96.1). Five parallel and separate closed circuits through the basal ganglia have been proposed. These are the motor, oculomotor, dorsolateral prefrontal, lateral orbitofrontal, and limbic loops (Rodriguez-Oroz et al., 2009). It is now generally accepted that these loops form three major divisions—sensorimotor, associative, and limbic—that are related to motor, cognitive, and emotional functions, respectively (Table 96.1). The functions of the sensorimotor striatum are subserved mainly by the putamen, which derives its afferent cortical inputs from both motor cortices. Sensorimotor pathways are somatotopically organized, and the pathway ultimately terminates in the premotor and primary motor cortices and the supplementary motor area (SMA). Cognitive functions are largely mediated by the associative striatum, particularly the dorsal caudate nucleus, which receives afferent input from the homolateral frontal, parietal, temporal, and occipital cortices. Projections from this pathway ultimately terminate in the prefrontal cortex. The limbic striatum subserves emotional and motivational functions. Its input derives from the cingulate, temporal, and orbitofrontal cortices, the hippocampus, and the amygdala. It mainly comprises the ventral striatum, with ultimate projections to the anterior cingulate and medial orbitofrontal cortices (Rodriguez-Oroz et al., 2009). Whether these divisions are interconnected or organized in parallel remains a topic of debate.

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PART III

Neurological Diseases and Their Treatment

Divisions of the Striatum

TABLE 96.1

ORIGIN OF STRIATAL

TERMINATION OF BASAL

Division

Afferents

Striatal Nucleus

Ganglia Efferents

Function

Sensorimotor

Motor cortex

Putamen

Movement

Associative

Frontal cortex Parietal cortex Temporal cortex Occipital cortex Hippocampus Amygdala Cingulate cortex Temporal cortex Orbitofrontal cortex

Dorsal caudate

Premotor cortex Primary motor cortex Supplementary motor area Prefrontal cortex

Anterior cingulated cortex Medial orbitofrontal cortex

Emotion Motivation

Limbic

Ventral striatum

Within each basal ganglia circuit lies an additional level of complexity. Each circuit contains two pathways by which striatal activity is translated into pallidal output. These two pathways are named the direct and indirect pathways, depending on whether striatal outflow connects directly with the GPi or first traverses the GPe and STN before terminating in the GPi. The direct and indirect pathways have opposite effects on outflow neurons of the GPi and SNr (Fig. 96.2, A). In the motor direct pathway, excitatory neurons from the cerebral cortex synapse on putaminal neurons, which in turn send inhibitory projections to the GPi and its homolog, the SNr. The GPi/SNr sends an inhibitory outflow to the thalamus (see Fig. 96.2, B). Activity in the direct pathway disinhibits the thalamus, facilitating the excitatory thalamocortical pathway and enhancing activity in its target, the motor cortices. Thus, the direct pathway constitutes part of an excitatory cortical-cortical circuit that likely functions to maintain ongoing motor activity. In the indirect pathway, excitatory axons from the cerebral cortex synapse on putaminal neurons. These neurons send inhibitory projections to the GPe, and the GPe sends an inhibitory projection to the STN. The net effect of these projections is disinhibition of the STN. The STN in turn has an excitatory projection to the GPi (see Fig. 96.2, C). Activity in the indirect pathway thus excites the GPi/SNr, which in turn inhibits the thalamocortical pathway. Thus, the net effect of increased activity in the indirect pathway is cortical inhibition. There is growing appreciation of the importance of direct connection from the cortex to the STN, the so-called hyperdirect pathway, and to the thalamus (Coude et al., 2018). The striatum also receives robust afferent input from the SNc. This projection from the SNc, an important modifier of striatal activity, facilitates activity in the direct pathway, mediated via D1 dopamine receptors, and inhibits activity in the indirect pathway via D2 dopamine receptors (see Fig. 96.2, A). Disorders of the basal ganglia result in prominent motor dysfunction, though not generally in frank weakness. The absence of direct primary or secondary sensory input and lack of a major descending pathway below the level of the brainstem suggest that the basal ganglia moderates rather than controls movement. The direct pathway is important in initiation and maintenance of movement, and the indirect pathway apparently plays a role in the suppression of extraneous movement. From this model of basal ganglia connectivity, hypotheses about the motor function of the basal ganglia have been proposed. One hypothesis is that the relative activities of the direct and indirect

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Cognition

pathways serve to balance the facilitation and inhibition of the same population of thalamocortical neurons, thus controlling the scale of movement. A second hypothesis proposes that direct pathway-mediated facilitation and indirect pathway-mediated inhibition of different populations of thalamocortical neurons serve to focus movement in an organization reminiscent of center-surround inhibition. These hypotheses relate activity in the direct and indirect pathways mainly to rates of firing in the STN and GPi. Thus, death of neurons in the SNc, as in nigrostriatal degeneration associated with PD, decreases activity in the direct pathway and increases activity in the indirect pathway. These changes cause an increased rate of firing of subthalamic and GPi neurons, with excessive inhibition of thalamocortical pathways, and produce the behavioral manifestations of bradykinesia in PD (Fig. 96.3, A). On the other hand, predominant loss of indirect pathway neurons, as in HD, interferes with suppression of involuntary movements. Choreic involuntary movements are the usual result (see Fig. 96.3, B). Direct electrophysiological recordings of the STN and GP during stereotactic functional neurosurgical procedures confirm that the GPi and STN are overly active in patients with PD. The activity of these nuclei returns toward normal with effective pharmacotherapy, and chorea is associated with lower firing rates of neurons in these nuclei. Unfortunately, this model does not completely explain some important features of movement disorders. For example, bradykinesia and chorea coexist in HD and in patients with PD treated with levodopa (LD). Thalamic lesions that might be expected to worsen parkinsonism by reducing excitatory thalamocortical activity do not do so. Pallidal lesions that might be expected to worsen chorea by decreasing inhibition of thalamocortical pathways instead are dramatically effective at reducing chorea. The model is even more problematic when applied to dystonia. It has been suggested that in dystonia there is overactivity of both the direct and indirect pathways. Yet, intraoperative recordings in dystonia have shown low rates and abnormal patterns of neuronal firing in the GPi. A simple change in firing rate of the STN or GPi is thus insufficient to explain the underlying physiology of dystonia. It is likely that disordered patterns and synchrony of pallidal firing, as well as changes in sensorimotor integration and the control of spinal and brainstem reflexes, are important. These factors are under investigation, but current models remain useful for understanding the rationale of pharmacological and ablative surgical procedures for certain movement disorders.

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CHAPTER 96 Parkinson Disease and Other Movement Disorders

MC

SMA

glu (D2) GABA

PMC

Putamen glu dopamine (D1) GPe

MC

glu VA/VL

SN

PMC

glu

Putamen

glu

dopamine

(D1)

GPe

STN

GPi

GABA GABA

GABA

GABA

STN

GPi GABA

glu

A

VA/VL

SN

GABA GABA

glu

(D2) GABA

GABA

SMA

glu MC

SMA

PMC

glu

Parkinson disease MC

Putamen glu dopamine (D1) GPe

A

SMA

PMC

glu

VA/VL

SN

glu

Putamen

glu

(D2)

dopamine

(D1)

VA/VL

GABA GABA STN

GPi

GABA

GPe

SN

GABA

GABA GABA

B Fig. 96.2 Schematic drawing of internuclear connections of basal ganglia, including (A) direct and indirect pathways and (B) direct pathway. (See Fig. 96.3 for depiction of indirect pathway.) Excitatory pathways in solid lines, inhibitory pathways in dotted lines. D1, Dopamine D1 receptor; D2, dopamine D2 receptor; GABA, γ-aminobutyric acid; glu, glutamate; GPe, external segment of the globus pallidus; GPi, internal segment of the globus pallidus; MC, motor cortex; PMC, premotor cortex; SMA, supplementary motor area; SN, substantia nigra; STN, subthalamic nucleus; VA/VL, ventral anterior/ventrolateral thalamic nuclei.

Although much of the emphasis has been on GPi and SNr efferents to the thalamocortical system, there is growing evidence that descending pathways, particularly to the zona incerta and PPN, are important in movement disorders. The PPN appears to play a role in locomotion, muscle tone, and akinesia. A number of other pathways also seem particularly relevant to myoclonus, including a corticolemniscal-thalamocortical circuit and a spinobulbar-spinal circuit that primarily involves the spinoreticular tracts, nucleus reticularis gigantocellularis of the medullary reticular formation, and the reticulospinal tracts. The Guillain-Mollaret triangle is a network connecting the red nucleus, dentate nucleus, and inferior olive, which has been implicated in palatal myoclonus (PM) (also known as palatal tremor) and myorhythmia (Baizabal-Carvallo et al., 2015). The propriospinal pathways and segmental spinospinal loops are important in the genesis of propriospinal and spinal segmental myoclonus, respectively. It is beyond the scope of this chapter to review all the brain structures involved in motor control, but there has been considerable recent interest in the lateral habenula, located above the posterior thalamus. The lateral part of the habenula has an inhibitory influence on the SNc, but its exact role in various movement disorders is unknown, although it has been implicated in some mood disorders (Yang et al., 2018). Another structure that has received some interest, particularly as it relates to ET, is zona incerta. This nucleus appears to be an extension of the reticular nucleus of the thalamus, situated between the thalamus and the fields of Forel, with its fiber tracts conveying the pallidal output to the thalamus. Chiefly inhibitory (GABAergic), the zona incerta may

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glu Huntington disease

B Fig. 96.3 Schematic drawing of functional activities in the direct and indirect pathways in Parkinson disease (PD) and Huntington disease (HD). A, In PD, reduced dopaminergic facilitation of direct pathway and inhibition of indirect pathway due to death of dopaminergic neurons causes increased firing and increased inhibition of thalamocortical pathways, producing bradykinesia. B, In HD, loss of striatal neurons leads to reduced activity in indirect pathway, causing reduced inhibition of thalamocortical pathways, with production of excessive or involuntary movements. (See Fig. 96.2 for explanations to abbreviations.) D1, Dopamine D1 receptor; D2, dopamine D2 receptor; GABA, γ-aminobutyric acid; glu, glutamate; GPe, external segment of the globus pallidus; GPi, internal segment of the globus pallidus; MC, motor cortex; PMC, premotor cortex; SMA, supplementary motor area; SN, substantia nigra; STN, subthalamic nucleus; VA/VL, ventral anterior/ventrolateral thalamic nuclei.

act to synchronize activity generated by the basal ganglia and cerebellum. Indeed, there is a growing body of evidence of communication between the cerebellum and basal ganglia involving γ-aminobutyric acid (GABA) and other neurotransmitters (Bostan and Strick, 2018).

Biochemistry Our understanding of basal ganglia neurotransmitters and pharmacology is growing rapidly. In addition to dopamine, there are many other neurotransmitters that play a role in motor and nonmotor functions (Stayte and Vissel, 2014; Klein et al., 2014). Along with this growth is an expanding spectrum of practical applications for pathology, neuroimaging, and therapeutics. For example, catecholamine and amino acid neurotransmitters coexist with peptides. This co-localization may allow histopathological differentiation among medium spiny striatal projection neurons that secrete γ-aminobutyric acid (GABAergic neurons), further elucidating the specific nature and progress of striatal

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TABLE 96.2

Ganglia

Neurological Diseases and Their Treatment

Pharmacology of the Basal

Pathway

Transmitter

Striatal Afferents Cerebral cortex → striatum Cerebral cortex → STN Locus coeruleus → striatum Locus coeruleus → SN Raphe nuclei → striatum Raphe nuclei → SN Thalamus → striatum SNc → striatum

Glutamate Glutamate Norepinephrine Norepinephrine Serotonin Serotonin Acetylcholine? Glutamate? Dopamine, cholecystokinin

Intrinsic Connections Striatal interneurons Striatum → GPi Striatum → SNr Striatum → GPe GPe → STN STN → GPi, SNr, GPe

GABA, acetylcholine Somatostatin, neuropeptide Y Nitric acid, calretinin GABA, substance P GABA, dynorphin, substance P GABA, enkephalin, glutamate

Striatal Efferents GPi → thalamus SNr → thalamus

GABA GABA

GABA, γ-Aminobutyric acid; GPe, external segment of the globus pallidus; GPi, internal segment of the globus pallidus; SN, substantia nigra; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata; STN, subthalamic nucleus.

neurodegeneration. Neuroimaging technology has been aided by the development of radiopharmaceutical ligands with such discrete targets as the dopamine transporter on the presynaptic dopamine neuron and subpopulations of dopamine receptors on the postsynaptic neuron. The pharmaceutical industry is searching for ways to provide better-targeted and more physiological stimulation of neurotransmitter receptors and is expanding its investigations from the primary targets themselves to approaches that may modify responsiveness of the primary targets. The major neurotransmitters of the basal ganglia are outlined in Table 96.2 (see also Fig. 96.2). Most excitatory synapses of the basal ganglia and its connections—including those from the cerebral cortex to the striatum, the STN to the GPi, and the thalamocortical projections—use glutamate. Projections from the striatum to the GPe and GPi, from the GPe to the STN, and from the GPi to the thalamus are inhibitory and employ GABA. Medium spiny GABAergic neurons in the direct pathway co-localize substance P and dynorphin. GABAergic neurons in the indirect pathway co-localize enkephalin. Dopamine is the major neurotransmitter in the nigrostriatal dopamine system; it has excitatory or inhibitory actions depending on the properties of the stimulated receptor. Acetylcholine is found in large aspiny striatal interneurons and the PPN. Norepinephrine, important in the autonomic nervous system, is most concentrated in the lateral tegmentum and locus coeruleus. Serotonin is found in the dorsal raphe nucleus of the brainstem, hippocampus, cerebellum, and spinal cord. For each of these neurotransmitters, multiple types of receptors may exist. Glutamate is active at a number of types of ligand-gated ion channel receptors named for their selective agonists: N-methyld-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazole

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propionic acid (AMPA), and kainate. The NMDA receptor has been the focus of particular attention because of its potential role in excitotoxic neuronal injury. There are also metabotropic glutamate receptors (Reiner and Levitz, 2018). Glutamate is not only an excitatory neurotransmitter by opening calcium channels, but it is also involved in many metabolic processes by creating short- and long-term changes in synaptic excitability that are thought to be fundamental in brain plasticity. GABA, the main inhibitory neurotransmitter in the brain, is synthesized by glutamic acid decarboxylase (GAD) from glutamate. There are three classes of GABA receptors, GABAA, GABAB, and GABAc. The subclasses are largely differentiated by their relative sensitivity to benzodiazepines. For example, benzodiazepines can increase the inhibitory action of a GABAA synapse. GABAA receptors are ligand-gated chloride channels and have many subtypes. The GABAB receptor is a metabotropic receptor. Five types (D1 through D5) and two families (D1 and D2) of dopamine receptors have been identified (Klein et al., 2019). The D1 family of receptor is adenylate cyclase dependent and contains subtypes D1 and D5. D1 receptors reside primarily in the direct pathway, cerebral cortex, and limbic system. D2 receptors are located primarily in the indirect pathway, cerebral cortex, and limbic system, as well as in the pituitary gland. There are many types of cholinergic receptors, designated as M1–M5, which mediate both excitatory and inhibitory effects (Liu and Su, 2018). Most striatal cholinergic receptors are muscarinic. In the norepinephrine system, there are two primary receptor systems, α and β. There are many distinct receptor subtypes of serotonin receptors, including G protein–coupled receptors in the 5-HT1, 5-HT2, 5-HT4, 5-HT5, 5-HT6, and 5-HT7 families and the 5-HT3type ligand-gated ion channels. Adenosine A2A receptors are co-localized with striatal dopamine D2 receptors on GABAergic medium spiny neurons, which project via the indirect striatopallidal pathway to the GPe. Drugs targeting specific subpopulations of receptors are in use or under development for movement disorders, but there remains a knowledge deficit about the relative clinical utility of specific receptor agonists and antagonists. There is a growing interest in the tetrahydrocannabinol and the cannabinoid system but its role in motor control or various movement disorders is still not well understood, although there is evidence that the cannabinoids modulate dopaminergic effects (Bloomfield et al., 2016; Covey et al., 2017; Kluger et al., 2015). CB1 receptor is the principal receptor in the central nervous system (CNS), particularly abundant in the basal ganglia (Davis et al., 2018). TRVP1 (transient receptor potential vanilloid type1) receptors also respond to cannabinoids. The main endogenous ligands for the CB1 receptor are anandamide and 2-arachidonoylglycerol (2-AG).

MECHANISMS OF NEURODEGENERATION Many of the neurodegenerative movement disorders share the property of neuronal damage caused by the accumulation of aggregation-prone proteins that have toxic effects (Table 96.3). For a protein to function normally, it must be properly synthesized and folded into its normal three-dimensional structure. Nascent proteins are aided in folding by molecular chaperones. Proteins that are not properly folded, are otherwise damaged, or are beyond their useful lives are degraded by the ubiquitin-dependent proteasome protein degradation system (Atkin and Paulson, 2014). In the ubiquitin-dependent proteasome system, proteins are first labeled for degradation by attachment of a polyubiquitin chain (Fig. 96.4). This three-step process involves activation, conjugation, and ligation steps catalyzed by three types of enzymes—E1,

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CHAPTER 96 Parkinson Disease and Other Movement Disorders

TABLE 96.3

Toxic Proteins and Neurodegenerative Movement Disorders

α-Synuclein

Tau

Polyglutamine Tract

Parkinson disease Diffuse Lewy body disease Multiple system atrophy

Four-repeat tau Progressive supranuclear palsy Corticobasal degeneration Frontotemporal dementia with parkinsonism (chromosome 17) Parkinsonism dementia complex of Guam Postencephalitic parkinsonism

Huntington disease Spinocerebellar ataxias Dentatorubral-pallidoluysian atrophy

U

Mechanisms of Neurodegeneration Related to Misfolded Protein Stress

BOX 96.1

U UCHL1

U U

U

Loss of protein function Interaction of the mutant protein with the wild-type protein Interaction with other proteins, including transcription factors Caspase activation Apoptosis Suppression of proteasome function Interference with mitochondrial function Oxidative stress Microglial activation

E1 Activation U

U

U

U E2 Conjugation

U

U

U U U 26S Proteasome

E3 Ligation Protein

Protein fragments

Ubiquinated protein Fig. 96.4 Ubiquitin-Dependent Proteasome Proteolysis. Once a protein is tagged for degradation, it is tagged with a polyubiquitin chain, a three-step process involving first activation, then conjugation, then ligation. Ubiquitinated protein enters 26S proteasome, where it is degraded into protein fragments, and polyubiquitin chain is degraded back to monomeric ubiquitin. E, Enzyme; U, ubiquitin; UCHL1, ubiquitin carboxy-terminal hydrolase 1.

E2, and E3, respectively. Polyubiquitinated protein enters the 26S proteasome, a cylindrical complex of peptidases. The end products of proteasome action are protein fragments and polyubiquitin. The polyubiquitin is then degraded and recycled to the cellular ubiquitin pool, a process requiring enzymatic action by ubiquitin carboxy-terminal hydrolase 1. The cascade of pathogenic events linking abnormal protein aggregation to cell death is the subject of intense investigation. Although aggregates are the most striking physical change in surviving cells, the actual role of the aggregate remains a mystery. Indeed, many now believe that the formation of aggregates may be a protective mechanism sequestering the wayward protein from vulnerable cell processes (Espay et al., 2019). Nevertheless, there are now many clinical trials designed to suppress α-synuclein as a potential disease-modifying strategy (Jankovic, 2019). Misfolded proteins may produce the most mischief as they form protofibrils. A number of mechanisms have been described. In some cases, these are specifically related to the type of protein, but in many other cases, they are nonspecific mechanisms shared by all the misfolded protein diseases. There is growing evidence that preformed fibrils generated from full-length and truncated recombinant α-synuclein enter neurons, probably by endocytosis, and act as “seeds” that induce recruitment of soluble endogenous α-synuclein into insoluble

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Lewy body–like inclusions, resulting in progressive prion-like spread of neurodegeneration (Recasens et al., 2014). Some potential mechanisms of neurodegeneration related to misfolded protein stress are listed in Box 96.1. The mutant protein may be unable to perform a vital function or may interfere with the function of the wild-type protein. Mutant protein, protofibrils, or aggregates might interfere with other proteins. Interference with transcription factors may be particularly important in this regard. Mutant proteins may activate caspases or in other ways activate the apoptotic cascade. They may interfere with intracellular transport or other vital processes. They may suppress activity of the proteasome, enhancing protein aggregation. They may interfere with mitochondrial function, making cells more vulnerable to excitotoxicity. In addition to the ubiquitin-proteasome system, lysosomes play an important role in degrading intracellular proteins by a process termed autophagy (Chu, 2019). When the function of the ubiquitin proteasome system is not sufficient to clear the accumulating cellular proteins, the autophagy lysosome pathway becomes the other important route for degradation of aggregated/misfolded proteins as well as sick or abnormal mitochondria. Indeed, mitophagy is an increasingly recognized mechanism for removing sick mitochondria and maintaining cellular health (Wang et al., 2019). Accumulation of iron, increased oxidative stress, and microglial activation have also been thought to play important roles in the pathogenesis of various neurodegenerative disorders (Dusek et al., 2012). Many neurodegenerative movement disorders can be linked to abnormal synthesis, folding, or degradation of specific proteins or protein families and the notion that progression of neurodegenerative disease is mediated via seeding of misfolded proteins has extended to a broad range of mutated proteins, including α-synuclein, tau, huntingtin, SOD-1, and TDP-43. The synucleinopathies include PD, Lewy body disease (LBD), and multiple system atrophy (MSA). The tauopathies include progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), familial frontotemporal dementia (FTD) with parkinsonism (FTDP), postencephalitic parkinsonism (PEP), post-traumatic

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parkinsonism, and amyotrophic lateral sclerosis (ALS)-PD of Guam. The polyQ disorders include HD, dentatorubral-pallidoluysian atrophy (DRPLA), and many spinocerebellar ataxias (Ling et al., 2010; Williams and Lees, 2009). Within the CNS, certain neuronal populations seem selectively vulnerable to the various pathogenic mechanisms of cell death. This preferential degeneration of specific neuronal populations ultimately determines the phenotype of the disorder. Better understanding of the various pathogenic cellular mechanisms and selective vulnerability may lead to neuroprotective therapeutic strategies that favorably modify the natural course of the neurodegenerative disease.

PARKINSONIAN DISORDERS Parkinson Disease In his monograph, The Shaking Palsy (1817), James Parkinson identified the hallmark features of the illness through descriptions of cases observed in the streets of London as well as in his own patients (Obeso et al., 2017). Over time, Parkinson disease or idiopathic PD has replaced the original term paralysis agitans as the name for the clinical syndrome of asymmetrical parkinsonism, usually with rest tremor, in association with the specific pathological findings of depigmentation of the SN due to loss of melanin-laden dopaminergic neurons containing eosinophilic cytoplasmic inclusions (Lewy bodies) (see Chapter 24). Dopamine deficiency in parkinsonian brain was described by Hornykiewicz in 1959, a discovery that ultimately led to highly effective pharmacotherapy with LD and direct-acting dopamine agonists (DAs). Recently, genetic forms of parkinsonism that are clinically indistinguishable from PD have been linked to mutations in several genes (Rousseaux et al., 2017). The discovery of different genetic forms of parkinsonism with variable penetrance has led to the current concept of PD as a syndrome with genetic and environmental etiologies, but, overall, gene mutations are a rare cause of parkinsonism, particularly in those patients with late-onset disease (Deng et al., 2018; Trinh and Farrer, 2013) (Chapter 24).

Epidemiology In community-based series, PD accounted for more than 80% of all parkinsonism, with a prevalence of approximately 360 per 100,000 and an incidence of 18 per 100,000 per year (de Lau and Breteler, 2006). PD is an age-related disease, showing a gradual increase in prevalence beginning after age 50, with a steep increase in prevalence after age 60. Disease before 30 years of age is rare and often suggests a hereditary form of parkinsonism. Prevalence rates in the United States are higher than those in Africa and China, but the role of race remains unclear. Within the United States, race-specific prevalence rates vary, with some studies suggesting a similar prevalence among Whites and Blacks. Unfortunately, Blacks make up only a small fraction of most specialty clinic populations and thus are underrepresented in clinic-based studies and clinical trials. One study showed the world’s highest prevalence of PD may be among the Amish in the US Northeast—nearly 6% of those 60 years of age or older, more than three times the reported 1%–2% prevalence for the rest of the country (Racette et al., 2009). Clinical features. Typically, the onset and progression of PD are gradual. We have developed a screening tool that can be used to detect early symptoms of PD (York et al., 2020). The most common presentation is with rest tremor in one hand, often associated with decreased arm swing and shoulder pain (Ha and Jankovic, 2012; Jankovic, 2008). Although 4–5 Hz rest tremor is considered the typical tremor of PD, the more troublesome tremor experienced by patients with PD is postural tremor, either re-emergent tremor occurring after a latency of a few seconds following the assumption of position of outstretched arms, or the postural tremor of PD (Jankovic, 2016a).

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Hoehn and Yahr Stage

TABLE 96.4 Stage

Disease state

Original Scale I Unilateral involvement only, minimal or no functional impairment II Bilateral or midline involvement, without impairment of balance III First sign of impaired righting reflex, mild to moderate disability IV Fully developed, severely disabling disease; patient still able to walk and stand unassisted V Confinement to bed or wheelchair unless aided Modified Scale 0 No signs of disease 1 Unilateral disease 1.5 Unilateral plus axial involvement 2.0 Bilateral disease without impairment of balance 2.5 Mild bilateral disease with recovery on pull test 3.0 Mild to moderate bilateral disease, some postural instability, physically independent 4.0 Severe disability, still able to walk or stand unassisted 5.0 Wheelchair bound or bedridden unless aided

In contrast to the rest and re-emergent tremor which may be related to dopamine deficiency, the PD action-postural tremor appears to correlate with serotonergic deficiency (Jankovic, 2018a). Bradykinesia and rigidity are often detectable on the symptomatic side (Loane et al., 2013), and midline signs such as reduced facial expression or mild contralateral bradykinesia and rigidity may already be present. The presentation may be delayed if bradykinesia is the earliest symptom, particularly when the onset is on the nondominant side. The disorder usually remains asymmetrical throughout much of its course. With progression of the illness, generalized bradykinesia may cause difficulty arising from a chair or turning in bed. Patients typically develop stooped posture and in some cases the flexion of the trunk can become quite severe, the so-called camptocormia (see Videos 96.1 and 96.2) (Wijemanne and Jankovic, 2019). Some patients may also develop deformities in the hands and feet which can resemble arthritis, the so-called “striatal deformities” (see Video 96.3) (Wijemanne and Jankovic, 2019). The gait and balance are progressively affected, and falls may occur. Sudden arrests in movement, also called freezing or motor blocks, soon follow, first with gait initiation, turning and traversing narrow or crowded environments, and then during walking (see Video 96.4). Bulbar functions deteriorate, impairing communication and nutrition. The tremor-dominant form of PD generally has a more favorable clinical course than PD dominated by gait disorder and postural instability (Thenganatt and Jankovic, 2014a). The Unified Parkinson’s Disease Rating Scale (UPDRS) has been used to quantitate the various motor symptoms and signs of PD and to chart the course of the disease. This traditional scale, now known as the Movement Disorder Society (MDS)-UPDRS, has been revised to clarify some ambiguities in the original version and to capture early motor and also nonmotor symptoms associated with PD (http://www.movementdisorders.org). The Hoehn and Yahr staging, first described before effective dopaminergic treatment became available, outlines the milestones in progression of the illness from mild unilateral symptoms through the end-stage nonambulatory state. A modified version of the Hoehn and Yahr stage is commonly used in contemporary clinical trials (Table 96.4).

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CHAPTER 96 Parkinson Disease and Other Movement Disorders Nonmotor symptoms are increasingly recognized as a major cause of disability in PD and contribute prominently to declining quality of life, particularly in the more advanced stages of the disease (Marinus et al., 2018). Autonomic symptoms include reduced gastrointestinal transit time with postprandial bloating and constipation, urinary frequency and urgency (sometimes with urge incontinence), impotence, disordered sweating, and orthostatic hypotension. Cognitive and behavioral changes are also very common. Attention and concentration wane. Executive dysfunction with diminished working memory, planning, and organization is common. Global dementia occurs in approximately 30% of patients, increasing in frequency with the age of the patient. Those with prominent early executive dysfunction and more severe motor signs seem particularly at risk. Anxiety, depression, and other mood disorders are common in PD. Sleep disturbance is nearly universal in PD and is multifactorial. Disordered sleep onset and maintenance lead to fragmentation of nocturnal sleep. A variety of motor movements including RLS and periodic leg movements of sleep may be seen, and many patients have rapid eye movement (REM) sleep behavior disorder (RBD) with active motor movements during REM sleep. The following question was found to have 94% sensitivity and 87% specificity in detecting RBD: “Have you ever been told, or suspected yourself, that you seem to ‘act out your dreams’ while asleep (for example, punching, flailing your arms in the air, making running movements, etc.)?” (Postuma et al., 2012). Some patients with PD have sleep apnea. Vivid dreams and nightmares are very common, particularly in treated patients. Sleep disorders in PD variably relate to the pathological changes of the disease itself, arousals due to immobility, comorbid primary sleep disorders, and side effects of antiparkinsonian medications. Many patients with PD are excessively sleepy during the day, sometimes with serious consequences such as unintended sleep episodes while driving. In most cases, this excessive daytime drowsiness is related to dopaminergic drugs. Fatigue is a common and complex symptom of PD. The differentiation of fatigue from excessive daytime sleepiness, depression, apathy, and other conditions can be difficult, and there is not yet a useful body of literature on its assessment and treatment. Clinicopathological studies have found that the clinical variable that best predicts the typical pathological changes of PD, in the absence of other diagnoses known to cause parkinsonism, is an asymmetrical illness with rest tremor along with rigidity or bradykinesia and marked improvement with LD, motor fluctuations, dyskinesias, and hyposmia (Adler et al., 2014). Misdiagnosed cases generally are found to have MSA, PSP, or subcortical vascular disease. When making the diagnosis of early PD, the clinician should be aware of a number of red flags (Box 96.2) (see Chapter 24). Cognitive impairment within the first year should raise the possibility of Alzheimer disease (AD), dementia with Lewy bodies (DLB), corticobasal syndrome (CBS), PSP, or FTDP. Symmetrical or prominent midline or bulbar signs suggest MSA or PSP. Early gait disorder with falls points to the diagnosis of PSP or to subcortical vascular disease. Dependence on a wheelchair within 5 years of onset is suggestive of PSP or MSA. Early orthostatic hypotension or incontinence points to the autonomic dysfunction of MSA. Severe sleep apnea, inspiratory stridor, or involuntary sighing also suggests MSA. Apraxia, alien limb, or cortical sensory loss is typically seen in CBS. Routine laboratory studies are not helpful in the diagnosis of PD, and their use should be reserved for patients with atypical features. There is a growing interest in serums and cerebrospinal fluid (CSF) biomarkers that may differentiate between PD and atypical parkinsonism. In this regard, several studies have found that neurofilament light chain (NFL) protein levels have been found elevated in the serum and CSF of patients with atypical parkinsonism but not in PD (Marques et al., 2019). When genetic causes (see below) are suspected, testing F ECF

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“Red Flags” Suggesting a Diagnosis Other Than Parkinson Disease

BOX 96.2

Early or prominent dementia Symmetrical signs Bulbar dysfunction Early gait disorder Falls within the first year Wheelchair dependence within 5 years Early autonomic failure Sleep apnea Inspiratory stridor Apraxia Alien limb Cortical sensory loss

for specific PD-related monogenic mutations or by whole-exome or whole-genome sequencing may be indicated when coupled with appropriate genetic counseling (Sokol et al., 2017). Neuroimaging studies such as computed tomography (CT) and magnetic resonance imaging (MRI) are usually not very helpful in making a diagnosis of PD, because they are generally normal or show only incidental abnormalities. Sometimes neuroimaging abnormalities can be useful in suggesting alternative diagnoses such as PSP or MSA (see below). The radiopharmaceutical 6-[18F]-fluorodopa (F-dopa) is taken up by dopaminergic neurons in the SN and metabolized to 6-[18F]-fluorodopamine. Positron emission tomography (PET) scans using this radiopharmaceutical agent show reduced F-dopa uptake in dopaminergic nerve terminals in the putamen and caudate proportional to the severity of degeneration in the ipsilateral SN and symptoms in the contralateral hemibody (Fig. 96.5). Although these tests are used in PD research, they are not readily clinically available at this time. Single-photon emission CT (SPECT) with radioligand that labels the dopamine transporter on nerve terminals in the striatum (DaTscan) is a very helpful tool in differentiating PD from ET, drug-induced parkinsonism (DIP), or functional (psychogenic) parkinsonism (Isaacson et al., 2017; Jankovic, 2011). Since most atypical parkinsonian disorders have striatal dopaminergic denervation, DaTscan is not helpful in differentiating these disorders from PD. Routine electrophysiological testing is not helpful in the diagnosis of PD.

Pathology The most striking pathological changes in PD occur in the SNc. The SN appears pale to the naked eye. Microscopic changes include neuronal loss, gliosis, and the presence of extracellular pigment. Surviving neurons may show characteristic cytoplasmic inclusions (Fig. 96.6). These inclusions, called Lewy bodies, have a dense eosinophilic core and a pale halo (except for those located in the cortex) (Jellinger, 2012). They contain hyperphosphorylated neurofilament proteins, lipids, iron, ubiquitin, and α-synuclein. Pigmented nuclei elsewhere in the brainstem, including the locus coeruleus, dorsal motor nucleus of the vagus, and others, may also show Lewy bodies and characteristic degenerative changes. The substantia innominata and intermediolateral cell column in the spinal cord also are affected. Patients with PD and dementia show more diffuse Lewy body pathology or comorbid AD. Even the myenteric intestinal and cardiac plexus of patients with PD may contain Lewy bodies, showing that PD is not just a CNS disease. A staging system introduced by Braak (Goedert et al., 2013) has been developed to characterize the progression of neuropathological changes associated with PD. According to Braak staging, during the presymptomatic stages (1 and 2), the PD-related inclusion body pathology remains confined to the medulla oblongata and olfactory

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B

A

Fig. 96.5 Positron emission tomography scan with [11C]RTI-32, which labels the presynaptic dopamine transporter in a normal control (A) and a subject with early Parkinson disease (PD) (B). There is asymmetrically reduced uptake in PD, indicating asymmetrical loss of presynaptic dopaminergic neurons. (Courtesy Mark Guttman, MD.)

olfactory, sleep, and autonomic involvement in patients with PD, the staging proposal has been challenged for many reasons and inconsistencies, such as absence of cell counts to correlate with the described synuclein pathology, absence of immunohistochemistry to identify neuronal types, absence of observed asymmetry in the pathological findings that would correlate with the well-recognized asymmetry of clinical findings, absence of bulbar symptoms as early features of PD, and the observation that brain synucleinopathy consistent with Braak stages 4 and 6 has been found in individuals without any neurological signs. Although the Braak hypothesis and the central role of α-synuclein in the pathogenesis of PD have been challenged (Espay et al., 2019) these concepts provide a useful framework for understanding the progression of neurodegeneration in PD.

A

Etiology

B Fig. 96.6 Brainstem Lewy Bodies. A, Hematoxylin and eosin-stained section of substantia nigra with a pigmented neuron containing two Lewy bodies. Each is an eosinophilic cytoplasmic inclusion with a halo, displacing neuromelanin. B, α-Synuclein-immunostained Lewy body in a neuron of the substantia nigra; α-synuclein protein is stained red in this preparation. (Courtesy Elizabeth Cochran, MD.)

bulb. In stages 3 and 4, the SN and other nuclear grays of the midbrain and basal forebrain are the focus of initially subtle and then severe changes, and the illness reaches its symptomatic phase. In the end stages (5 and 6), the pathological process encroaches upon the telencephalic cortex. Although the Braak hypothesis is supported by early F ECF

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Studies of large numbers of patients with PD have suggested that PD is a multifactorial illness with likely genetic and environmental determinants (Rousseaux et al., 2017; Jankovic and Tan, 2020). Twin studies suggest that heredity plays a relatively small role in the population at large, but the hereditary component is greater if one twin has disease onset at younger than age 50. Moreover, PET studies of twins suggest that most monozygotic twins of patients with PD show subclinical declines in dopamine innervation, strengthening the evidence for a significant hereditary contribution irrespective of age at onset. Although the majority of cases of PD appear to be sporadic, it is becoming increasingly evident that genetic factors play an important role in the pathogenesis of PD, particularly if onset is earlier than age 50 (see Chapter 24). Some 20%–25% of patients have at least one first-degree relative with PD, and first-degree relatives are two to three times as likely as relatives of controls to develop PD. The most cogent evidence for genetic contribution to the pathogenesis of PD has been provided by reports of large multicase kindreds with dominantly inherited autopsy-proven PD. A genome scan in the Contursi kindred of Greek-Italian origin found a genetic marker on chromosome 4q21-q23 linked to the PD phenotype. Subsequent studies identified at least three different mutations in the α-synuclein gene (SNCA), the first monogenetic form of PD, designated PARK1 (see Table 24.1). In addition to the typical PD features, this family 02 .4.(1( 4 (

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CHAPTER 96 Parkinson Disease and Other Movement Disorders exhibited dementia, severe central hypoventilation, orthostatic hypotension, prominent myoclonus, urinary incontinence, and pathological involvement of the brainstem pigmented nuclei, hippocampus, and temporal neocortex. Later, the application of quantitative realtime PCR amplification of the SNCA gene showed that some families with a PD phenotype, originally designated as PARK4, had duplication and triplication of the gene, with marked increase in the amount of α-synuclein protein. Thus, an overexpression of α-synuclein may lead to neurodegenerative disease, with features overlapping with PD, DLB, and MSA. Based on screening, the entire coding region of the gene in a large number of PD patients shows that mutation in the SNCA gene is a rare cause of PD. Discovery of a linkage between an autosomal recessive, young-onset, LD-responsive form of PD to a locus on chromosome 6q25.2-27 led to subsequent identification of numerous mutations in the gene called parkin (PARK2). This 500-kb, 12-exon gene encodes a 465-amino acid protein with E3 ubiquitin-ligase activity through interaction with the ubiquitin-conjugating enzyme UbcH7 (E2). Associated with the Golgi complex, the parkin protein has also been thought to be involved in vesicular transport. Parkin strongly binds to a variety of proteins and microtubules, a disruption of which in patients with parkin mutations affects vesicular transport and may contribute to the nigrostriatal degeneration. Whereas normal parkin is involved in ubiquitination and subsequent degradation of certain proteins by proteasomes, mutated parkin protein loses this activity and thus may lead to an accumulation of proteins, causing a selective neural cell death without formation of Lewy bodies. In addition to typical PD features, patients with PARK2 exhibit a variety of atypical features such as hyperreflexia, dystonia, leg tremor, autonomic dysfunction, sensory axonal peripheral neuropathy, marked sleep benefit, LD-induced dyskinesias, psychosis, and other behavioral and psychiatric problems. Although PARK2 has been identified in patients with late age at onset, up to half of patients with onset of PD before age 40 years have parkin mutations. A growing number of novel genes have been implicated in the pathogenesis of PD (Deng et al., 2018; Trinh and Farrer, 2013) (see Chapter 24). In addition to α-synuclein (SNCA gene), there are many other monogenetic causes of PD (see Table 24.1) (Deng et al., 2018) Mutations in the PTEN-induced putative kinase 1 (PINK1) gene on chromosome 1p36 were identified in autosomal recessive families with early-onset parkinsonism (PARK6). The PINK1 gene codes for a putative serine-threonine kinase located in the mitochondria, thus providing further support for the role of oxidative stress in the pathogenesis of PD. The mean age at onset is in the fourth decade, and the course is quite benign, associated with LD-induced dyskinesias. These clinical features are similar to those of another autosomal recessive form of PD (PARK7) localized to the same chromosomal region in the DJ-1 gene. Besides slow progression and good, prolonged response to LD, patients with a DJ-1 mutation may exhibit blepharospasm, leg dystonia, anxiety, and parkinsonism-dementia-ALS complex. In contrast to parkin mutations that may account for up to 50% of young-onset PD, the DJ-1 mutations account for approximately 1% of all young-onset PD cases. Another locus mapped to 12p11.23-q13.11 (PARK8) was initially identified in a Japanese family with typical PD inherited in an autosomal dominant pattern with incomplete penetrance and has been subsequently found to be the most common form of familial adult-onset PD (Marras et al., 2016). The course of the disease is relatively benign, usually presenting with unilateral hand or leg tremor without cognitive deficit; the patients respond well to LD. Other clinical phenotypes have included parkinsonism with dementia, hallucinations, dysautonomia, amyotrophy, or both and otherwise typical ET. Autopsy studies demonstrate variable pathology,

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ranging from Lewy body and tau neurofibrillary tangle pathology to no pathological changes. The gene responsible for PARK8 on 12p11.2-q13.1, called LRRK2 (leucine-rich repeat kinase 2), belongs to the ROCO protein family and includes a protein kinase domain of the MAPKKK class and several other major functional domains. The gene product, a protein called dardarin (from Basque word dardara, meaning “tremor”), is a novel protein that probably functions as a cytoplasmic kinase involved in phosphorylation of proteins such as α-synuclein and tau. LRRK2 is closely associated with a variety of membrane and vesicular structures, membrane-bound organelles, and microtubules, suggesting its role in vesicular transport and membrane and protein turnover, including the lysosomal degradation pathway. This mutation has been found to be particularly frequent in PD patients of North African origin and in Ashkenazi Jewish patients (Inzelber et al., 2014). The penetrance is quite variable, and many elderly individuals have the mutation but no signs of PD have been reported. It is beyond the scope of this chapter to discuss all the various genetic causes of PD but the reader is referred to Chapter 24 and other reviews on this topic (Deng et al., 2018). The variable penetrance and growing number of causative and susceptibility genes, coupled with a growing number of commercially available DNA tests, has obvious implications for genetic counseling (Sokol et al., 2017). Evidence for environmental causes of PD comes primarily from two sources: the fortuitous discovery of parkinsonism in parenteral drug users exposed to the contaminant MPTP and epidemiological associations of sporadic PD or other parkinsonisms with certain lifestyle or occupational exposures. The discovery that a handful of drug addicts had developed a severe LD-responsive form of parkinsonism following parenteral administration of a meperidine analog contaminated with the mitochondrial protoxin MPTP suggested that environmental toxins might cause PD. The discovery of MPTP-induced parkinsonism in humans was a sentinel event in our understanding of the disease because it pointed to a class of environmental toxins that might be important in sporadic disease. Although MPTP spawned the development of reproducible models of disease in many kinds of animals, its role in human disease is limited to the cluster of cases in drug addicts and a few others. Intriguing studies have confirmed that certain pesticides (e.g., paraquat, rotenone) can reproduce the pathology of PD in animals, but their role in human disease remains undefined. Epidemiological studies suggest that exposure to environmental metals or organic toxins may be associated with an increased risk of PD or an earlier age at onset. Case-controlled studies have suggested that the risk of PD is increased in persons who have worked in the agricultural industry, have been exposed to pesticides, or have sustained significant head injury. Whether exposure to welding predisposes to earlier onset of PD, possibly as a result of manganese poisoning, is controversial (Jankovic, 2005). On the other hand, the risk of PD seems lower in those with a high dietary intake of antioxidant-rich foods, as well as caffeine drinkers and those who have smoked cigarettes. Although PD and cancer are two distinct diseases that result from either degeneration or over-proliferation, respectively, several recent studies have provided evidence that while PD provides some type of biological protection against most types of cancers, the disease confers increased risk for other cancers such as melanoma. The relationship between PD and melanoma is being explored, but the higher frequency of melanoma does not appear to be due to LD. It is possible that high concentrations of α-synuclein in the skin of patients with PD may increase their risk of melanoma by inhibiting tyrosine hydroxylase, an enzyme involved in dopamine and melanin biosynthesis or by some other mechanism (Pan et al., 2012).

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Treatment Before discussing specific treatment strategies for PD, it is important to recognize that the quantitative assessment of clinical symptoms and progression of the course is an essential component of any therapeutic trial (Jankovic, 2008; Jankovic and Tan, 2020 Jankovic and Tan, 2020). In addition to sensitive clinical rating scales (e.g., MDS-UPDRS), reliable diagnostic, presymptomatic, and progression biomarkers are needed (Marek et al., 2018; Wu et al., 2011).

Neuroprotective or disease-modifying therapies for Parkinson disease. A preclinical period lasting years, its slow progression rate,

and our increasing understanding of disease etiopathogenesis make PD an ideal candidate for neuroprotective therapeutic strategies. However, double-blind placebo-controlled trials designed to explore therapies that may have favorable disease-modifying effects and slow disease progression have been thus far disappointing. The first “neuroprotective” trial, DATATOP (Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism), randomized patients with early PD to treatment with placebo, tocopherol, selegiline (deprenyl), or both, using the time until the patients needed potent symptomatic dopaminergic therapy, LD, as a proxy endpoint for disease progression. The selective monoamine oxidase (MAO-B) inhibitor, selegiline, successfully delayed this endpoint, but interpretation of the study was contaminated by the drug’s mild symptomatic antiparkinsonian and antidepressant properties, as well as the potential effects of its amphetamine metabolites. Although diseasemodifying effects of selegiline have been suggested by some clinical trials, further studies are needed before it can be concluded that selegiline is neuroprotective in PD. Another MAO-B inhibitor, rasagiline, has been shown to have modest symptomatic benefit (Jankovic et al., 2014), but its effects on disease progression are also still being debated. In a randomized multicenter, double-blind, placebo-controlled, parallelgroup study prospectively examining rasagiline’s potential diseasemodifying effects (ADAGIO [Attenuation of Disease Progression with Azilect Given Once-Daily]), delayed-start design was used to assess the potential disease-modifying effects of rasagiline (Olanow et al., 2009). A total of 1176 patients with early untreated PD (mean time from diagnosis, 4.5 months) from 129 centers in 14 countries were randomized into 4 treatment groups (either 1 or 2 mg/day, early-start versus delayed-start treatment, 9 months each). Early-start treatment consisted of 72 weeks of rasagiline (either 1 or 2 mg once daily), and delayed-start treatment consisted of 36 weeks of placebo followed by 36 weeks of rasagiline (either 1 or 2 mg once daily [active treatment phase]). The primary analyses of the trial were based on change in total UPDRS score and included slope superiority of rasagiline over placebo in the placebo-controlled phase, change from baseline to week 72, and noninferiority of early-start versus delayed-start slopes during weeks 48 through 72 of the active phase. The 1-mg dose group met all three endpoints, but there was no observable benefit with the higher 2-mg dose, although when analyzing the upper quartile group, the 2-mg dose group met all the primary endpoints. Some possible explanations for the seemingly confusing outcome include early symptomatic treatment helping some compensatory mechanism, cumulative symptomatic effect, and other possibilities. Development of neuroprotective strategies has been challenging, partly because of lack of reliable and sensitive biomarkers of progression (Jankovic and Sherer, 2014; Jankovic and Tan, 2020). Animal models are essential in preclinical testing of potential symptomatic and neuroprotective therapies (Le et al., 2014). One of the most exciting developments of potential neuroprotective or disease-modifying therapies is the use of α-synuclein monoclonal antibodies to reduce α-synuclein formation and rescue dying neurons (Savitt and Jankovic, 2019a; Tran et al., 2014). Symptomatic treatment of Parkinson disease. Many types of medications are available for symptomatic treatment of PD:

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anticholinergics, amantadine, LD, MAO inhibitors (MAOIs), catecholO-methyltransferase inhibitors (COMTIs), and DAs (Jankovic et al., 2014; Obeso et al., 2017). Anticholinergics such as trihexyphenidyl and benztropine antagonize the effects of acetylcholine at muscarinic receptors postsynaptic to striatal interneurons. They reduce tremor and rigidity but have no effects on bradykinesia. Toxicity relates to antagonism of acetylcholine at central receptors, causing confusion, and peripheral receptors, causing blurred vision, dry mouth, constipation, and urine retention. Although amantadine has been available for nearly 4 decades (it was originally marketed as an antiinfluenza, antiviral agent), its antiparkinsonian mechanisms have been poorly understood. It has been thought to stimulate release of endogenous dopamine stores, block reuptake of dopamine from the synaptic cleft, and have anticholinergic properties. However, amantadine has been found to have antiglutamatergic properties and as such is the only antiparkinsonian drug that improves LD-induced dyskinesia. Extended release formulation of amantadine has been found to improve not only dyskinesia but also motor fluctuations (Pahwa et al., 2017). Combining LD with carbidopa, an aromatic acid decarboxylase inhibitor that prevents its peripheral metabolism, markedly reduces its peripheral adverse effects, particularly nausea. The global antiparkinsonian efficacy of LD is so dramatic and predictable that a positive therapeutic response is used to define the disease itself. Adverse effects of LD include nausea and vomiting, orthostatic hypotension, sedation, confusion, sleep disturbance, alterations of dream phenomena, hallucinations, and dyskinesias (see Video 96.6). Many studies have concluded that DAs such as pramipexole, ropinirole, and rotigotine, when introduced early in the course of PD treatment, may delay LD-related complications such as motor fluctuations and dyskinesias. But evidence is lacking to support the hypothesis that early introduction of DAs slows progression of the disease or even improves long-term quality of life (Espay and Lang, 2017). The PROUD study (Pramipexole on Underlying Disease), which assessed early versus delayed pramipexole treatment in early PD, involved 535 untreated PD patients who were randomized to double-blind placebo or pramipexole (1.5 mg/day) for 6–9 months and continued with pramipexole for up to 15 months. The researchers found no difference in UPDRS (−0.4 UPDRS units) or PDQ-39 scores in the 411 patients who completed the 15-month study, but at the end of the placebo-controlled phase, the difference in adjusted means was −4.8 UPDRS units (95% confidence interval [CT], −6.3, −3.2; P < .0001), and there was a significant difference in PDQ-39 (P = .0001), both in favor of pramipexole (Schapira et al., 2010). Furthermore, many studies have shown that LD is more effective than DAs in reducing motor symptoms in early as well as advanced stages of PD (PD MED Collaborative Group, 2014). In a pragmatic, open-label, randomized trial involving 1620 patients with a newly diagnosed PD randomized to receive a DA (N = 632), a monoamine oxidase inhibitor (N = 460), or LD (N = 528), after median follow-up of 3 years there was a slightly better (1.8 points) PDQ39 mobility score with LD than with the other two treatments (PD MED Collaborative Group, 2014). Although the study suggested small but persistent benefits when PD patients were initially treated with LD compared with LD-sparing therapy, the study did not adequately address whether patients with young-onset PD should be treated differently than those with late-onset PD. Despite the findings from the PD MED study, most parkinsonologists would probably still employ LD-sparing strategy in patients with young-onset PD. Because of various adverse effects related to their ergot structure, particularly fibroproliferative lesions of heart valves, lung, and other tissues, bromocriptine, pergolide, and cabergoline have been discontinued from clinical use. Apomorphine, a nonergoline DA, is water soluble and lipophilic and is therefore suitable for intravenous,

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CHAPTER 96 Parkinson Disease and Other Movement Disorders subcutaneous, sublingual, intranasal, or transdermal administration. Apomorphine is available as an acute intermittent subcutaneous injection, as a rapid rescue from hypomobility off episodes (end-ofdose wearing off and unpredictable on/off episodes) associated with advanced PD. DAs cause side effects similar to those of LD, although orthostatic hypotension, sleepiness, and hallucinations are more common or severe. Continuous apomorphine infusion has been found to meaningfully reduce off time in PD patients who experience troublesome motor fluctuations (Katzenschlager et al., 2018). One major concern with DAs is the relatively high frequency of a variety of behavioral problems that include pathological gambling, compulsive shopping and eating, hypersexuality, and other impulse-control disorders (ICD) (Zhang et al., 2019). Patients with PD who experience ICD seem to have a variety of associated psychiatric symptoms, such as psychoticism, interpersonal sensitivity, obsessive-compulsive symptoms, and depression (Jaakkola et al., 2014) and seem to be prone to dopamine dysregulation syndrome, an addictive behavior and excessive use of dopaminergic medication (Warren et al., 2017). Selegiline and rasagiline block MAO-B-dependent dopamine degradation and have modest effects in potentiating the action of LD. These drugs are now used very infrequently, but some clinicians prescribe these MAO-B inhibitors as the initial pharmacological agents in newly diagnosed patients in an attempt to delay LD therapy. This approach is in part supported by the ADAGIO study (Olanow et al., 2009). COMTIs (entacapone and tolcapone) block peripheral degradation of peripheral LD and central degradation of LD and dopamine (tolcapone), increasing central LD and dopamine levels. Hepatotoxicity associated with tolcapone has limited its use. Triple-combination therapy containing LD, carbidopa, and entacapone is available for patients with moderately advanced PD. The primary role of COMTIs is to prolong the effects of LD, so they are useful as adjunctive drugs for patients who experience LD-related motor fluctuations. Besides increasing LD-related dyskinesias, COMTIs may cause nausea, postural hypotension, diarrhea, and orange discoloration of urine, but they are generally well tolerated. There is no evidence that COMTIs prevent or delay the onset of LD-related motor complications. Symptomatic pharmacological treatment should begin when the patient is noticing functional, occupational, or social disability related to PD symptoms. Prospective studies have suggested that approximately 70% of patients with PD will require symptomatic therapy within 2 years of disease onset. Less potent therapies such as selegiline, rasagiline, amantadine, and DAs may be useful for initial therapy, particularly in patients with young-onset PD, but LD should be used when more potent therapy is indicated or in patients with late-onset disease. The argument that LD might be toxic to dopaminergic neurons is based on (1) the recognition that dopamine metabolites increase oxidative stress and (2) the observation that LD is toxic to cultures of mesencephalic neurons in vivo. There is, however, no in vivo evidence from animal or human studies that LD accelerates disease progression, and it is difficult to reconcile the potential of dopamine toxicity with the obvious fact that the drug prolongs life in patients with PD. A 9-month study called the Earlier versus Later L-DOPA (ELLDOPA) trial compared different doses of LD with placebo and found no evidence of LD toxicity (Jankovic and Poewe, 2012). Nevertheless, as a result of “LD phobia,” many patients and physicians still unnecessarily delay LD therapy in patients who would clearly benefit from symptomatic relief (Espay and Jankovic, 2017). Clinical experience with LD treatment of PD indicates that there is a progressive increase in the prevalence of drug-related motor fluctuations (wearing off, dyskinesia) over time, and that about half of patients experience wearing off, and a third experience dyskinesias

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within 2 years after initiation of LD therapy. Wearing off results from loss of DA storage in the striatum as a result of loss of nigrostriatal terminals. Experiments in animal models relate the development of dyskinesia to changes in striatal glutamate receptor sensitivity consequent to pulsatile stimulation of striatal dopamine receptors. Continuous dopamine receptor stimulation with LD or with long-acting DAs prevents or reverses this phenomenon. In eliciting a description of the patient’s response to medication, it is important to understand the severity of symptoms in the morning on arising and the latency, magnitude, and duration of benefit from each dose of LD. Information about the onset of motor and nonmotor symptoms during wearing off as well as the phenomenology, timing, and distribution of dyskinesia. The usefulness of historical information may be augmented by careful patient education on symptom recognition and the development of a shared vocabulary. Completing motor diaries (Fig. 96.7) helps both the patient and the treating physician recognize patterns of motor response and adjust the medications accordingly. Wearing off is the most common type of motor fluctuation. It refers to the return of parkinsonian symptoms following the previous dose in advance of the next scheduled antiparkinsonian dose. On/off is the unpredictable reappearance of parkinsonism at a time when central levels of antiparkinsonian drugs are expected to be within the target therapeutic range. Delayed on is a prolongation of the time required for the central antiparkinsonian drug effect to appear. Dose failure is a complete failure to develop a favorable response to an incremental dopaminergic dose. This may be related to protein intake which interferes with the transport of LD across the intestinal wall as a result of competition for facilitated transport by large amounts of neutral amino acids. A variety of dyskinesias can further complicate the response to LD. Peak-dose dyskinesias are usually choreiform or stereotypical movements, such as head bobbing movement of the head or choreic movements of limbs and trunk, present at the peak of the therapeutic response. Off-period dystonia usually appears in the more severely affected foot in the morning before the first daily doses, sometimes reappearing during wearing off. Diphasic dyskinesias are usually large-amplitude dyskinetic movements of the lower body during the time of increasing and decreasing LD levels. Armed with a few basic principles and a commonsense approach, the clinician can usually smooth out fluctuations for most patients with appropriate selection of drugs and dose (Jankovic and Poewe, 2012) (Figs. 96.8 and 96.9). Delay to onset of therapeutic benefit can be hastened by taking the medication on an empty stomach (if tolerated without nausea), avoiding or reducing protein intake, or by crushing the LD tablet and mixing it with a carbonated beverage. The duration of benefit increases when the individual dose is increased or dopamine metabolism is blocked with an MAO-B or COMTIs. This, however, may increase the risk of dyskinesia and the patient may do better on smaller, more frequent LD doses. Thus fractionation of LD dose is usually the initial strategy in an attempt to smooth out fluctuations and prevent wearing off symptoms. In addition to the fluctuating response, some patients, particularly those with advanced disease, may acquire LD-resistant motor symptoms such as freezing, progressive gait dysfunction, dysarthria and dysphagia, and recurrent falling due to loss of balance and postural instability. Other features of advanced illness (cognitive impairment, autonomic dysfunction, psychiatric complications) may limit the types and dosage of tolerated medications. Freezing, sudden immobility of the feet while walking, often with falls, may be seen in either the off or the on period. Although off-period freezing may improve with optimization of medications, on-period freezing is usually resistant to pharmacological treatment. Physical therapy, including strategies that

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Time

Medication

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Asleep

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Fig. 96.7 Sample Diary in Parkinson Disease. For each hour, the patient indicates whether and which antiparkinsonian drugs he or she has taken, then places a mark to indicate motor state for most of the hour.

utilize sensory cues, such as stepping over a horizontal laser beam, may be helpful. Dysarthria and dysphagia are often treated by speech therapists, although documentation of improvement from these techniques is scant. Cognitive impairment increases mainly with the age of the patient and with disease severity. Preliminary reports suggest that cholinesterase inhibitors might be useful in PD-associated dementia, but these studies require confirmation in carefully controlled trials. Orthostatic hypotension can be managed conservatively with salt supplementation, fludrocortisone, midodrine, and droxidopa for orthostatic hypotension (Kaufmann et al., 2014). Urological medications may improve bladder dysfunction, and dietary changes along with medications such as linaclotide and lubiprostone may improve constipation. Hallucinations occur in approximately 30% of treated patients; a loss of insight that the visions are not real or the appearance of psychotic thinking signals a particularly disabling complication. Hallucinations often improve with atypical antipsychotics such as quetiapine and

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clozapine. Also, pimavanserin, a non-dopaminergic and selective serotonin inverse agonist with high affinity at the 5-HT2A receptor has been found to be effective in the treatment of psychosis and hallucinations related to dopaminergic therapy (Cummings et al., 2014). Cholinesterase inhibitors, in addition to improving cognitive function, may reduce hallucinations in some patients. Sleep disorders may respond to hypnosedatives, tricyclic antidepressants, mirtazapine, trazodone, quetiapine, or nighttime dopaminergic therapy. Excessive daytime sleepiness may respond to methylphenidate, modafinil, or armodafinil. Surgical treatment of Parkinson disease. Despite optimal medical therapy, many patients with moderate to advanced disease have a poor quality of life because of fluctuating response, troublesome dyskinesia, or LD-unresponsive symptoms. Palliative surgical approaches such as stereotactic destruction of physiologically defined overactive brain nuclei (thalamotomy, pallidotomy) have been replaced by deep brain stimulation (DBS) using implanted pulse generators. The

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Treatment of motor symptoms of Parkinson disease Diagnosis of PD Established

Uncertain

Functional impairment?

DAT or VMAT imaging

Yes Consider alternative Dx and Rx

Minimal or none

Mild sxs or young Exercise ± MAOB-I (selegiline, rasagiline)

Troublesome sxs or elderly Anticholinergics, BoNT for tremor

Disease progression Initiate DA therapy

(pramipexole, ropinirole, rotigotine)

Initiate levodopa

Disease progression Entacapone, opicapone, amantadine, safinamide, istradefylline, apomorphine, inhalable levodopa

Add or increase levodopa Experimental therapeutics Motor complications

Dose adjustments, continuous levodopa or DA delivery

DBS or FUS

Fig. 96.8 Treatment of Motor Symptoms of Parkinson Disease. Algorithm for the treatment of Parkinson disease (PD). BoNT = botulinum neurotoxin; DA, Dopamine agonist; DAT, dopamine transporter; DBS, deep brain stimulation; Dx, diagnosis; FUS, focused ultrasound; MAOB-1,monoamine oxidase inhibitor type 1; MAOI, monoamine oxidase inhibitor; Rx, treatment; VMAT2, vesicular monoamine transporter 2.

chief advantage of DBS over ablative lesioning is that the stimulation parameters can be customized to the needs of the patient to optimize the benefits. With improvements in technology the outcomes of DBS will likely continue to improve (Okun, 2019). Thalamic DBS is most frequently used to control high-amplitude tremor (either PD or ET), but STN or GPi are the most frequent targets for DBS treatment of patients with PD with disabling LD-related complications. To address the question whether optimal medical therapy or DBS provides more robust improvement, 255 patients at seven Veterans Affairs and six university hospitals were enrolled in a randomized controlled trial designed to compare the effects of DBS (STN, n = 60; or GPi, n = 61) and “best medical therapy” (n = 134) after 6 months of treatment (Weaver et al., 2009). Patients treated with DBS gained a mean of 4.6 hours/day of on time without troubling dyskinesia, compared to 0 hours/day for patients who received best medical therapy (P < .001). Furthermore, motor function improved by 5 or more points on the motor UPDRS in 71% of DBS and 32% of medical therapy patients. This was accompanied by improvements in the majority of PD-related HRQOL (health-related quality of life) measures and only minimal decrement in neurocognitive testing. The overall risk of experiencing a serious adverse event, however, was 3.8 times higher in the DBS than in the medical therapy group (40% F ECF

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vs. 11%). In a follow-up analysis of the Veterans Affairs Cooperative Studies Program outcomes, STN and GPi DBS were analyzed after 24 months in 299 patients, and there were no differences in mean changes in the motor (Part III) UPDRS between the two targets (Follett et al., 2010). Patients undergoing STN required a lower dose of DAs than those undergoing pallidal stimulation (P = .02), and visuomotor processing speed declined more after STN than after GPi stimulation (P = .03). On the other hand, there was worsening of depression after STN DBS, but mood improved after GPi DBS (P = .02). Slightly more than half of the patients experienced serious adverse events, but there was no difference in the frequency of these events between the two groups. Based on these and other studies, there is emerging evidence that GPi DBS may be particularly suitable for patients who may have troublesome dyskinesias as well as mild cognitive or behavioral impairment, whereas bilateral STN DBS may be the surgical choice for patients who are cognitively intact but in whom reduction in LD dosage is the primary goal. While DBS is a proven effective therapeutic strategy, its success depends on the appropriate selection of patients and the experience and skill of the stereotactic surgeon in order to optimize the results and minimize complications. Advances in DBS technology, such as the use of adaptive stimulation, improving connectivity, directional stimulation (Pollo et al., 2014), and searching for new targets,

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Treatment of motor complications in Parkinson disease Levodopa therapy

Dyskinesias

Fractionate levodopa or use ER formulations Add: MAOI (rasagiline, selegiline, safinamide) DA agonist (ER or transdermal formulations) A2A antagonist (istradefylline)

Motor fluctuations

Discontinue sinemet CR, MAOI, entacapone

Reduce levodopa SC or sublingual apomorphine, inhalable levodopa rescue continuous infusions: LCIG SC infusion apomorphine

Severe motor fluctuations Add amantadine or amantadine ER, LCIG

No improvement Consider: zonisamide, clozapine, quetiapine, topiramate, levetiracetam

STN or GPi DBS

Fig. 96.9 Treatment of Levodopa-Related Motor Complications in Parkinson Disease. A2A, Adenosine A2A receptor; COMTI, catechol-o-methyl-transferase inhibitor; CR, Controlled release; DA, Dopamine agonist; DBS, deep brain stimulation; ER, extended release; GPi, globus pallidus interna; LCIG, levodopa-carbidopa infusion gel; MAOI, monoamine oxidase inhibitor; SC, subcutaneous; STN, subthalamic nucleus.

will undoubtedly provide additional benefits from this procedure and reduce complications (Baizabal-Carvallo et al., 2012). It should be noted that there is a trend toward recommending DBS earlier in the course of PD (Charles et al., 2014). Unilateral focused ultrasound lesioning of the STN or thalamus (in tremor-dominant forms of PD) has been found to be beneficial in some patients, particularly if the symptoms are markedly asymmetric (Bond et al., 2017; Martínez-Fernández et al., 2018). Finally, spinal cord stimulation is increasingly being explored in patients with PD who are most troubled by their gait disorder (Samotus et al., 2018).

Multiple System Atrophy MSA is a neurodegenerative disorder manifested by dysautonomia and various combinations of parkinsonism and ataxia (Krismer and Wenning, 2017; Stamelou et al., 2013). Originally referred to as Shy-Drager syndrome, MSA is subdivided into two major categories according to the predominant clinical manifestation. Predominantly parkinsonian MSA (MSA-P) replaces the term striatonigral degeneration. Cerebellar MSA (MSA-C) replaces the now obsolete term olivopontocerebellar atrophy. MSA is considerably less common than PD, with a prevalence of 4–5 per 100,000, compared to 360 per 100,000 for PD. This sporadic neurodegenerative disorder with a mean age at onset of 54 years may be difficult to differentiate from PD, particularly in the early stages. The most common signs of dysautonomia in pathologically confirmed cases are bladder dysfunction (89%), particularly urinary incontinence (44%) and urinary retention (26%), bowel dysfunction (77%), particularly constipation (46%) and fecal incontinence (27%), orthostatic

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hypotension (75%), sexual dysfunction (64%), RBD (54%), sweating dysfunction (40%), sleep apnea (37%), and nocturnal stridor (30%) (Iodice et al., 2012). In contrast to PD, MSA-P usually presents with symmetrical parkinsonism, often without tremor, with early instability and falls. Most patients become wheelchair bound within 5 years after onset (see Video 96.12). Several clinical studies have addressed differentiating between MSA-P and parkinsonism, and a collection of “red flags” has been generated and recently validated as having high diagnostic specificity (Stefanova et al., 2009). The red flags were grouped into six categories: (1) early instability, (2) rapid progression, (3) abnormal postures (includes Pisa syndrome, disproportionate anterocollis, and/or contractures of hands or feet) (Fig. 96.10), (4) bulbar dysfunction (includes severe dysphonia, dysarthria, and/or dysphagia), (5) respiratory dysfunction (includes diurnal or nocturnal inspiratory stridor and/or inspiratory sighs) (Mehanna and Jankovic, 2010), and (6) emotional incontinence (includes inappropriate crying and/or laughing). They proposed that a combination of two out of these six red-flag categories be used as additional criteria for the diagnosis of probable MSA-P. Other characteristic features of MSA include early hypokinetic dysarthria, distal myoclonus, and cold hands and feet with bluish discoloration of the distal extremities. MSA patients also have more autonomic symptoms at baseline and more progression to global anhidrosis than patients with PD (Iodice et al., 2012). The autonomic symptoms (particularly sexual dysfunction) and RBD may precede the onset of motor symptoms by years or even decades. About 10% of patients originally diagnosed with pure autonomic failure eventually transition to MSA (Singer et al., 2017). Patients with MSA-C have parkinsonism with

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Fig. 96.11 Glial cytoplasmic inclusions in basal ganglia, immunostained with α-synuclein—typical of multiple system atrophy. (Courtesy Elizabeth Cochran, MD.)

Fig. 96.10 Patient with multiple system atrophy showing anterocollis and Pisa sign.

prominent cerebellar signs, especially wide-based ataxic gait. Although there may be a positive response to LD, this is generally relatively short lived and often associated with facial and oromandibular dyskinesia. In a prospective study of 141 patients with moderately severe MSA (mean age at symptom onset 56.2± 8.4 years) who had a median survival of 9.8 years (95% CI 8.1–11.4), shorter survival was suggested by the parkinsonian variant of MSA and incomplete bladder emptying, and shorter symptom duration at baseline and absent LD response predicted rapid progression (Wenning et al., 2013). Clinical tests of autonomic dysfunction may be helpful in diagnosis or treatment (Mostile and Jankovic, 2010). Testing of cardiovascular reflexes such as heart rate variability at rest and during forced respiration, as well as blood pressure changes during head-up tilt, may help establish a clinical diagnosis of MSA. A lack of responsiveness of growth hormone to clonidine challenges and denervation on rectal sphincter electromyography (EMG) are also characteristic findings. T2-weighted MRI brain scans may show a hyperintense rim at the lateral edge of the dorsolateral putamen, with decreased signal within the putamen. Cruciform hyperintensity within the pons, the so-called hot-crossbun sign, may also be a helpful marker (Brooks et al., 2009). PET scan with [11C]PMP that images subcortical acetyl cholinesterase (AChE) activity was significantly more decreased in MSA-P and PSP than in PD, possibly reflecting greater impairment in the pontine cholinergic group (PPN); this may account for the greater gait disturbances in the early stages of these two disorders compared to PD (Gilman et al., 2010). There is a need for development of highly specific and sensitive biomarkers that support the diagnosis and track the progression of the disease. In this regard, NFL protein levels have been found elevated in the serum and CSF of patients with MSA but not in PD but this does not differentiate between MSA and other forms of atypical parkinsonism (Marques et al., 2019). At autopsy, MSA brains show neuronal loss and gliosis in the striatum, SN, locus coeruleus, inferior olive, pontine nuclei, Purkinje cells, intermediolateral cell column, and the Onuf nucleus in the sacral spinal

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cord. Glial cytoplasmic inclusions containing α-synuclein (Fig. 96.11) are the most characteristic histological features linking the different types of MSA. Neuron-to-oligodendrocyte transfer of α-synuclein by prion-like spread, leading to oligodendroglial and myelin dysfunction associated with chronic neuroinflammation, has been suggested to lead to the MSA pattern of neurodegeneration (Jellinger, 2014). There is a severe depletion of cholinergic neurons in the PPN and laterodorsal tegmental nucleus. The etiology of MSA remains unknown, but genetic factors do not seem to play an important role. Treatment of MSA is difficult (Castro et al., 2017; Stamelou et al., 2013). There are no specific interventions, and symptomatic therapies provide only partial relief of disability. Parkinsonism may respond to LD, particularly early in the disease course, but the results are not dramatic or sustained. DAs are not helpful and may be poorly tolerated because of orthostatic hypotension. There is no effective treatment for the cerebellar signs. Orthostatic hypotension may improve with nonpharmacological measures such as liberal salt and water intake, compression stockings, and sleeping with the head up, but most patients require pharmacotherapy with fludrocortisone, midodrine, droxidopa, or other agents (Kaufmann et al., 2014). Treatment of orthostatic hypotension often worsens supine hypertension. Even in the best hands, MSA has a poor prognosis, with a mean survival of 7–9 years.

Progressive Supranuclear Palsy First described in 1964 by Steele, Richardson, and Olszewski as a progressive illness characterized by vertical supranuclear ophthalmoplegia, axial rigidity, pseudobulbar palsy, and mild dementia, PSP has evolved into a broad spectrum of syndromes with different pathological substrates (Boxer et al., 2017; Höglinger et al., 2017; Stamelou et al., 2013). In addition to the classic Richardson syndrome, other subtypes include PSP-parkinsonism (with features suggestive of PD), pure akinesia with gait freezing, CBS, non-fluent variant primary progressive aphasia, behavioral variant FTD, and PSP presenting with cerebellar ataxia (Boxer et al., 2017). In addition, based on four core clinical features of PSP (oculomotor dysfunction, postural instability, akinesia, and cognitive dysfunction) other variants of PSP have been described. These include PSP with predominant ocular motor dysfunction (PSP-OM), with predominant postural instability (PSP-PI), with predominant parkinsonism (PSP-P), with predominant frontal presentation (PSP-F), with progressive gait freezing (PSP-PGF), with predominant corticobasal syndrome (PSP-CBS), with predominant speech and language disorder (PSP-SL), with predominant ataxia (PSP-C), and with predominant primary lateral sclerosis (PSP-PLS) (Boxer et al., 2017; Höglinger et al., 2017).

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Fig. 96.12 Typical facial expression of a patient with progressive supranuclear palsy, illustrating worried or surprised appearance, with furrowed brow and fixed expression of lower face.

After vascular parkinsonism (Mehanna and Jankovic, 2013), which can also have PSP-like features, PSP represents the third most common cause of parkinsonism, but it is still a relatively rare disease, with prevalence estimates ranging from 1.39 to 6.4 per 100,000. Men are affected more often than women. The diagnosis of PSP is made based on clinical criteria (Höglinger et al., 2017; Stamelou et al., 2013). PSP typically begins with a gait disorder and falling in the sixth to seventh decades of life. Patients develop an akinetic rigid state with symmetrical signs and prominent axial rigidity. In contrast to the flexed posture of patients with PD, those with PSP may have an extended trunk or retrocolic neck posture. A characteristic facial appearance features a wide-eyed stare, furrowing of the forehead with frowning expression (“procerus sign”), and deepening of other facial creases, allowing experienced clinicians to make an instant diagnosis (Fig. 96.12; see also Videos 96.7–96.11). Pseudobulbar palsy with dysarthria and dysphagia lend the patient a characteristic dysarthria with spasticity, hypokinesia, and ataxia and often “silent” aspiration. Frontal lobe features are common. There is striking executive dysfunction early in the disease course; concrete thought, difficulty shifting set, decreased verbal fluency, and personality changes such as impulsivity and poor judgment are nearly universal. One of the characteristic, although not specific signs of PSP is the applause sign, which is manifested by persistence of applauding by the patient beyond the number of claps performed by the examiner. This is highly correlated with impairments in executive, visuospatial, and language function as well as measures of disease severity (Schönecker et al., 2019). A progressive apathetic state ensues, but true dementia may not be prominent until the advanced stages of the disease. The presence of square wave jerks should suggest the diagnosis of PSP, although this neuro-ophthalmological sign may also be observed, but much less frequently, in other parkinsonian disorders (Waln and Jankovic, 2018). Abnormal vertical saccades, best demonstrated by examination for opticokinetic nystagmus, compared to horizontal saccades, is one of the earliest ophthalmological signs of PSP. Typically, the vertical saccades are more impaired when the opticokinetic tape moves in an upward rather than downward direction. Electro-oculographic recordings in PSP show decreased amplitude and normal latency of horizontal saccadic eye movements. Although considered a clinical hallmark of PSP, supranuclear vertical gaze palsy may not appear until later in the disease course, and some patients may never develop gaze palsy. Another neuro-ophthalmological sign in PSP is blepharospasm with or without apraxia of eyelid opening (Waln and Jankovic, 2018).

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B Fig. 96.13 Globose neurofibrillary tangle and tufted astrocytes in progressive supranuclear palsy (PSP). A, Tau-immunostained globose neurofibrillary tangles in neurons of globus pallidus. B, Gallyas silver-stained tufted astrocytes in globus pallidus of patient with PSP.

In contrast to PD, patients with PSP tend to have a more broad-based gait with knee extension, and instead of turning en bloc they tend to pivot on their toes and sometimes even cross their legs, which contributes to frequent falls (Jankovic, 2015a). Atypical presentations are often seen, especially pure akinesia manifested by severe motor blocks while walking (freezing). PSP is rapidly progressive; by the fourth year of illness, half of patients need assistance for walking and have troublesome dysarthria and visual symptoms. Dysphagia becomes prominent shortly thereafter. There are no diagnostic tests for PSP, but elevated serum and CSF levels of NFL have been found in patients with PSP compared to those with PD (Marques et al., 2019). Although not diagnostic, NFL can serve as a possible biomarker. Typical MRI signs of PSP include midbrain atrophy, increased signal in the midbrain and GP, atrophy or increased signal in the red nucleus, third ventricle dilation, and atrophy of the frontal or temporal lobes. On the midsagittal view of the MRI, as a result of atrophy of the rostral midbrain tegmentum, the most rostral midbrain, the midbrain tegmentum, the pontine base, and the cerebellum appear to correspond to the bill, head, body, and wing, respectively, of a hummingbird or a penguin. At autopsy, the midbrain in PSP is atrophied, and the sylvian aqueduct is dilated. The SN is depigmented and appears orange and shrunken. The locus coeruleus may also show some depigmentation, but this is less prominent than in idiopathic PD. Other structures may also show atrophy, most notably the frontal lobe, STN, and superior cerebellar peduncle. Histopathologically, the degenerative process involves mainly the basal ganglia, diencephalons, and brainstem. Pathological findings include neuronal loss, gliosis, neurofibrillary tangles, and granulovacuolar degeneration in neurons of the brainstem. There are tufted astrocytes in the motor cortex and the striatum, and the typical neuronal lesion is the globose neurofibrillary tangle, made up of hyperphosphorylated four-repeat tau protein filaments (Fig. 96.13).

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CHAPTER 96 Parkinson Disease and Other Movement Disorders On the basis of an analysis of 103 pathologically confirmed consecutive cases of PSP, PSP was divided into two categories: Richardson syndrome, characterized by the typical features described in the original report, and PSP-P, in which the clinical features overlap with PD and the course is more benign (Williams and Lees, 2009). The latter group, representing about a quarter of all patients with PSP, has less tau pathology than the classic Richardson syndrome. The mean 4R-tau/3R-tau ratio of the isoform composition of insoluble tangle-tau isolated from the pons was significantly higher in Richardson syndrome (2.84) than in PSP-P syndrome (1.63). PSP almost always occurs sporadically, yet an increasing number of familial cases suggests a genetic etiology in some cases. Pedigrees with apparent dominant and recessive inheritance have been described. Affected families may show phenotypical heterogeneity, with some affected persons showing dementia, dystonia, gait disorder, or tics. Mutations in the tau gene have been reported in patients with a familial PSP-like illness, but these have been quite rare, and mutations are not believed responsible for most PSP cases. However, patients with PSP are homozygous for a common haplotype that contains a normally occurring polymorphism in the tau intron immediately preceding exon 10. There is growing support for the notion of altered regulation of tau gene expression in PSP. Genetic polymorphisms are increasingly being identified, some of which might increase risk for PSP via effects on tau. No toxic, viral, or other environmental risk factors have been described. Dopaminergic agents, particularly LD, may provide temporary improvement in bradykinesia in approximately 40% of patients, but LD usually does not improve dysarthria, gait, or balance problems. No other drug has been shown to provide any meaningful improvement in symptoms of PSP. A randomized placebo-controlled trial of donepezil showed modest cognitive improvements but poor tolerability. Amitriptyline may be helpful in improving pseudobulbar affect and emotional incontinence. Botulinum toxin injections may be useful to treat blepharospasm or retrocolic neck posture in PSP. The prognosis of PSP is poor, with serious impact on quality of life and a median duration of survival of approximately 8 years. It is possible that future strategies targeting toxic tau, currently investigated in other tauopathies, may also exert disease-modifying effects in PSP.

Corticobasal Degeneration In 1967, Rebeiz and colleagues described three patients with akinetic rigidity, apraxia, dystonia, tremor, and aphasia, who at autopsy had pale achromatic ballooned neurons similar to those seen in Pick disease. The condition was named corticodentatonigral degeneration with neuronal achromasia in 1989 but has since become known simply as corticobasal degeneration. Although CBD generally brings to mind a particular motor syndrome of asymmetrical rigidity, apraxia, and cortical sensory dysfunction, its underlying pathological features may be seen in other clinical syndromes including PSP, progressive aphasia, and FTDP. One study based on 35 cases from the Queen Square Brain Bank, in which there were 21 clinically diagnosed cases of CBS and 19 pathologically diagnosed with CBD, was designed to address the clinical and pathological overlap between CBD and PSP (Ling et al., 2010). Of 19 pathologically confirmed CBD cases, only five had been diagnosed correctly in life (sensitivity =26.3%). All had a unilateral presentation, a clumsy useless limb, limb apraxia, and myoclonus; four had cortical sensory impairment and focal limb dystonia, and three had an alien limb. Eight cases of CBD had been clinically diagnosed as PSP, all of whom had vertical supranuclear palsy, and seven had falls within the first 2 years. Of 21 cases with CBS, only five had CBD (positive predictive value = 23.8%); six others had PSP pathology, five

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had AD, and the remaining five had other non-tau pathologies. Fortytwo percent of CBD cases presented clinically with a PSP phenotype, and 29% of CBS cases had underlying PSP pathology. The authors suggested the CBD-Richardson syndrome for the overlap cases and concluded that CBD “is a discrete clinico-pathological entity but with a broader clinical spectrum than was originally proposed” (Ling et al., 2010). CBD is one of the least common and most asymmetrical forms of atypical parkinsonism (Stamelou et al., 2013). The mean age at onset is 60–64 years. In its most recognizable form, it is predominantly a motor disease, but its presentation is clinically heterogeneous. In addition to parkinsonism with strikingly asymmetrical rigidity, CBD patients often exhibit asymmetrical dystonia, myoclonus, apraxia, alien limb, and cortical sensory loss. They may also present with primary progressive aphasia and may evolve into global dementia (see Videos 96.13– 96.16) (Lee et al., 2011). Patients with CBS have asymmetrical and often focal cortical atrophy on MRI, with widening of the sylvian and interhemispheric fissures and dilation of frontal, parietal, and temporal sulci (Josephs, 2017). Fluorodeoxyglucose PET scans show asymmetrical hypometabolism in the thalamus and motor cortex. SPECT scans show marked asymmetry of cortical blood flow. At autopsy, patients with a clinical syndrome consistent with CBD have gross brain atrophy. Typical microscopic changes are tau-positive neuronal and glial lesions, especially gray and white matter astrocytic plaques and threadlike lesions, and neuronal loss in the cortex and SN. The inclusions are formed of hyperphosphorylated four-repeat tau. Overlap with other conditions including AD, PSP, PD, FTDP, and hippocampal sclerosis is common (Ling et al., 2010). As with other tauopathies, the etiology of CBD is unknown. There are no familial forms of the illness, and no mutations in the tau gene have been identified. There is clinical and pathological overlap with other tauopathies, and patients with CBD share a similar tau haplotype with patients with PSP. There is no treatment for the degenerative process. Parkinsonian features do not seem to respond to LD or other dopaminergic drugs. Benzodiazepines, particularly clonazepam, may help myoclonus. Botulinum toxin injections may improve focal dystonia early in the disease and help relieve pain and facilitate care in advanced disease. The prognosis is poor, with a reported median survival after onset of about 7 years.

Dementia with Lewy Bodies DLB is the second most prevalent degenerative dementia after AD. In one study, among 542 incident cases of parkinsonism, 64 had DLB and 46 had PD dementia (PDD); the pathology was consistent with the clinical diagnosis in 24 of 31 patients (77.4%) who underwent autopsy (Savica et al., 2013). DLB is a progressive dementia characterized especially by fluctuating cognitive impairment, prominent disruption of attention and visuospatial abilities, visual hallucinations, and parkinsonism (see Video 96.5). RBD and depression are also very common. These behavioral symptoms are typically present at least 1 year prior to the onset of motor (parkinsonian) features (McKeith et al., 2017). Patients with DLB are extremely sensitive to dopamine receptor antagonists and experience severe parkinsonism when treated with neuroleptics. Characteristic pathological changes include cortical and brainstem (SN) Lewy bodies. Spongiform changes, neurofibrillary tangles, and dystrophic Lewy neuritis may also be seen, and overlap with AD is considerable. Treatment of DLB is difficult but medications used in the treatment of both PD and dementia are often employed here. Although antiparkinsonian agents are used to treat parkinsonian

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signs, the degree of sensitivity of parkinsonian signs to dopaminergic therapy has not been well defined. Psychiatric and behavioral symptoms may improve with atypical antipsychotics, and cholinesterase inhibitors such as rivastigmine may improve delusions and hallucinations. PD dementia is defined as cognitive impairment that includes cognitive and motor slowing, executive dysfunction, and impaired memory retrieval. The relationship of PDD to AD and other dementing disorders such as DLB has not yet been well defined. Although some investigators suggest that clear clinicopathological separation is possible between the three disorders, the differences in neuropathological and neurochemical characteristics suggest that there is a continuum.

Frontotemporal Degeneration with Parkinsonism Frontotemporal degeneration is a group of disorders characterized by behavioral changes and neuropsychological evidence of frontal lobe dysfunction. They include PSP, CBD, Pick disease, pallidopontonigral degeneration, disinhibition-dementia-parkinsonism-amyotrophy, familial multiple system tauopathy with presenile dementia, familial subcortical gliosis, FTD, FTD with ALS, FTD with inclusion body myopathy, and FTDP-17. In up to 60% of patients with FTD, there is a positive family history. Genetic loci on chromosomes 17 (FTDP-17), 9 (FTD with ALS; FTD with inclusion body myositis), and 3 (FTD) have been described. The prototype of FTDP is an inherited parkinsonism-dementia disorder, initially described as Wilhelmsen-Lynch disease (disinhibition-dementia-parkinsonism-amyotrophy complex) and subsequently found to be due to mutations in the tau gene on chromosome 17q21. Although tau mutations account for many of these diseases, similar phenotypes have been attributed to mutations in other genes such as p97 (also known as valosin-containing protein) on chromosome 9p21-p12, CHMP2B (charged multivesicular body protein 2B) on the pericentromeric region of chromosome 3, and progranulin (PGRN) on chromosome 17q21 (1.5 Mb centromeric of tau). Plasma and CSF levels of progranulin have been found to be reduced nearly fourfold in affected and unaffected subjects with PGRN mutations, and low (75% reduction) plasma progranulin levels may be used as a screening tool for PGRN mutations. There is considerable phenotypical, genotypical, and pathological heterogeneity in FTDP (Spillantini and Goedert, 2013). The disorder most often begins in the 50s or 60s with personality and behavioral changes that include disinhibition and aggressiveness as well as frontal executive dysfunction. Other common signs include social misconduct, stereotyped verbalizations, impaired recent memory, and parkinsonism. Some families present with early parkinsonism. Many mutations have been reported in the tau gene. They comprise mainly three groups: mutations in the coding region for a microtubule-binding domain, resulting in a dysfunctional protein; mutations outside the microtubule-binding domains; and mutations that alter the ratio of three- to four-repeat tau isoforms. Pathological findings include tau-positive neuronal and glial inclusions distributed variably throughout the brain. In patients with prominent parkinsonism, there is severe neuronal loss in the SN. The response of parkinsonism to symptomatic treatment is not known. The prognosis is poor, with death occurring within 10 years.

Parkinsonism-Dementia Complex of Guam A high incidence of an ALS-like illness among the Chamorros, indigenous people of Guam, was noticed more than 50 years ago. In the same population, a smaller number of people had a syndrome of parkinsonism with dementia, the parkinsonism-dementia complex

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(PDC). Some had both motor neuron disease and PDC. Early in its course, PDC appears variably like PD, atypical parkinsonism, or PSP; however, in the end stages, it most resembles PSP. Familial aggregation of cases has been noted, but prior attempts to elucidate a hereditary basis to the illness proved fruitless. A similar constellation of ALS and PDC has been reported on the Kii peninsula of Japan. Pathologically, the disorder is characterized by neuronal degeneration and abundant neurofibrillary tangles in the brain and spinal cord. A recent reanalysis of a patient registry suggests that both the spouses and the offspring of persons with PDC have a significantly higher risk of themselves developing ALS-PDC, suggesting both environmental and genetic risk factors. The critical age for exposure to the environmental factor was adolescence or early adulthood. Despite extensive analysis of the diet and other environmental factors, the etiology of PDC of Guam remains unknown, although neurotoxic damage from the cycad nut has been implicated.

Guadeloupean Parkinsonism A form of atypical parkinsonism has been described in the French West Indies. The so-called Guadeloupean parkinsonism shows clinical features of LD-unresponsive parkinsonism, postural instability with early falls, and pseudobulbar palsy. More than 25% of these patients have a phenotype like that of PSP. The etiology of this form of parkinsonism is unknown, but exposure to dietary or other environmental toxins is suspected. The disease may be associated with the use of indigenous plants (Annona muricata [synonyms: soursop, corossol, guanabana, graviola, and sweetsop]) that contain the mitochondrial complex I and dopaminergic neuronal toxins, reticuline and coreximine.

Vascular Parkinsonism After PD, vascular parkinsonism is the second most common form of parkinsonism encountered in movement disorders clinics, accounting for 8% of all parkinsonian patients (Mehanna and Jankovic, 2013). Vascular changes on imaging studies are common, but the cause and effect are not always clearly established. Among stroke patients, parkinsonism is more common in patients with lacunar stroke. Adultonset diabetes, chronic hypertension, and hyperlipidemia seem to be the most common risk factors associated with vascular parkinsonism (De Pablo-Fernandez et al., 2018). Vascular parkinsonism usually presents as “lower body parkinsonism” with a broad-based shuffling gait and prominent start and terminal hesitation, as well as freezing (see Videos 96.17 and 96.18). Postural instability and a history of falls are common. Many patients have dementia and corticospinal findings of incontinence. In a systematic review of 25 articles, patients with vascular parkinsonism were older, had a shorter duration of illness, presented with symmetrical gait difficulties, were less responsive to LD, and were more prone to postural instability, falls, and dementia (Kalra et al., 2010). Pyramidal signs, pseudobulbar palsy, and incontinence were more common in vascular parkinsonism, but tremor was not a main feature. Structural neuroimaging was abnormal in 90%–100% of vascular cases, compared to 12%–43% of PD cases. In contrast to PD, there is usually no abnormality in presynaptic striatal dopamine transporters as measured by SPECT in vascular parkinsonism. The pathology includes subcortical vascular disease with preservation of dopaminergic cells in the SN. There is a growing body of evidence that microstructural changes of normal-appearing white matter are common in the brains of patients with vascular parkinsonism (Salsone et al., 2019; van Veluw et al., 2017).

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CHAPTER 96 Parkinson Disease and Other Movement Disorders The symptoms of vascular parkinsonism are unlikely to show a significant response to LD, but a therapeutic trial is worth pursuing because as many as half of patients improve. Physical therapy may also be useful.

Bilateral Striatopallidodentate Calcification (Fahr Disease) Calcification of the basal ganglia has many causes. It is an incidental finding in up to 1% of all CT brain scans. Basal ganglia calcifications can also be seen in infectious, metabolic, and genetic disorders affecting this brain region. There are familial and sporadic forms. When symptoms occur, they usually begin in adulthood between age 30 and 60 years. Cognitive dysfunction, seizures, cerebellar signs, dysarthria, pyramidal signs, psychiatric illness, gait disorder, and sensory impairment are common. About half of symptomatic patients have movement disorders. Among these, parkinsonism and chorea are most common. Fewer than 10% of patients have tremor, dystonia, athetosis, or orofacial dyskinesia. The presence of symptoms correlates with the amount of calcification. Calcification is most often seen in the GP but may also occur in the caudate, putamen, dentate, thalamus, and cerebral white matter, as well as internal capsules. Calcium is deposited in the perivascular extracellular space. Dominant and recessive inheritance patterns with many different gene mutations have been described (Deng et al., 2015). There is no specific treatment other than symptomatic management.

Postencephalitic Parkinsonism Between 1916 and 1927, a worldwide epidemic of encephalitis lethargica killed approximately 250,000 persons and left an additional 250,000 with chronic disability. These survivors of the acute illness developed parkinsonism, usually within 10 years of the infection. PEP resembles PD, although more prominent behavioral and sleep abnormalities occur early in the disease course, extraocular movements are often abnormal, and oculogyric crises are common. Other common movement disorders include chorea, dystonia, tics, and myoclonus. Pyramidal tract signs are common. The pathological appearance of PEP includes degeneration of SN neurons, with neurofibrillary tangles in surviving neurons. Although the etiology is presumed to be a virus, none has ever been identified. There have been no subsequent epidemics of encephalitis lethargica, although sporadic cases of PEP are occasionally reported. The symptoms of PEP tend to be responsive to LD, but behavioral complications such as hallucinations and delusions are common, limiting therapy.

Drug-Induced Parkinsonism Dopamine receptor-blocking drugs reproduce the major clinical features of PD, although signs are usually symmetrical, and the tremor is more often present during posture holding than at rest (Savitt and Jankovic, 2018; Ward and Citrome, 2018). The most common causes of DIP are the typical neuroleptic antipsychotic drugs, antidopaminergic antiemetics, and drugs that deplete presynaptic nerve terminals of dopamine, such as reserpine, tetrabenazine, deutetrabenazine, and valbenazine. Despite the marketing efforts by the drug manufacturers to minimize the risk of tardive dyskinesia (TD) with the atypical (third-generation) neuroleptics, all these drugs have been reported to cause TD. Among the newer, or atypical, antipsychotics, the relative propensity to cause DIP is as follows: risperidone = ziprasidone > olanzapine > quetiapine > clozapine. This ranking reflects their respective affinity for the D2 receptor. A number of other drugs have been associated with DIP: aripiprazole and other new atypical neuroleptics (Peña et al., 2011), selective serotonin reuptake inhibitors, lithium, phenytoin, methyldopa, valproic acid, and the calcium channel

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antagonists flunarizine and cinnarizine, which are not marketed in the United States. DIP generally appears subacutely after weeks to months of therapy. Although it is reversible, DIP may resolve very slowly over a period of up to 6 months, and symptomatic treatment with anticholinergics, amantadine, or LD may be required. Occasionally, parkinsonism does not resolve, suggesting that the offending drug likely has unmasked an underlying parkinsonism. The use of antipsychotic medications is a strong predictor of subsequent PD and patients taking neuroleptics may be five times more likely to begin antiparkinsonian medications than nonusers. In some cases of DIP when the offending dopamine receptor blocking drug is discontinued TD may emerge (Savitt and Jankovic, 2018).

Toxin-Induced Parkinsonism In 1982, a number of young California drug addicts developed acute and severe parkinsonism after intravenous injection of a synthetic heroin contaminated by MPTP. Subsequent study showed that the offending toxin was the metabolic product of MPTP produced by monoamine oxidase, 1-methyl-4-phenyl-propionoxypiperidine (MPP+). Postmortem examination in patients 10 years after the original exposure showed severe loss of SN neurons without Lewy body formation. Interestingly, despite the 10-year interval between exposure to the toxin and death, there was evidence of an active neurodegenerative process that included extracellular melanin and active neuronophagia. This suggests that intracellular mechanisms may promote neurodegeneration after a distant environmental insult. MPTP-induced parkinsonism is responsive to LD, but the response is complicated by early development of motor fluctuations and dyskinesias, which may become severe, and psychiatric complications such as hallucinations. Cognitive function usually remains intact. Acute carbon monoxide poisoning is associated with parkinsonism. MRI scans show high-intensity white-matter lesions and necrosis of the GP bilaterally. Cognitive signs including decreased short-term memory, attention, and concentration are common. Patients with neurological sequelae of carbon monoxide intoxication may experience gradual clinical and radiological improvement over months to years. Manganese toxicity is associated with LD-unresponsive symmetrical parkinsonism with dystonic features such as oculogyric crisis. The disorder may progress for years after cessation of exposure (Jankovic, 2005). Striatal MRI T2-weighted hyperintensity may be present during the acute phase of poisoning. F-dopa PET scans in subjects with manganism show normal presynaptic dopamine function, suggesting postsynaptic pathology. The fungicide maneb (manganese ethylene-bis-dithiocarbamate) has also been shown to induce a toxic parkinsonism.

TREMOR Physiological Tremor A fine tremor of the outstretched limbs is a universal finding. Physiological tremor appears to originate in the heartbeat, mechanical properties of the limbs, firing of motoneurons, and synchronization of spindle feedback. Its frequency ranges from 7 to 12 Hz. It is usually not noticeable except with electrophysiological recording, but its amplitude is accentuated by fatigue, anxiety, fear, excitement, stimulant use, and medical conditions such as hyperthyroidism (Box 96.3).

Essential Tremor

Epidemiology and Clinical Features ET is one of the most common movement disorders. In population-based studies, the prevalence increases steadily with age,

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BOX 96.3

Tremor

Neurological Diseases and Their Treatment

Physiological Classification of

Mechanical Oscillations Physiological tremor Oscillations Based on Reflexes Neuropathic tremor Oscillations Due to Central Neuronal Pacemakers Palatal tremor Essential tremor Orthostatic tremor Parkinsonian rest tremor Holmes tremor Oscillations Due Feedback Loops Cerebellar tremor Holmes tremor

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Fig. 96.14 Writing sample from a man with asymmetrical postural and action tremor of essential tremor.

Feed-Forward/

occurring in up to 10% of patients older than 60 years of age. Metaanalysis of epidemiological studies has found the prevalence of ET to range between 0.01% and 20.5%, but the pooled prevalence is 0.9% (Louis and Ferreira, 2010). In its purest form, ET is a monosymptomatic illness characterized by gradually increasing-amplitude postural and kinetic tremor of the forearms and hands (with or without involvement of other body parts) in the absence of endogenous or exogenous triggers or other neurological signs. In clinic-based series, as many as 50% of patients exhibiting ET do not conform to this clinical picture, suggesting substantial heterogeneity and an overlap in some cases with dystonia and parkinsonism (Fekete and Jankovic, 2011). The clinical definition of ET is problematic because there are no pathological, biochemical, genetic, or other established and validated diagnostic criteria. The Movement Disorders Society issued a “consensus statement” on classification of tremors (Bhatia et al., 2018). It defined ET as isolated tremor syndrome of bilateral upper limb action tremor at least 3 years’ duration with or without tremor in other locations (e.g., head, voice, or lower limbs), absence of other neurological signs, such as dystonia, ataxia, or parkinsonism. They acknowledged that patients frequently have a family history, of tremors and small doses of alcohol may improve the tremor, but they felt that these clinical features are not consistent enough to be included in the definition of ET. They also introduced the term “ET-Plus,” a new tentatively and uncertainly defined entity characterized by the presence of additional neurological signs other than action tremor. This has engendered much controversy, and many believe that ET-Plus is more common than ET. There seems to be a bimodal distribution for age at onset, peaking in the 2nd and 6th decade of life. The typical patient becomes aware of a barely perceptible postural or action tremor, usually in the distal arms and hands. The head and lower limbs are less commonly affected. Head tremor (titubation) is milder than limb tremor and is predominantly of a side-to-side, “no-no” type. Head tremor is often associated with cervical dystonia and some patients with head tremor merely have dystonic tremor as a manifestation of their cervical dystonia without associated ET (Merola et al., 2019). Tremor of the face, trunk, and voice may also be present in patients with ET. The kinetic tremor is typically higher in amplitude than the postural tremor (Fig. 96.14). In contrast to PD where the handwriting is small, the handwriting in patients with ET is tremulous.

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A striking improvement after ingestion of a small amount of ethanol is seen in 50% of patients and may be helpful in diagnosis (Mostile and Jankovic, 2010). Over time, the tremor worsens, causing increasing functional disability. Only a fraction of affected persons seek medical attention, and there is often a long latency from onset to presentation for care. At the time of diagnosis, nearly all patients with ET have significant social, functional, or occupational disability, and as many as 25% must make occupational adjustments as a result of tremor-related disability. ET is thought to be a monosymptomatic illness without changes in cognition, strength, coordination, or muscle tone, and the results of the neurological examination are usually normal. However, detailed studies of patients with ET have demonstrated frontostriatal cognitive deficits, changes in tandem gait, and other (albeit subtle) evidence of cerebellar dysfunction. The worsening of ET over time likely relates to two phenomena. First, the frequency of tremor in ET decreases over time, and its amplitude increases. This results from decreased attenuation of lower-frequency tremor secondary to age-related changes in the mechanical properties of limbs and muscle. A second possible contributor is true progression of the underlying disorder. According to recent studies, the severity of ET relates to disease duration independent of aging and age-related changes in mechanical properties of the muscles and limbs. The diagnosis of ET is made by history and physical examination. A tremor rating scale known as The Essential Tremor Rating Assessment Scale (TETRAS) has been developed by the Tremor Research Group to assess ET and has been found to correlate well with quantitative assessments using the kinesia system (Mostile et al., 2010).

Etiology As many as two-thirds of patients give a positive family history of tremor, and first-degree relatives of patients with ET are 5–10 times more likely to have ET than first-degree relatives of control subjects. Direct questioning or examination of first-degree relatives increases the yield of family history to as high as 96%. In some families, pedigree analysis suggests ET is an autosomal dominant trait, with virtually complete penetrance by age 50 years. Twin studies suggest both hereditary and environmental factors are important in disease expression. Hereditary ET is genetically heterogeneous, with several described loci including ETM1 (FET1) on chromosome 3, ETM2 on chromosome 2, a D3 receptor gene (DRD3) localized on 3q13.3, and a locus on chromosome 6p23 (Kuhlenbäumer et al., 2014). One study involving a North American population demonstrated a significant association between a LINGO1 variant and ET, but further studies are needed before this association can be confirmed (Deng et al., 2019).

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CHAPTER 96 Parkinson Disease and Other Movement Disorders The mechanism of disease production in these genetic disorders remains unknown, and no consistent pathological structural changes have been found in postmortem brain or nervous tissue, although cerebellar degeneration and Lewy bodies have been found in a few autopsied brains (Fekete and Jankovic, 2011; Louis et al., 2013). A number of lines of evidence point to cerebellar dysfunction in ET; abnormal tandem gait is one example. The tremor may resolve following ipsilateral cerebellar lesions. Motor control studies show evidence of abnormal production of ballistic movements in a pattern that suggests abnormalities in cerebellar timing. PET scans have shown evidence of bilaterally increased cerebellar activity at rest and during tremor. The demonstration of reduced N-acetyl-l-aspartate (NAA) relative to total creatine in the cerebellar cortex by magnetic resonance spectroscopy (MRS) suggests that the cerebellar disorder may be degenerative.

Treatment Patients with mild ET whose main source of disability is tremor during meals and whose tremors respond to ethanol often benefit from a cocktail before meals. The two most commonly used pharmacological treatments are β-adrenergic blockers and primidone. Placebo-controlled studies have shown that β-adrenergic blockers (e.g., 120–320 mg of propranolol per day) reduce tremor amplitude in 40%–50% of patients. Common side effects of these beta-blocker drugs include bradycardia, fatigue, nausea, diarrhea, rash, impotence, and depression. Beta-blockers are contraindicated in patients with congestive heart failure, asthma, third-degree atrioventricular block, and diabetes. Primidone improves ET about 50% in short-term controlled trials and has been suggested to be more effective for head tremor than other agents. Because of the risk of acute side effects such as vertigo, nausea, and unsteadiness, primidone is usually started at a dose of 25 mg at bedtime and then titrated as tolerated to its effective dose range of 50–350 mg daily. It can be given as a single nighttime dose or in divided-dose increments. Long-term primidone therapy is usually well tolerated. Propranolol and primidone combination therapy may be more effective than either agent alone. A double-blind placebo-controlled study of topiramate found that this antiepileptic drug may reduce ET. Other drugs such as alprazolam, gabapentin, pregabalin, clonazepam, acetazolamide, and nimodipine may also provide benefit in some patients with ET. Botulinum toxin injection in the wrist flexors in patients with prominent hand tremor and into cervical muscles in patients with head tremor provided a meaningful reduction in the amplitude of the tremor for about 3–4 months after each injection (Mittal et al., 2019a; Niemann and Jankovic, 2018). The pipeline of experimental therapeutics is beginning to expand and includes various tremor suppression devices, peripheral nerve stimulation and drugs that modulate GABA type A receptors and calcium-activated potassium channels, and Cav3 T-type calcium channel blockers. Thalamic DBS has been reported to suppress contralateral tremor as much as 75% in up to 90% of cases, and bilateral stimulation can be performed safely with long-lasting benefits, although dysarthria and gait and balance problems may occur, particularly with bilateral stimulation (see Video 96.19) (Baizabal-Carvallo et al., 2014). Adverse effects are relatively rare and may include intracranial hematoma, postoperative seizures, dysarthria, paresthesia, dysequilibrium, headaches, dyspraxia, and word-finding difficulty. Problems with the stimulator itself are relatively uncommon but include lead fracture or migration and failure of the impulse generator. Reoperation may be necessary to correct device-related adverse effects. DBS should be considered for cognitively intact, otherwise healthy patients with disabling medication-resistant tremor. Unilateral focused ultrasound thalamotomy was evaluated in 27 patients with troublesome ET, who were randomized (2:1) to compare this with sham procedures (Bond et al., 2017). Using

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the Clinical Rating Scale for Tremor (CRST) as the primary endpoint along with several secondary outcomes the on-medication median tremor scores improved 62% after active treatment and 22% after sham procedures (P = .04).

Primary Writing Tremor Primary writing tremor is a rare condition characterized by a 4- to 7-Hz tremor in the hand while assuming a writing posture or during the writing task itself. Most patients are men. About one-third have a positive family history of writing tremor, and a similar number give a history of improvement after ethanol ingestion. Surface EMG shows isolated extensor tremor, alternating tremor in flexors and extensors, or co-contraction of flexors and extensors. Writing tremor may be difficult to distinguish clinically from ET and from task-specific or writing dystonia. Primary writing tremor is not usually associated with the phenomenon of overflow, typically seen in dystonia, and electrophysiological studies suggest it is distinct from both conditions. Accelerometry suggests that the primary writing tremor reflects the normal rhythmic movement of writing, but the amplitude of the movements is enhanced. The tremor may respond to β-adrenergic blockade or primidone or anticholinergic medications, but botulinum toxin injections provide the most benefit. Thalamic DBS has also been reported effective in some cases.

Orthostatic Tremor Orthostatic tremor consists of a high-frequency (14–18 Hz) isometric tremor in the legs during standing (see Video 96.21) (Yaltho and Ondo, 2014). Patients may not be aware of the tremor but complain of unsteadiness and vibration or discomfort in the legs that are relieved by leaning against a stationary object, by walking, or by sitting down. Leaning on the arms may precipitate a similar frequency tremor in the arms, and a tremor of the closed jaw has also been reported. Orthostatic tremor may be visible or palpable and can be confirmed by the appearance on EMG of high-frequency tremor when standing. Unlike parkinsonian tremors and ETs, orthostatic tremor shows significant side-to-side coherence, suggesting a central generator. PET scans have shown increased resting cerebellar activity similar to that seen in ET. A recent study has suggested that coherent high-frequency tremor in the legs may be a normal response to perceived unsteadiness when standing still, and that orthostatic tremor may be an exaggeration of this response. Clonazepam is thought to be the most effective pharmacological treatment, although there are reports of benefit from LD and gabapentin.

Neuropathic Tremor Tremors associated with neuropathy are usually postural and kinetic tremors with a frequency between 3 and 6 cycles per second. Demyelinating neuropathies have a particular association with tremor. The diagnosis is made when a typical tremor affects a person with neuropathy in the absence of other tremorgenic neurological disorders. The pathophysiology of neuropathic tremor is believed to be disordered feedback control related to abnormal peripheral sensory input. Some patients develop tremor after a peripheral injury, sometimes associated with abnormal posture as well as reflex sympathetic dystrophy or complex regional pain syndrome. The mechanism of this peripherally induced movement disorder is not understood. Pharmacological treatment is usually disappointing, but some patients respond to beta-blockers or clonazepam.

Cerebellar Tremor The tremor typically associated with cerebellar disease is a slow tremor that is absent during rest but appears and progressively increases in

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amplitude with movement, particularly with fine adjustments required for a precise movement. Sitting or standing unsupported may induce a tremor of the trunk and head (titubation). A variant of cerebellar outflow tremor is known as Holmes tremor, or rubral tremor (Raina et al., 2016). This tremor is present during rest, posture holding, and action. At rest, it is slower and less rhythmic than parkinsonian rest tremor. Holmes tremor results from acquired structural lesions in the ipsilateral cerebellar dentate nucleus and superior cerebellar peduncle. The usual causes are multiple sclerosis, stroke, and head injury. Pharmacological treatment of Holmes tremor is difficult, although some patients respond to LD. Thalamotomy or thalamic DBS may be useful in some cases (Oliveria et al., 2017) (see Video 96.20).

Hereditary Geniospasm (Chin Tremor) Hereditary geniospasm is characterized by involuntary vertical movement of the tip of the chin with quivering and mouth movements. Geniospasm may be spontaneous or stress induced. Trembling becomes apparent in infancy or early life. Trembling episodes last minutes. The attacks become somewhat less frequent with age. The disorder is genetically heterogeneous, with linkage to chromosome 9q13-21 in some but not all families. Geniospasm has been suggested to be a form of hereditary essential myoclonus (EM).

Fragile X Premutation Male carriers of the fragile X premutation have been found to have a neurodegenerative syndrome characterized by the onset after age 50 years of kinetic tremor, gait ataxia, executive cognitive dysfunction, parkinsonism, dysautonomia, erectile dysfunction, and peripheral neuropathy (Hagerman and Hagerman, 2013). Daughters of the patients often have ovarian failure. Bilateral cerebellar hyperintensities have been reported on T2-weighted MRI studies in some cases. Overexpression and CNS toxicity of the fragile X mental retardation 1 gene (FMR1) messenger ribonucleic acid (mRNA) has been thought to cause this fragile X-associated tremor/ataxia syndrome (FXTAS). There are other, more unusual tremors that physicians should be able to recognize but their discussion is beyond the scope of this chapter (Ure et al., 2016). Functional (psychogenic) tremors are discussed below.

CHOREA Huntington Disease The first complete description of HD is attributed to George Huntington in 1872. He accurately reported the salient clinical features of the disease, its pattern of transmission from parent to child, and its dismal prognosis. HD is a highly penetrant autosomal dominant disease characterized by a progressive movement disorder associated with psychiatric and cognitive decline, culminating in a terminal state of dementia and immobility (Testa and Jankovic, 2019).

Epidemiology Prevalence figures for HD vary depending on the geographical area, but the best estimate is 10 per 100,000. The disorder is reported in all races, although it is much more common in Scotland and Venezuela and less common in Finland, China, Japan, and Black South Africans. HD usually begins between the ages of 30 and 55 years, although it has been reported to begin as early as age 2 and as late as age 92. Approximately 5% of cases begin in patients younger than 21 years; the juvenile phenotype differs from the adult phenotype, and patients are often misdiagnosed. HD is a progressive degenerative disease that affects movement, behavior, and cognitive function.

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Clinical Features When clinical illness begins, it does so gradually, and it is best to define a “zone” rather than a time of onset. Patients with HD may present with motor signs, particularly chorea (about 60%), with behavioral signs (about 15%), or with both motor and behavioral signs (about 25%). Patients themselves may be unaware or unconcerned about early cognitive and motor changes. Concerned family members often bring them to medical attention. A change in the ability to generate saccadic eye movements and their speed is often the earliest sign. Eventually, a blink or head thrust may be required to initiate saccadic eye movements. The motor disorder usually begins with clumsiness and fidgetiness that evolves into chorea. The presence and severity of chorea vary markedly from person to person and over time. Some patients, particularly in early stages of the disease, are able to camouflage their chorea by incorporating the involuntary movements into seemingly volitional gestures such as touching their face or adjusting glasses (parakinesia). Chorea may not be recognized initially by family members or other observers. In addition to chorea, patients with HD have bradykinesia and motor impersistence, with difficulty sustaining ongoing movement. They may be unable to maintain forced eye closure, hold the mouth open, or protrude the tongue for long periods. With advancing disease, there is progression of bradykinesia, and dystonic movements appear. The chorea may become somewhat less prominent or may continue to worsen. The gait disorder of HD is complex, irregular, and dance-like, produced by a combination of chorea, parkinsonism, lapses in tone of antigravity muscles, and ataxia. The walking patient with HD resembles a marionette, lurching, swaying, dipping, and bobbing. Tandem walking becomes difficult, then impossible. Ultimately, progressive bradykinesia and intractable falls lead to the wheelchair- or bed-bound state. Dysarthria and dysphagia progressively impair communication and nutrition. Most patients spend the last several years of their lives in nursing home settings and die of complications such as pneumonia and head injury. Mean survival is 17 years, but the natural history varies and is influenced by genetic and environmental factors. Generally, patients with onset at a younger age have the largest number of CAG repeats and tend to progress more rapidly than patients with onset at an older age. The juvenile HD differs from the adult phenotype, with prominent parkinsonism and dystonia, even early in the course, and with myoclonus, seizures, and cognitive decline. Behavioral changes contribute mightily to disability in HD; 98% of patients show one or more behavioral symptoms. The most common changes in early disease are irritability, anxiety, and mood disturbance. Irritability may be accompanied by verbal or physical aggression. Patients with HD often have a low threshold for anger and react to minimal provocation with an explosive response. Depressed mood is very common; 30% of patients meet criteria for major depressive disorder. Mania and hypomania are seen less commonly than depression. The risk of suicide is increased as much as sixfold over the general population. Unmarried and childless persons living alone, those who are depressed, and those with a family history of suicide are particularly at risk for suicide. Fear of the disease leads to an increased risk of suicide, even in first-degree relatives of affected individuals who are at autopsy found not to have inherited the mutant gene. Psychosis is rare and may be difficult to treat. Obsessive-compulsive disorder has been reported but can be difficult to differentiate from frontal lobe personality with perseveration. Apathy increases in concert with disease severity and is a nearly universal feature of advanced disease. Behavioral and psychiatric disorders may predate the onset of overt HD by as long as a decade, reflecting early pathological changes in the nonmotor areas of the striatum. Because some behavioral signs may be episodic and respond to pharmacotherapy, their severity does not progress in a linear fashion with cognitive and motor changes. Behavioral signs seem to improve

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CHAPTER 96 Parkinson Disease and Other Movement Disorders in the terminal stages of the illness, but ascertainment may be hindered by the severe physical disability of such patients. Cognitive changes are universal in HD. The dementia of HD fits the description of subcortical dementia, with disordered attention, concentration, motivation, insight, judgment, and problem solving rather than traditional cortical signs such as aphasia and apraxia. Executive dysfunction renders affected persons unable to work, drive, and manage family finances relatively early in the disease course, but prominent global dementia occurs later. The diagnosis of HD in a patient with a typical clinical picture and a confirmed family history is straightforward. Unfortunately, the family history may be vague or it may be negative because of competitive mortality, misdiagnosis, denial, inaccurate parental information, or obfuscation. In addition, there is a small but definite new mutation rate as expansion occurs with transmission of a premutation. Although there is a broad differential diagnosis of chorea, there are few alternative causes of the fully developed syndrome. When the clinical suspicion of HD is high, the most cost-effective diagnostic procedure is genetic testing. The direct DNA test for the CAG repeat expansion in the huntingtin (HTT) gene, formerly called IT15, which codes for the huntingtin (HTT) protein is highly sensitive and specific. A repeat CAG expansion length of 37 and longer is considered pathogenic, resulting in motor, cognitive, and neuropsychiatric manifestations of HD. CAG repeat lengths between 27 and 36 are considered to be intermediate in range, with some risk of expansion into the disease range during meiosis and manifested by typical HD in subsequent generations. Traditionally, these intermediate CAG repeat lengths have not been associated with clinical disease, but there has been a growing number of reports of patients with clinical (and neuropathological) evidence of HD who possess CAG repeats in the intermediate range (Savitt and Jankovic, 2019b). The availability of the HD genetic test makes possible the identification of mutant gene carriers long before they become symptomatic. However, because of concerns about the potential for occupational, insurance, and social discrimination and the lack of neuroprotective treatment interventions, only a minority of eligible at-risk subjects pursue testing. This, however, may change as potential disease-modifying therapies are being developed (see below). Those who pursue testing do so either to help with reproductive choices or because their uncertainty about the future is unbearable. Women are more likely to request presymptomatic testing than men at equal risk. Although prenatal testing is also available, relatively few prenatal tests have been performed. Interested researchers working in concert with lay organizations have outlined principles that guide clinicians in the preparation of potential gene carriers for predictive genetic testing. These guidelines discourage genetic testing in asymptomatic minors and recommend genetic and psychological counseling before and after testing (Migliore et al., 2019). One obvious concern is the risk that once given a positive genetic test result, the patient may have a major depression or other psychopathology or may attempt suicide. When carefully managed, presymptomatic test programs are safe. In studies of life events after gene-carrier detection, less than 1% of patients have a potentially severe adverse outcome such as attempted or completed suicide or hospitalization for psychiatric illness. Adverse outcomes may be seen in patients whose predictive test suggests they are not gene carriers, the “survivor guilt” phenomenon. Depressive symptoms in such patients tend to become apparent several months after the testing process is completed. A premorbid history of depression increases the risk of an adverse outcome of testing irrespective of test results, confirming the need for careful screening and counseling in genetic testing programs.

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B Fig. 96.15 Pathology of Huntington Disease. A, Glial fibrillary acidic protein immunostain of caudate nucleus of normal brain. B, Glial fibrillary acidic protein immunostain of caudate nucleus of patient with Huntington chorea. Note decreased neuronal density and marked reactive astrocytosis compared to normal brain. (Courtesy Elizabeth Cochran, MD.)

Neuroimaging studies can show generalized or preferential striatal atrophy, but these findings are not specific for the disorder. Although volumetric analysis of the striatum shows declining volume even in presymptomatic gene carriers, many obviously symptomatic patients do not have clinically apparent striatal atrophy. Somatosensory evoked potentials are abnormal in 94% of patients with HD, and abnormalities correlate with clinical signs of the illness. However, the usefulness of these and other electrophysiological studies for diagnosis or measuring illness progression remains unproven.

Pathology The pathology of HD includes prominent neuronal loss and gliosis in the caudate nucleus and putamen, along with regional and more diffuse atrophy (Fig. 96.15). At autopsy, HD brains show about 20% loss of brain weight, suggesting that the degenerative process is not confined to striatal tissues. Large cortical neurons in layer VI are also involved, as are neurons in the thalamus, SNr, superior olive, lateral tuberal nucleus of the hypothalamus, and deep cerebellar nuclei. Within the striatum, GABAergic medium spiny neurons bear the brunt of the degenerative process. Early, there is preferential loss of GABAergic neurons that co-localize enkephalin, dynorphin, and substance P. These neurons are thought to predominate in the indirect pathway, accounting for difficulties suppressing adventitious movement early in the disease course. With disease progression, all GABAergic medium spiny neurons are affected, including those in the direct pathway, explaining the emergence of parkinsonism in later disease. Juvenile-onset disease, more severe from the beginning, resembles late-stage HD with degeneration of GABAergic neurons in both pathways.

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B

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[11C]-Raclopride

Fig. 96.16 positron emission tomography scans of (A) normal control subject, (B) asymptomatic carrier of Huntington disease (HD) gene, and (C) person with symptomatic HD, showing progressive loss of D2-receptor-bearing striatal neurons.

Pathogenesis HD is a dominantly inherited condition caused by an unstable expanded CAG trinucleotide repeat in exon 1 of the huntingtin (HTT) gene on the tip of the short arm of chromosome 4, which codes for HTT (Testa and Jankovic, 2019). Because repeat instability of this mutation is much more common in spermatogenesis than in oogenesis, the offspring of men may have substantially greater CAG repeat lengths than their fathers. This feature accounts for the phenomenon of anticipation in HD. There is a well-documented inverse correlation between the CAG repeat length and the age at disease onset. The extreme manifestation of this relationship is the association of juvenile-onset illness with repeat lengths of 60 or greater and onset within the first decade with repeat lengths of 80 or greater. Approximately 5% of patients present before age 21 years; in nearly all cases of juvenile-onset disease, the mutant allele is inherited from the father. Likewise, very late disease presentations often are associated with repeat lengths between 36 and 41. The correlation between repeat length and age at onset is driven by a very tight relationship of these two factors at the two ends of the mutation spectrum. The repeat length, however, accounts for only about 50%–70% of the variance in age at disease onset, suggesting that other genetic or environmental factors are important. For this reason, the CAG repeat length is not a particularly useful tool for making predictions about disease onset, severity, or progression in individual patients. HD is a true dominant condition. Homozygotes do not have an earlier onset or more severe form of the illness, suggesting the disorder results from a toxic effect of the mutant protein, a so-called gain of function (Cubo et al., 2019). The HD gene controls the synthesis of HTT, a widely expressed protein of uncertain function. HTT is a cytoplasmic protein, but ubiquitinated, mutant, proteolytic N-terminal huntingtin fragments form protein aggregates in the cytoplasm and nucleus of neurons. Mutant HTT interacts with a number of HTTassociated proteins and when it misfolds it can become more toxic. A number of lines of evidence point to impaired mitochondrial function in HD, including abnormalities in complex I, II, III, and IV in caudate nuclei of affected brains. PET studies show reductions in striatal glucose metabolism and loss of dopamine D2 receptor-bearing neurons in the striatum (Fig. 96.16), and increased brain lactate levels. Systemic administration of the mitochondrial toxin 3-nitropropionic acid models the disease in animals. Intrastriatal administration of the excitotoxins kainate and quinolinic acid also reproduces the striatal lesions of HD. One theory that ties these animal models together is that of indirect excitotoxicity. Mitochondrial energy failure increases the vulnerability of the cell to excitotoxic injury because the resulting change in cell membrane potential results in loss of the magnesium ion from

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the NMDA receptor-associated ion channel, allowing ligand-associated depolarization of the postsynaptic receptor and excitotoxic-mediated damage. HTT may also interfere with the function of postsynaptic density protein 95, a scaffolding protein associated with NMDA and kainate receptors, rendering these glutamate receptors hypersensitive. Mutant HTT also interferes with gene transcription, leading to an alteration in cell phenotype and disrupting many cell functions. Mutant HTT may block the normal function of HTT to upregulate brain-derived neurotrophic factor. Mutant HTT likely also triggers apoptotic cell death, but its full effect on cellular function, interaction with other proteins, and how these actions lead to neurodegeneration in HD have not yet been fully elucidated.

Treatment As in all other neurodegenerative disorders, no treatment is yet proven to favorably influence disease progression (Schapira et al., 2014). As with other forms of neurodegeneration, many potential types of interventions might prove useful: blocking transcription of the mutant gene, enhancing chaperone function, interfering with association and aggregation of the protein, improving cell bioenergetics and mitochondrial integrity, and interfering with the triggers and ultimate steps in the process of apoptosis. Clinical trials of antioxidants designed to slow down the progression of the disease have been disappointing. One large-scale study assessed the potential neuroprotective effects of the mitochondrial complex 1 booster coenzyme Q10 (600 mg/day), or the antiexcitotoxic agent remacemide (600 mg/day), on the decline of the total functional capacity score over 30 months. The study demonstrated a trend toward slowing the decline in this measure of disability in the coenzyme Q10 treatment arm, but this did not achieve statistical significance. A number of other potential strategies have shown promise in transgenic disease models, although they have not been studied in human safety and efficacy trials. These include the caspase inhibitor minocycline, as well as creatine, lithium, ethyl eicosapentaenoic acid, cystamine, bile acids, and inhibitors of transglutaminase. As with other neurodegenerative diseases, there is no standard method for determining disease severity or its rate of change over time. Studies relying on clinical rating scales, such as the Unified HD Rating Scale, must be quite large and adequately powered to detect the disease-modifying effect. One intriguing discovery in HD is that, in transgenic models, turning off the HD gene not only stops progression of the experimental illness but also reverses pathological findings, including aggregates, and is associated with clinical improvement. Apparently, continued production of the mutant protein is required for maintenance of cell dysfunction and ultimately for cell death. This argues for a period of cellular dysfunction

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CHAPTER 96 Parkinson Disease and Other Movement Disorders before death and raises the possibility that neuroprotection might have the potential to at least partially reverse extant clinical features of the disease. In this regard, an antisense oligonucleotide designed to inhibit HTT messenger RNA and thereby reduce concentrations of mutant HTT has been tested in a randomized, double-blind, multiple-ascending-dose, phase 1-2a trial involving 46 patients with HD (Tabrizi et al., 2019). The intrathecal administration of 4 doses, 1 month apart, showed up to 38% reduction in the concentration of mutant HTT in CSF without any serious adverse effects. A confirmatory phase 3 trial, involving 660 patients, followed for up to 2 years is currently under way. Treatment of HD begins with an assessment of the nature of the patient’s complaints. Patients with chorea are often unaware of or untroubled by their involuntary movements (Jankovic and Roos, 2014). Although typical neuroleptics represent the conventional approach to chorea, they have been shown not to improve function in HD and are not used as much as in the past (Frank and Jankovic, 2010). Preliminary study suggests that the glutamate antagonist, amantadine, may improve chorea in HD and is well tolerated in doses up to 400 mg. Tetrabenazine and deutetrabenazine, inhibitors of the vesicular monoamine transporter 2 (VMAT2), that act by presynaptically depleting dopamine, have been approved by the US Food and Drug Administration (FDA) for the treatment of chorea associated with HD. Although similar to typical neuroleptics, these drugs may cause drowsiness, parkinsonism, depression, and akathisia; in contrast to the dopamine receptor blocking drugs, they do not cause TD (Bashir and Jankovic, 2018a). Some patients with prominent bradykinesia improve with dopaminergic therapy. Selective serotonin reuptake inhibitors seem to improve irritability, aggression, depression, and obsessive-compulsive symptoms. Irritability may respond to carbamazepine and some of the newer antiepileptic drugs. Quetiapine, an atypical antipsychotic with minimal risk for parkinsonism or TD, has been reported to be useful in patients with irritability and aggression.

Dentatorubral-Pallidoluysian Atrophy Dentatorubral-pallidoluysian atrophy is an inherited neurodegenerative disease that appears to be rare outside Japan but has been found to be relatively common in North Carolina: hence the alternative term Haw River syndrome. Typical symptoms of DRPLA include chorea, ataxia, myoclonic epilepsy, dystonia, parkinsonism, psychosis, and dementia. Onset is usually in the 20s, with death about 20 years later. Anticipation occurs with paternal transmission of the gene. The pathology of DRPLA includes degeneration of the dentate and red nuclei, the GP, and the STN. Neurodegeneration may also be found in the cerebral white matter, putamen, medulla oblongata, and spinal cord. Neuronal nuclear inclusions stain for ubiquitin and atrophin-1. There is also evidence for aberrant phosphorylation of the DRPLA protein complex and the nuclear membrane. DRPLA is associated with an expansion of CAG trinucleotide repeat in a gene on chromosome 12. In this region of the genome, the normal trinucleotide repeat length is 7–23. In DRPLA, the CAG repeat length is between 49 and 75. Because of the polyglutamine stretch in the mutant protein, neurodegeneration likely relates to interactions between the protein, other cellular components, and cellular proteins. The Haw River syndrome, described in a multigenerational African American family, is caused by the same repeat expansion as DRPLA. Clinical differences include lack of myoclonic epilepsy and the presence of subcortical white-matter demyelination, basal ganglia calcifications, and neuroaxonal dystrophy. No information is available about the treatment of DRPLA, but as in HD, the clinician should be guided by the nature and severity of symptoms.

Neuroacanthocytosis and McLeod Syndrome The term acanthocyte is derived from the Greek word for “thorn.” Acanthocytes are contracted erythrocytes with unevenly distributed

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thorny projections, often with terminal bulbs. Acanthocytes are seen in peripheral blood smears in patients with three neurological syndromes: abetalipoproteinemia, neuroacanthocytosis, and McLeod syndrome (Walker et al., 2006). A broad spectrum of movement disorders is seen in neuroacanthocytosis and McLeod syndrome. All forms of neuroacanthocytosis are rare disorders. Autosomal recessive neuroacanthocytosis is characterized by onset at around age 35 years of a progressive syndrome that includes a movement disorder and behavioral and cognitive changes. The movement disorder predominantly consists of chorea, dystonia, and tics; parkinsonism may occur in more advanced stages. There is also prominent orofacial dystonia with dystonic tongue protrusion interfering with eating. In addition, many patients exhibit lip and tongue biting and prominent dysarthria and dysphagia. Behavioral changes resemble those seen in HD: anxiety, depression, obsessive-compulsive disorder, and emotional lability. Subcortical dementia is a late feature. Seizures develop in approximately 50% of patients. There may be myopathy or axonal neuropathy, and the creatine kinase level is elevated. In patients with neuroacanthocytosis, acanthocytes usually make up 5%–20% of peripheral blood erythrocytes. Autopsy changes include atrophy of the caudate, putamen, GP, and SN, with marked neuronal loss and gliosis. The cerebral cortex is relatively spared. Mutations in the CHAC gene (recently renamed VPS13A) on chromosome 9 that lead to the production of chorein, a truncated protein of unknown function, have been found in this syndrome. Homologous proteins in animals seem important in intracellular trafficking. McLeod syndrome is an X-linked recessive disorder linked to a number of mutations in the XK gene, a gene for the Kell group of erythrocyte membrane glycoprotein antigens on the X chromosome (Roulis et al., 2018). McLeod syndrome usually begins around age 50 and has a slowly progressive course. The most common clinical feature is an axonal peripheral neuropathy. Some patients have evidence of myopathy as well, and all have elevations in serum creatine kinase level. The CNS illness is characterized by limb chorea. Oral movements and lip and tongue biting are less common than in neuroacanthocytosis. Facial tics are common, and some patients have dystonia. Seizures may be seen. Subcortical dementia and behavioral changes occur later in the disease course in approximately 50% of patients. Cardiomyopathy and hemolytic anemia are other common manifestations. Neuroimaging studies may show caudate atrophy with secondarily enlarged lateral ventricles. Increased T2-weighted signals in the lateral putamen may be seen on MRI scans. Pathological changes include intense caudate atrophy, loss of small cells, and gliosis in the dorsolateral putamen, with less severe changes in the GP. Milder changes may be present in the thalamus, SN, and anterior horns of the spinal cord. Neurons in the cerebral cortex, STN, and cerebellum are spared. The reported mutations in the XK gene result in absence or truncation of the protein product. Kell is an endothelin processing enzyme. Endothelins are important in proliferation and development of neural crest–derived cells and are thought to be important in neurotransmitter release in dopaminergic neurons. No information is available about treatment of neuroacanthocytosis, but the physician should be guided by the clinical manifestations.

Sydenham Chorea and Other Autoimmune Choreas Sydenham chorea (SC), one of the major manifestations of rheumatic fever, typically appears months after the initial streptococcal infection (Baizabal-Carvallo and Jankovic, 2012). Because of the widespread availability of antistreptococcal therapy, SC is now extremely rare in developed countries. It is a disorder of children, mainly girls, between ages 5 and 15, with a mean age at onset of 8.4 years. The chorea begins insidiously, but progresses over a period of weeks, and it generally resolves within about 6 months. Choreic movements are usually generalized,

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but asymmetric and hemichorea may also be seen. Behavioral accompaniments such as restlessness, irritability, and obsessive-compulsive traits are common. It is a self-limited disorder, usually lasting up to 6 months. Approximately 20% of cases recur, but multiple recurrences are rare. Mild enlargement of the basal ganglia may be seen on MRI brain scan. Pathologically, SC is characterized by inflammation of the cortex and basal ganglia. Anti–basal ganglia antibodies can be detected by enzyme-linked immunosorbent assay and Western immunoblot. The mechanism of basal ganglia damage is likely molecular mimicry, with cross-reaction between antibodies directed against streptococcal and striatal antigens. Because it is often self-limited, the decision to treat SC depends on the magnitude of each patient’s disability. A recent comparative trial suggested that valproic acid is the most effective treatment, followed by carbamazepine and haloperidol. The typical neuroleptics, such as haloperidol, however, are now rarely used in the treatment of chorea and instead VMAT2 inhibitors, such as tetrabenazine, deutetrabenazine, and valbenazine are now considered the drugs of choice (Bashir and Jankovic, 2018b). Because SC tends to be self-limited, periodic attempts should be made to wean from therapy. Intravenous methylprednisolone followed by oral prednisone may be useful in refractory cases. Later in life, people who have survived SC may have a recrudescence of chorea in the presence of hormonal stresses like pregnancy (chorea gravidarum) or estrogen treatment. Besides SC, there are many other autoimmune choreas, including systemic lupus erythematosus and paraneoplastic choreas (BaizabalCarvallo and Jankovic, 2012; Baizabal-Carvallo et al., 2013) and NMDAR encephalitis (Baizabal-Carvallo and Jankovic, 2018).

BOX 96.4

Other Choreic Disorders

Other Static encephalopathy Head injury Demyelinating disease Thalamotomy Heredodegenerative disease

There are many causes of chorea but here we will focus only on the more common ones or those in which understanding of pathogenesis has improved. A condition previously referred to as benign hereditary chorea has been re-defined with the discovery of its genetic cause. Inherited as an autosomal-dominant disorder, this disorder has been linked to mutations in the NKX2-1 (previously called TITF1) gene coding for a transcription essential for the organogenesis of the brain, lung, and thyroid. Since all three of these sites are affected, the condition has also been referred to as “BLT syndrome.” Initially defined as a nonprogressive syndrome of inherited childhood-onset chorea with a good outcome in the absence of an underlying degenerative disease, the phenotype has been expanded markedly as new cases with mutations of the NKX2-1 gene are being reported (Patel and Jankovic, 2014). Chorea is present from early childhood, usually from the first decade of life, but a variety of other movement disorders and nonmotor features have been described. These include hypotonia in early infancy, delayed walking ability, dystonia, myoclonus, and tics as well as a variety of behavioral and cognitive features including attention-deficit/hyperactivity disorder. Because of the heterogeneity of clinical features, the term NKX2-1 disease has been suggested for this disorder. Mutations in the adenylate cyclase 5 (ADCY5) gene have been associated with a variety of movement and behavioral disorders, including episodic and fluctuating chorea, dystonia, myoclonus, cognitive decline, delayed motor and speech milestones, hypotonia, ataxia, unexplained falls, and myopathy-like facial appearance (Carecchio et al., 2017). The disorder is frequently misdiagnosed as dyskinetic cerebral palsy (Monbaliu et al., 2017). A homozygous loss-of-function mutation in the PDE2A gene has been associated with early-onset hereditary chorea (Salpietro et al., 2018).

Ballism Ballism is usually a high-amplitude proximal ballistic flinging movement (see Chapter 24, Box 24.5) that most commonly affects the limbs

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Etiology of Hemiballism

Structural Lesions Cerebrovascular Disease Infarction Transient ischemic attack Hemorrhage Arteriovenous malformation Subarachnoid hemorrhage Subclavian steal syndrome Infection Syphilis Tuberculoma Toxoplasmosis Acquired immunodeficiency syndrome Influenza A Tumor Pituitary microadenoma Metastasis Immune-Mediated Systemic lupus erythematosus Sydenham chorea Behçet disease Scleroderma

Metabolic Nonketotic hyperosmolar hyperglycemia Drug-Induced Phenytoin and other anticonvulsants Oral contraceptives Neuroleptics (tardive)

on one side of the body (HB), but involvement in both legs (paraballism) or both sides of the body (biballism) is also possible. Ballism overlaps with choreas, and both movements may coexist. Acute-onset ballism often evolves into and is replaced by chorea. Animal models with lesions in the STN result in a mixture of choreic and ballistic movements. The development of ballism varies with the underlying etiology. HB related to stroke appears suddenly or emerges more slowly in a recovering plegic limb. Approximately 20% of cases relate to structural lesions within the contralateral STN and in 20% of cases no lesion can be demonstrated by MRI. In other cases, the lesion is usually found in the afferent or efferent projections of the STN. Rarely, other etiologies, even ipsilateral to the movement, have been described. Although the underlying lesion is usually cerebrovascular disease in the elderly and infectious or inflammatory disease in younger patients, any type of structural lesion, appropriately placed, can produce the characteristic movement. Metabolic disorders such as nonketotic hyperglycemia and drug exposure may also cause HB (Box 96.4). The mechanism of ballism is not well understood but loss of STN excitation of the GPi results in a loss of inhibitory drive to the thalamus, giving rise to excessive

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CHAPTER 96 Parkinson Disease and Other Movement Disorders motor activity which may be represented clinically by the ballistic movements. Low firing frequency of the STN has been confirmed in a few cases, using intraoperative recording. Long-term prognosis and outcome closely relate to the underlying etiology. Movements often regress or become more choreic over several months, but they can be quite exhausting or disabling when present, and treatment is usually only indicated acutely and in patients whose movements do not resolve spontaneously. Although the rarity of the condition has precluded controlled clinical trials, there is ample evidence from case series and reports that dopamine antagonists and dopamine depleters (VMAT2 inhibitors) effectively decrease choreic movements. Beneficial results have also been obtained using gabapentin and valproic acid.

DYSTONIA Childhood-Onset Generalized Primary Dystonia Epidemiology and Clinical Features Dystonia is a disorder dominated by sustained muscle contractions, which often cause twisting and repetitive movements or abnormal postures (Albanese et al., 2013; Balint et al., 2018) (see also Chapter 24). Generalized dystonia is quite rare, with an estimated prevalence of approximately 1.4 per 100,000. Most cases of primary generalized dystonia that begin in childhood have DYT-TOR1A dystonia, caused by a mutation in the torsin A gene (TOR1A) on chromosome 9q32-34 (Dauer, 2014; Marras et al., 2016) (see also Chapter 24). Also referred to as Oppenheim dystonia and previously called dystonia musculorum deformans, DYT1 is an autosomal dominant disorder with relatively low penetrance. DYT1 dystonia is one of several movement disorders particularly common in persons of Ashkenazi Jewish descent (Inzelberg et al., 2014). The reported prevalence of DYT1 dystonia is as high as 20–30 per 100,000. Half of patients are affected by age 9, and onset in patients older than 40 years of age is extremely rare. The earliest symptom is usually an action-induced dystonia in the leg or arm. Onset in the cervical, facial, laryngeal, or pharyngeal region is rare. In approximately 70% of patients, dystonic movements spread to the trunk and other limbs, and the condition generalizes over about 5 years. Patients with earlier onset and onset in the leg are more likely to develop generalized dystonia than those presenting later or with arm dystonia. Generalized dystonia produces severe disability, and most patients with this severe form of the illness are nonambulatory. Even in generalized disease, however, laryngeal and pharyngeal dystonia remains rare. The diagnosis of childhood-onset primary generalized dystonia is made clinically in a patient with onset before age 26 of limb dystonia, with subsequent spread; absence of other movement disorders, with the exception of tremor; normal intellect and neurological examination; and absence of a pronounced response to LD (see also Chapter 24). Routine laboratory and neuroimaging studies do not contribute to the diagnosis. Simultaneous recording of EMG activity from antagonist muscles often reveals simultaneous contraction of antagonistic muscles and spread or overflow of activity to muscles not involved in the intended action. Such studies are not required for the diagnosis. DNA testing is available for DYT1 dystonia, but the low penetrance of the disease limits the usefulness of this test for prenatal or presymptomatic diagnosis.

Pathology Pathological studies in childhood-onset primary generalized dystonia are limited. Although traditionally thought not to be associated with pathological changes, brains from genetically confirmed DYT1 dystonia patients showed perinuclear inclusion bodies in the midbrain

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reticular formation and periaqueductal gray matter of the PPN, cuneiform nucleus, and griseum centrale mesencephali. These inclusions stained positive for ubiquitin, torsin A, and the nuclear envelope protein lamin A/C. In addition, tau/ubiquitin-immunoreactive aggregates were found in the SNc and locus coeruleus. If confirmed by other studies, these findings support the notion that DYT1 dystonia is associated with impaired protein handling, particularly in brainstem nuclei such as the PPN.

Pathogenesis The low penetrance of DYT1 dystonia, combined with variable expression that may range from an asymptomatic state to severe life-threatening dystonia (dystonic storm), may obscure its hereditary nature in many families. The disorder is genetically homogeneous in Ashkenazi Jews, 90% of whom are found to have the DYT1 mutation (Inzelberg et al., 2014). Non-Jewish patients are genetically more heterogeneous. The DYT1 mutation is a GAG deletion in the TOR1A gene on chromosome 9, with an estimated frequency of 1 per 2000 to 1 per 6000 in Ashkenazi Jews and about 1 per 20,000 to1 per 30,000 in non-Jewish populations. The high prevalence of DYT1 in Ashkenazi Jews is related to a founder mutation estimated to have originated about 350 years ago in Lithuania or Byelorussia and the subsequent large increase in the population from a limited number of ancestors. The pathogenesis of generalized dystonia remains poorly understood, but progress is being made in unraveling the cellular and molecular mechanism of the genetic forms of dystonia (Dauer, 2014). Torsin A is a protein of unknown function that is homologous to the adenosine triphosphatases and heat-shock proteins. Its structure suggests a role in endoplasmic reticulum function, intracellular trafficking, or vesicular release. Mutant torsin A may interfere with these functions or may contribute to misfolded protein stress. Besides DYT1 there are many other genetic and non-genetic causes of dystonia (see Table 24.6A and 24.6B and Box 24.3). There is experimental, clinical, neuroimaging, and electrophysiological evidence of dysfunction at the cortical, subcortical, brainstem, cerebellar, and spinal levels. Although sensation in patients with dystonia is normal, it has been suggested that there is disordered sensory function as suggested by the presence of alleviating maneuvers (see Chapter 24), a characteristic feature of dystonia (Patel et al., 2014). Deep brain recordings support abnormally low firing rates in the GPi, with an abnormal pattern of firing as well. During sustained dystonia, metabolic activity in the midbrain, cerebellum, and thalamus is increased. Functional neuroimaging of the dopamine system suggests decreased dopamine neurotransmission in the striatum, but decreased striatal dopamine has not been confirmed in postmortem tissue. Because dystonia may respond to pallidal lesions or stimulation, a central role of the GPi has been proposed. It is likely, however, that the pathophysiology of dystonia involves many factors that include changes in the rate and pattern of neuronal firing, the degree of synchronization of firing, and aberrant focusing of sensory input. There is no diagnostic test for dystonia, although simultaneous EMG recording of agonist and antagonist muscles may show inappropriate co-contraction. But this is not required for diagnosis of dystonia.

Treatment Rather limited information is available on the medical treatment of childhood-onset primary generalized dystonia. Apart from an obvious neurotransmitter deficiency or excess, there is no compelling rationale for the use of any particular pharmacotherapy, and no drug has been found to be universally effective for symptom control (Balint et al., 2018; Jankovic, 2009a; Thenganatt and Jankovic, 2014b). In the absence of genetic confirmation of the DYT1 mutation, a trial of

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LD should be considered in all patients with childhood-onset dystonia because up to 10% will have dopa-responsive dystonia (DYT5a) (Wijemanne and Jankovic, 2015). In patients younger than 20 years of age, some 50% will respond well to high-dose anticholinergic therapy. The response rate is better in patients treated within 5 years of onset. Baclofen, clonazepam, benzodiazepines, and dopamine-depleting medications may be useful in some patients. The treatment of childhood-onset primary generalized dystonia is a trial-and-error process. Treatment should be initiated with very small doses, and the dose should be increased slowly and gradually. Botulinum toxin injections may be considered to treat one or a few particularly problematic body areas in patients with generalized dystonia. Chronic intrathecal baclofen has been reported to help some patients with dystonia, especially those with concomitant spasticity. Thalamotomy has been replaced by GPi or STN DBS as the treatment of choice for disabling medically intractable generalized or segmental dystonia. Long-term studies have established the sustained efficacy of DBS in patients with dystonia (Panov et al., 2013). Advances in DBS techniques and in defining the appropriate targets have resulted in improved outcomes in patients with dystonia treated with DBS (Cheung et al., 2014; Meoni et al., 2017; Ostrem et al., 2017).

Adult-Onset Primary Focal and Segmental Dystonia

involvement with adductor or abductor spasmodic dysphonia affects phonation, resulting in a harsh and strangled or breathy voice, respectively. Whispering and singing are often relatively unaffected in such patients. The occupational or task-specific dystonias are those that arise in the context of repetitive or skilled use of a body part. The most common task-specific dystonia is writer’s cramp, in which action dystonia of the arm and hand develop during writing. Musicians, hair stylists, court reporters, and others who work repetitively with the hands may find these specific skills similarly affected. Players of wind instruments may develop embouchure dystonia, with difficulty maintaining the proper mouth and lip posture. Occasionally an adult patient presents with a pure truncal dystonia with flexion, extension, or lateral bending. As noted before, truncal dystonia is a typical manifestation of tardive dystonia. Isolated foot dystonia in an adult may be the initial manifestation of isolated dystonia although it is more commonly the initial presentation of an underlying neurodegenerative disorder, PD, or other form of parkinsonism, or SPS (see below). Some patients may become initially aware of their foot or leg dystonia while running, the so-called runner’s dystonia, another example of task-specific dystonia (Wu and Jankovic, 2006). The diagnosis of adult-onset primary focal or segmental dystonia is made clinically. Neuroimaging studies are useful if an underlying cause is suspected but are generally normal.

Epidemiology and Clinical Features

Pathogenesis

A community-based postal survey of primary dystonia suggested the prevalence of adult-onset primary focal or segmental dystonia was 12.9 per 100,000. Cervical dystonia and blepharospasm were most commonly represented. The focal and segmental primary dystonias generally begin in adulthood with dystonic movements in the hand and arm, neck, or face. When spread occurs, the ultimate distribution tends to maintain a segmental pattern. Cervical dystonia is the most frequently diagnosed form of focal dystonia, accounting for about half of focal dystonia cases. Patients with cervical dystonia present with neck pain, difficulty maintaining a normal head position, and sometimes tremor. Dystonic tremor, which may be present not only in patients with cervical dystonia but also in those with limb dystonia, is usually an irregular oscillatory movement that stops when the patient is allowed to place the head or limb in the position of the dystonic pulling—the null point. There is a directional preponderance to dystonia movements that is usually maintained throughout the course of the disease. Alleviating maneuvers (also referred to as “sensory tricks”) are often discovered and used by the patients to ameliorate the dystonia (see Chapter 24) and include resting the head against a wall or high-backed chair or touching the chin or back of the head lightly with one hand. Spontaneous remissions may be seen in as many as 20% of patients, although recurrence is common. Blepharospasm is one of the most common forms of focal dystonia. Symptoms of blepharospasm are often preceded by photosensitivity and a gritty or otherwise abnormal sensation in the eye. Increased blinking may follow, or frank spasms of eyelid closure may begin. Symptoms of blepharospasm are typically worse with driving, reading, or watching television and when exposed to bright light, wind, or stress. Many patients notice improvement in their blepharospasm when they talk or sing and when they place a finger on the eye orbit (alleviating maneuver). Blepharospasm is often accompanied by oromandibular dystonia (cranial dystonia), or the latter may occur in isolation. Oromandibular dystonia typically causes involuntary jaw opening or closure (with trismus and bruxism), tongue protrusion, dysarthria, and dysphagia. Because the actions of eating and speaking activate the dystonia, these tasks are particularly affected. Alleviating maneuvers used by patients with oromandibular dystonia include touching the face or inserting an object such as a pencil into the mouth. Vocal cord

Besides generalized dystonia, many studies have suggested that focal and segmental dystonia might also have a genetic basis (Albanese et al., 2013; Balint et al., 2018; Dauer, 2014). Approximately 25% of adult-onset focal or segmental dystonia patients have a positive family history of dystonia, which would be consistent with an autosomal dominant condition with low penetrance (see also Chapter 24). The pathogenesis of adult-onset primary focal or segmental dystonia is unclear, but similar mechanisms to childhood-onset primary generalized dystonia are proposed. Studies suggest that there is reduced intracortical inhibition in dystonia, believed related to impaired cortical and striatal GABA levels. Several lines of evidence suggest that abnormal central somatosensory processing may lead to insufficient sensorimotor integration in dystonia. PET scans suggest an abnormal pattern of regional glucose metabolism with hypermetabolism of the basal ganglia, cerebellum, and SMA.

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Treatment Medical treatment of adult-onset primary focal and segmental dystonia is difficult and employs those agents typically used in generalized dystonia. Adults are less able to tolerate effective doses of these agents, so the response to therapy is somewhat more disappointing than that seen in children. Botulinum toxin injections, on the other hand, are very helpful in the treatment of focal and segmental dystonia (Jankovic, 2017). Botulinum toxin injections have been proven effective in the treatment of blepharospasm and other facial dystonias, as well as cervical dystonia (Mittal et al., 2019b; Simpson et al., 2016). Clinical experience suggests they are also useful in the treatment of oromandibular, laryngeal, truncal, and limb dystonia. Overall, more than 75% of treated patients report moderate to marked improvement in dystonic pain or posture. The procedure is generally well tolerated, with weakness of injected muscles or occasionally neighboring muscles the most often reported side effect. Botulinum toxin injections have a relatively brief duration of action, requiring repeated injections every 3–6 months. Secondary resistance occurs in some chronically treated patients, especially those injected frequently with higher doses of the toxin (Jankovic, 2018b). Patients who fail to respond to botulinum toxin injections may be offered surgical interventions. Blepharospasm can be treated by orbital myectomy, although this procedure is now rarely needed as botulinum

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CHAPTER 96 Parkinson Disease and Other Movement Disorders toxin provides adequate relief in most patients. Likewise, cervical rhizotomy or myectomy are rarely performed, even in patients with cervical dystonia who are resistant to botulinum toxin therapy. Pallidal or STN DBS has been tried with good results in some patients with refractory cranial-cervical dystonia, but this procedure is most frequently used in patients with generalized dystonia (Meoni et al., 2017; Ostrem et al., 2017).

X-linked Dystonia-Parkinsonism (Lubag) DYT/PARK-TAF1 (DYT3), or Lubag, is an X-linked condition with progressive dystonia and parkinsonism affecting Filipino adult men descended from maternal lines from the Panay Island (Marras et al., 2016). In addition to dystonia and parkinsonism, patients may manifest tremor, chorea, and myoclonus. The phenotypical heterogeneity is evident in colorful descriptions of the disorder in the local dialect. Lubag means “intermittent,” and wa’eg “sustained twisting or posturing,” suggesting the predominantly dystonic form of the illness. Sudsud refers to shuffling gait, suggesting the parkinsonian form of the illness. Lubag affects men in the fourth or fifth decades, although much earlier-onset cases have been described. Symptoms predominantly relate to dystonia, although parkinsonism is present in more than 30% of patients. A nearly pure parkinsonian phenotype is thought to predict a more benign prognosis. PET studies have shown both postsynaptic and presynaptic dopaminergic changes. Some brains of patients with this dystonia-parkinsonism syndrome have been found to have a mosaic pattern of striatal gliosis. In some patients, parkinsonian symptoms are LD-responsive, although there are reports that LD worsens symptoms in some predominantly dystonic patients.

Dopa-Responsive Dystonia Dopa-responsive dystonia (DRD) is an uncommon condition with a prevalence of 0.5–1 per 1,000,000. Girls are preferentially affected. DRD is a childhood-onset generalized dystonia with a dramatic, sustained, and uncomplicated response to low doses of LD. The disorder begins in the first decade of life, usually with an action leg dystonia. The condition then progresses to the fully formed illness that ranges in severity from mild focal to disabling generalized dystonia associated with marked gait difficulty and postural instability with a positive pull test. Early-onset cases may be mistakenly diagnosed as cerebral palsy. The most characteristic historical feature is prominent diurnal fluctuation, although this is present in only 50% of the cases. Affected patients may be almost normal in the morning, becoming progressively more disabled over the course of the day, with peak disability due to generalized dystonia and parkinsonism late in the evening. DRD is usually dominantly inherited with incomplete penetrance (DYT5a). DYT5 results from mutations in the guanosine triphosphate cyclohydrolase 1 (GCH1) gene on chromosome 14 (Wijemanne and Jankovic, 2015). Over 100 different mutations of the gene have been identified, and therefore commercially available DNA testing identifies only the most common mutations. Guanosine triphosphate cyclohydrolase 1 is an enzyme involved in the synthesis of tetrahydrobiopterin, a cofactor for tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of LD. Other mutations affecting enzymes involved in tetrahydrobiopterin synthesis, such as tyrosine hydroxylase (DYT5b), have also been implicated in DRD. The DYT5b form of DRD is recessively inherited. Patients with DRD have low levels of tyrosine hydroxylase and therefore low levels of dopamine but F-dopa PET and postmortem studies confirm normal numbers of dopaminergic neurons. DRD responds very well to low doses of LD (100–300 mg daily). Patients with DRD do not typically develop the motor fluctuations and dyskinesias associated with chronic LD therapy in PD. DAs and anticholinergic drugs may also be useful.

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Another childhood-onset dystonia related to deficient dopaminergic neurotransmission is aromatic acid decarboxylase deficiency. This disorder is recessively inherited. Dystonia, parkinsonism, oculogyric crises, autonomic symptoms, and progressive neurological impairment begin in childhood. There are deficiencies in central biogenic amines including dopamine, norepinephrine, epinephrine, and serotonin. Because the enzyme deficiency is distal to LD in the dopamine synthetic pathway, the symptoms are not LD responsive. However, direct-acting DAs and MAOIs may be useful.

Myoclonus Dystonia (DYT11) In myoclonus dystonia (MD), dystonia is the predominant symptom, but myoclonus in body parts not necessarily affected by dystonia is also present. Some patients have pure myoclonus. Symptoms usually begin before the teenage years and predominantly affect the head, arms, and upper body. The involuntary movements may be exquisitely sensitive to ethanol. Psychiatric features including affective disorder, obsessive-compulsive disorder, substance abuse, anxiety, phobic or panic disorders, and psychosis have been described. Cognitive decline has also been reported. No other neurological deficits are seen, and the course is usually benign. The pathology is unknown. A number of heterozygous mutations in the ε-sarcoglycan gene on chromosome 7 have been reported in families with MD. Another dystonic disorder associated with myoclonus is DYT-KCTD17 (DYT26), an autosomal dominant disorder of childhood or adult onset, manifested by myoclonus and cranial-cervical dystonia. MD responds poorly to medical therapy, but beneficial responses to clonazepam, valproic acid, and trihexyphenidyl have been reported. Thalamic stimulation may also be beneficial.

Rapid-Onset Dystonia Parkinsonism (DYT12) Rapid-onset dystonia parkinsonism (RDP), DYT/PARK-ATP1A3 (DYT12), is a very rare disorder in which signs of parkinsonism and upper-body dystonia develop subacutely (Heinzen et al., 2014). Onset ranges from childhood to adulthood. Dystonia preferentially affects bulbar muscles and progresses over a period of days to weeks but then remains stable. Although sporadic cases have been reported, most cases belong to a small number of families showing dominant inheritance with incomplete penetrance. A genetic locus on chromosome 19 has been discovered. Low levels of homovanillic acid have been detected in the spinal fluid, but PET scans using presynaptic markers fail to demonstrate a loss of dopaminergic neurons. There is no evidence of neurodegeneration, and symptoms do not improve with administration of LD. Mutations in the Na+/K+-ATPase α3 gene, ATP1A3, on chromosome 19q13 were found to be associated with RDP (see also Chapter 24).

Wilson Disease (Hepatolenticular Degeneration) Clinical Features

Wilson disease (WD) is a rare, autosomal recessive, heredodegenerative disorder thought to affect 1–2 per 100,000 persons (Dusek et al., 2015; Hedera, 2019). The WD gene, termed ATP7B, on the long arm of chromosome 13 encodes copper-transporting P-type ATPase. Over 600 mutations have been identified and most patients carry at least two mutations. Because of the biallelic mutations in the ATP7B gene there is a loss of function of copper transporter ATPase, which results in an impaired excretion of copper into the bile and subsequent accumulation of copper in the liver and brain. Excessive copper not incorporated into copper-binding protein, ceruloplasmin, leads to cytotoxic effects in hepatic and central nervous tissues. Many patients present in childhood with symptoms and signs of liver disease ranging from cirrhosis to fulminant liver failure associated with progressive accumulation of copper. Once cirrhosis has developed, extrahepatic copper

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deposits begin to form, especially in the brain, eyes, and kidneys. Some patients present with hemolytic anemia, hypersplenism, or renal failure. Nearly half of all patients with WD present with CNS symptoms and signs. Neurological signs usually present during adolescence or early adulthood, but presentations up to age 51 have been reported. Neurological presentations include parkinsonism, postural and kinetic tremor, ataxia, titubation, chorea, seizures, dysarthria, and dystonia (see Video 96.22). A fixed stare with a smiling expression (risus sardonicus) and drooling are classic features of the illness but are not seen in all cases. Dystonia is a common sign, present in about a third of patients at presentation. Dystonia may be focal, segmental, or generalized. Dementia, if present, is mild, but psychiatric symptoms are common and may be quite disabling. Mood and personality disorders, behavioral changes, and psychosis are reported. In the presence of neurological signs, ophthalmological examination that includes slit-lamp examination essentially always demonstrates copper deposition in the Descemet membrane (Kayser-Fleischer rings; see Chapter 24, Fig. 24.1). Many patients with WD also have sunflower cataracts (Waln and Jankovic, 2018). Laboratory studies often show abnormalities in hepatic enzymes, aminoaciduria, low uric acid, and demineralization of bone. MRI scan usually shows decreased signal intensity (hypodensity) in the striatum and superior colliculi and increased signal intensity in the midbrain tegmentum (except for red nucleus) and in the lateral SNr, giving the appearance of “face of the giant panda” on T2-weighted images. Low serum ceruloplasmin, elevated 24-hour copper excretion, and the presence of Kayser-Fleischer rings are useful in making the diagnosis, but confirmation by demonstrating elevated hepatic copper is occasionally required in ambiguous cases.

Pathology Gross inspection of the brain often reveals cerebral atrophy and shrunken discolored putamen and GP. Microscopically, WD brains show both preferential striatal and generalized neuronal loss. There is diffuse gliosis with Alzheimer types I and II astrocytes, as well as Opalski cells, cells of microglial origin.

Pathogenesis The mutated ATP7B gene on chromosome 13 regulates a copper-transporting adenosine triphosphatase. Although the neurological disorder clearly relates to harmful effects of intracellular copper, the precise mechanisms of cell dysfunction and death are not well understood.

Treatment The goal of treatment of WD is to reduce the body burden of copper and to prevent its reaccumulation (Aggarwal and Bhatt, 2018). Traditionally, acute chelation began with d-penicillamine, but more recent treatment strategies stress somewhat less toxic therapies such as trientine and zinc or ammonium tetrathiomolybdate. The effectiveness of initial de-coppering is monitored by serially measuring urine copper excretion and plasma copper levels. Although there may be an acute deterioration associated with the mobilization of copper stores, most patients improve over time. Long-term therapy must be maintained, usually with trientine and zinc. d-Penicillamine is associated with a number of systemic toxicities including dermatopathy, neuromuscular junction disorders, thrombocytopenia, and Goodpasture syndrome. Ammonium tetrathiomolybdate (WTX101), which offers potential advantages over zinc, penicillamine, and trientine in that it blocks copper absorption and forms complexes with copper in the blood, is emerging as the most effective and safest treatment of WD, but this drug is still considered experimental. Asymptomatic siblings should be tested for the disease because timely treatment prevents the

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illness. Orthotopic liver transplantation is curative but has been used largely in patients with fulminant hepatic failure who have not yet developed significant neurological signs. The response of neurological symptoms to liver transplantation is not completely understood.

Neurodegeneration with Brain Iron Accumulation Neurodegeneration with brain iron accumulation (NBIA), formerly known as Hallervorden-Spatz disease, includes pantothenate kinase-associated neurodegeneration (PKAN) and a variety of other genetic neurodegenerative disorders associated with accumulation of iron in the brain, particularly the basal ganglia (Dusek et al., 2012; Hayflick et al., 2018). PKAN is an autosomal recessive neurodegenerative disorder presenting in childhood with the insidious onset of dystonia and gait disorder. Rigidity, dysarthria, spasticity, dementia, retinitis pigmentosa, and optic atrophy develop and progress relentlessly until death in early childhood. T2-weighted MRI brain scans show areas of reduced attenuation in the GP surrounding an area of hyperintensity, the eye of the tiger sign (McNeill et al., 2008). Autopsy studies show a brown discoloration of the GPi and SNr, reflecting pathological accumulation of iron. Microscopic changes include neuronal loss, gliosis, loss of myelinated fibers, and axonal swellings (spheroids). Families with typical PKAN have mutations in the pantothenate kinase gene (PANK2) on chromosome 20. Pantothenate kinase is an important regulatory enzyme in coenzyme A synthesis. Aceruloplasminemia, characterized by anemia, iron overload, diabetes, and neurodegeneration caused by homozygous mutation of the ceruloplasmin gene, may be associated with dystonia and akinetic-rigid syndrome. The four subtypes of NBIA—PKAN, neuroferritinopathy, infantile neuroaxonal dystrophy (INAD), and aceruloplasminemia—can be differentiated by gradient echo (T2*) and fast-spin echo (FSE) MRI (McNeill et al., 2008). Another subtype of NBIA, PLA2G6-associated neurodegeneration (PLAN), is manifested by early childhood-onset axial hypotonia, spasticity, bulbar dysfunction, ataxia, and dystonia. Previously diagnosed as INAD, NBIA2, or Karak syndrome, PLAN may also present as adult-onset LD-responsive dystonia-parkinsonism without iron on brain imaging. The PLA2G6 gene on chromosome 22q13.1 encodes a calcium-independent phospholipase A2 enzyme that catalyzes the hydrolysis of glycerophospholipids. Iron chelation with deferiprone and fosmetpantotenate, a phosphopantothenic acid prodrug which aims to replenish phosphopantothenic acid have been reported to result in regression of symptoms after several months of treatment. Another form of NBIA, mitochondrial membrane protein-associated neurodegeneration (MPAN). may present as juvenile-onset LD-responsive parkinsonism as well as progressive dystonia-parkinsonism, optic atrophy, and axonal motor neuronopathy (Gregory et al., 2019).

Post-traumatic Dystonia and Peripherally Induced Movement Disorders Dystonia resulting from central trauma most often presents as hemidystonia, but cervical, segmental, or axial dystonia can also be seen as sequelae of brain or spinal cord trauma. Most cases of post-traumatic dystonia occurred in children or adolescents who have survived severe head injury. Often the dystonia emerges as a traumatic hemiparesis and later improves or resolves. There may be a latent period between the trauma and development of the dystonia from 1 day to 6 years, followed by slow progression of dystonic symptoms. Younger patients tend to have longer latencies than those who are older at the time of the head injury. Focal lesions in the caudate, putamen, or thalamus contralateral to the affected side are usually found on neuroimaging studies. Lesions of the mesencephalon or dentatothalamic pathways have also been found. The prognosis of this form of post-traumatic dystonia is poor, with a low rate

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CHAPTER 96 Parkinson Disease and Other Movement Disorders of spontaneous improvement. Most cases are refractory to medical therapy, although some may respond to anticholinergic drugs. Botulinum toxin injections may be helpful in the treatment of focal or segmental dystonia. DBS may also provide some benefit, although the magnitude of response is much less than that seen in patients with primary dystonia. Although still somewhat controversial, there is growing evidence that dystonia may also occur after peripheral injury (Jankovic, 2009b). For example, oromandibular dystonia may follow dental surgery or facial and jaw trauma. Indeed edentulous dyskinesia, usually an orolingual stereotypy or dystonia occurring after loss of teeth, may be considered a classic example of peripherally induced movement disorder. Limb dystonia has also been reported to occur after peripheral trauma, often in the context of a work- or sports-related injury, especially after immobilization as a result of casting (Pirio Richardson et al., 2017). Peripherally induced dystonia tends to manifest with a fixed rather than mobile dystonia and may be associated with complex regional pain syndrome, also known as causalgia or reflex sympathetic dystrophy (Jankovic, 2009b; van Rooijen et al., 2011). The response of this condition to medical or other therapies is disappointing.

Paroxysmal Movement Disorders Paroxysmal movement disorders consist of intermittent movements that are now classified both clinically and genetically (Erro and Bhatia, 2019; Waln and Jankovic, 2015) (see also Chapter 24). Paroxysmal kinesigenic dyskinesia (PKD) is a disorder of childhood onset characterized by attacks of involuntary movements that include prominent dystonia, chorea, and other hyperkinesias. Because the attacks are often not witnessed and therefore appropriate phenomenological categorization is not possible, the less specific term, paroxysmal dyskinesia, is preferred. Boys make up 80% of cases. There is often a family history. Patients typically recount that episodes are triggered by rapid movement, often in response to an unexpected stimulus such as the telephone ringing. There may be a premonitory sensation in an affected limb, such as limb paresthesia before the onset of the abnormal involuntary movement. The movements may be unilateral or bilateral. The spells last less than 1 minute and occur up to 100 times daily. There is a tendency for spells to decrease in adulthood. Diagnosis depends on careful history taking; because the examination usually shows no abnormalities, typical spells may not be elicited in the examination setting, and neuroimaging and electrophysiological studies are usually normal. Paroxysmal nonkinesigenic dyskinesia (PNKD) usually begins in infancy and affects boys more than girls. The spells of PNKD occur less often but are more prolonged than those in PKD. Their frequency ranges from several episodes a month to several episodes a day, and their duration is generally between 10 minutes and several hours. They are not precipitated by action but may be triggered by ethanol, caffeine, fatigue, or stress. Unlike PKD, PNKD does not show a dramatic response to anticonvulsants. Some patients respond to clonazepam, other benzodiazepines, carbamazepine, gabapentin, anticholinergics, LD, acetazolamide, and neuroleptics. Mutations in many genes, such as PRRT2, MR-1, SCL2A1, SLC16A2, GLUT1, KNCMA1, SCN8, ECHS1, CACNA1A, ADCY5, and ATP1A3 have been identified to cause paroxysmal dyskinesia (Erro and Bhatia, 2019). Secondary paroxysmal dyskinesia has been thought to be quite rare (Waln and Jankovic, 2015). However, in one series, 26% of paroxysmal dyskinesia cases occurred in the context of another nervous system disease. Underlying etiologies include cerebrovascular disease, trauma, infection, and metabolic encephalopathy. The clinical manifestations of secondary paroxysmal dyskinesia are heterogeneous. Some are kinesigenic and some are not. Some are associated with premonitory sensations; others have no warning signs. Treatment of the underlying cause may improve the dyskinesia.

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TICS Tourette Syndrome Clinical Features The most common cause of childhood-onset tics is Tourette syndrome (TS), a complex neurological disorder, manifested not only by motor and phonic tics but also by many behavioral comorbidities, particularly attention-deficit and obsessive-compulsive disorders (Robertson et al., 2017; Thenganatt and Jankovic, 2016). The diagnosis of TS rests entirely on the history and physical examination. There is no diagnostic test for TS, but according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) (American Psychiatric Association, 2013) the following are criteria for the diagnosis of TS (refer to Box 24.8 for full DSM-5 diagnostic criteria): A. Both multiple motor and one or more vocal tics are present at some time during the illness, although not necessarily concurrently. B. The tics may wax or wane in frequency but have persisted for more than 1 year since first tic onset. C. Onset is before age 18 years. D. The disturbance is not attributable to the physiological effects of a substance (e.g., cocaine) or a general medical condition (e.g., HD, postviral encephalitis). Prevalence estimates for TS vary from 10 to 700 per 100,000, depending on the population studied and the study methods used. Meta-analysis of 21 studies yielded a prevalence of TS at 0.52% (Scharf et al., 2015). Although the prevalence of tics is greater among children in special schools and those with disorders in the autism spectrum, the vast majority of patients with TS have normal intelligence. Typical early signs of TS are motor tics, including eye blinks, facial grimacing, head jerks, shoulder shrugs, and a variety of limb and trunk movements (see Chapter 24). Phonic tics include sniffing, throat clearing, grunting, whistling, chirping, and words—including verbal obscenities (coprolalia) and obscene gestures (copropraxia). Over time, the tics wax and wane, and new tics emerge as other tics resolve. Tics may be simple or complex and can resemble any voluntary or involuntary movement. Tics are often preceded by regional or generalized premonitory feelings, such as an urge to move, increased tension, a compulsive need to move or make sound, and other sensations. These premonitory phenomena differentiate tics from other jerk-like movements such as myoclonus and chorea and highlight the sensory aspects of movement disorders (Patel et al., 2014). Symptoms tend to increase throughout childhood, typically peaking just prior to puberty and spontaneously subsiding after the age of 18 years. Behavioral changes are very common in TS, especially attention-deficit/hyperactivity disorder, obsessive-compulsive disorder, impulse control disorders, and a variety of conduct disorders. In one study involving 1374 patients with TS, 72.1% met the criteria for attention-deficit/hyperactivity disorder, obsessive-compulsive disorder (Hirschtritt et al., 2015).

Pathogenesis Although TS is clearly a biological genetic disorder, no causative gene or genes have been identified, although several susceptibility genes have been found through various genetic techniques, including genome-wide association studies (Deng et al., 2012; Yu et al., 2015). Possible reasons for the absence of reported causative genes include lack of specific diagnostic criteria, clinical and genetic heterogeneity, and bilineal transmission (inherited from both parents). Because there is a robust response to dopamine receptor–blocking medications, altered central neurotransmission has been proposed to underlie TS. PET studies, however, have failed to provide

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evidence of dopaminergic hyperactivity in TS. One PET study, using [11C]-flumazenil, and structural MRI provided evidence of decreased binding of GABAa receptors in TS patients bilaterally in the ventral striatum, GP, thalamus, amygdala, and right insula and increased binding in the bilateral SN, left periaqueductal gray, right posterior cingulate cortex, and bilateral cerebellum (Lerner et al., 2012). This suggests that the GABAergic system plays an important role in TS and provides evidence that TS represents a “disinhibition” disorder. Adult-onset tics usually represent recurrences of childhood tics or may be present in the setting of cocaine use or with exposure to other CNS stimulants, dopamine receptor blockers (tardive tics), and in association with neuroacanthocytosis. Rarely, movement disorders resembling tics may be of psychogenic (functional) origin (BaizabalCarvallo and Jankovic, 2014).

Treatment Treatment of TS must be individualized and should be reserved for patients who are experiencing interference from tics in the educational, social, or family spheres (Billnitzer and Jankovic, 2020) (Fig. 96.17).

Disabling tics are most effectively suppressed by dopamine-receptor blocking drugs such as fluphenazine (Wijemanne et al., 2014), and dopamine-depleting drugs such as tetrabenazine, deutetrabenazine, and valbenazine (Jankovic, 2016b, 2020). But many other drugs have been reported to be effective in treating tics, such as cannabinoids, nicotine, ondansetron, and ecopipam, a D1 receptor antagonist (Gilbert and Jankovic, 2014; Jankovic, 2015c). Obsessive-compulsive disorder responds to selective serotonin reuptake inhibitors. Comorbid ADHD can be safely treated with clonidine, methylphenidate, and other CNS stimulants. Guanfacine and clonidine have been found useful in patients with TS and impulse-control problems. Patients with disabling tics (with or without obsessive-compulsive disorder) may benefit from DBS of the thalamus or GPi (Martinez-Ramirez et al., 2018; Viswanathan et al., 2012). The American Academy of Neurology Practice Guideline made 46 recommendations regarding the assessment and management of TS, including treatment options such as Comprehensive Behavioral Intervention for Tics, antidopaminergic and other medications, botulinum toxin injections for focal motor and phonic tics, and DBS (Pringsheim et al., 2019).

Treatment algorithm for Tourette syndrome Motor and phonic tics

Assess for behavioral comorbidities (ADHD, OCD, etc.)

1. Characterize motor and phonic tics (clonic, dystonic, tonic, stereotypic, compulsive, blocking; premonitory urges, variability, suggestibility, suppressibility, persist during sleep) 2. Explore behavioral comorbidities (ADHD, OCD, etc.) 3. Explain neurobiological, neurophysiological, genetic basis 4. Discuss waxing and waning course, prognosis 5. Discuss treatment options and strategies (behavioral vs. pharmacological/surgical)

Educate the patient, family, teachers, classmates, etc.

Are symptoms troublesome?

Yes

No

Tics

Periodic follow-up

Prioritize and customize Treat tics before ADHD

Comorbidities

CNS stimulants, SSRI,SNRI

1. Behavioral treatment (e.g. CBIT, HRT) 2. Pharmacotherapy i. Alpha2A agonists (guanfacine) ii. Dopamine depleters/blockers iii. Topiramate iv. Aripiprazole, fluphenazine, risperidone 3. BoNT 4. DBS in medically refractory cases

Experimental therapeutics Ecopipam – D1 antagonist AZD5312 – H3 antagonist SNC-102 – GABA-glutamate Cannabis products – dronabinol, nabiximols, ABX-1431, etc. Serine hydrolase, D-cycloserine, amantadine, pimavanserin

Fig. 96.17 Treatment Algorithm for Tourette Syndrome. ADHD. attention deficit hyperactivity disorder; CBIT, comprehensive behavioral intervention for tics; CNS, Central nervous system; DBS, deep brain stimulation; GABA, γ-aminobutyric acid; HRT, habit reversal training; OCD, obsessive compulsive disorder; SNc, substantia nigra pars compacta; SNRI, selective noradrenergic reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor. F ECF

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CHAPTER 96 Parkinson Disease and Other Movement Disorders

MYOCLONUS Essential Myoclonus EM is diagnosed when myoclonus is present as an isolated neurological sign or is accompanied only by tremor or dystonia. EM can be sporadic or inherited. Dominantly inherited EM usually presents before age 20. EM is usually multifocal with upper body predominance. Although spontaneous jerks are seen, they are exacerbated by action. Alcohol may dramatically suppress the myoclonus. Sporadic forms of this illness are also described. Myoclonus-dystonia and EM are allelic disorders linked to the ε-sarcoglycan gene on chromosome 7. Besides DYT-SGCE (DYT11), other genetic forms of myoclonus-dystonia include GCH1 (DYT5a), DYT/PARK-TH (DYT5b), DYT-KCTD17 (DYT26) (see Chapter 24).

Posthypoxic Myoclonus (Lance-Adams Syndrome) The first cases of posthypoxic myoclonus (PHM) were described in 1963 by Lance and Adams (Jankovic, 2015c). PHM is a generalized myoclonus that occurs with recovery from the acute effects of severe brain hypoxia. The most common etiologies of the hypoxia are respiratory arrest (especially asthmatic), anesthetic and surgical accidents, cardiac disease, and drug overdose. The typical patient is in coma for several days to 2 weeks. Myoclonus and seizures may be present during the comatose phase. After recovery from coma, myoclonic jerks become apparent, especially with voluntary movements, which trigger volleys of high-amplitude jerks and intermittent pauses in the activated body part. The myoclonic movements typically flow to body parts not directly involved in the voluntary movements. The amplitude of the myoclonus is directly proportional to the delicacy of the attempted task, producing extreme disability in the performance of activities of daily living. Gait is disturbed not only by positive myoclonic jerks but also by negative myoclonus, resulting in falls. Other neurological signs are always present and include seizures, dysarthria, dysmetria, ataxia, and cognitive impairment. CSF studies have shown low levels of 5-hydroxyindoleacetic acid (5-HIAA), the main metabolite of serotonin. A role for GABA in this disorder is suggested by the production of myoclonus by injecting GABA antagonists into the rat thalamus. Autopsies in patients with PHM show changes related to hypoxic brain damage but do not reveal any specific structural changes in brainstem raphe nuclei. Myoclonus in posthypoxic rats responds to serotonin agonists that stimulate particular subtypes of serotonin receptors (5-HT1B, 5-HT2A/2B, and possibly 5-HT1D). Other studies in rat models have suggested that basal serotonin levels are normal, but there is an abnormality in release of serotonin by potassium chloride and NMDA. There is some tendency for improvement in myoclonus over time, but most patients have significant disability related to the movements. GABAergic drugs such as valproic acid and clonazepam are usually used in the treatment of PHM. Each is associated with improvement in approximately 50% of treated patients. Levetiracetam has been reported to be effective in some patients, but other GABAergic drugs such as vigabatrin and gabapentin are usually not helpful (Jankovic, 2015c). Piracetam, available in Europe and Canada but not in the United States, may also improve myoclonus by an imperfectly understood mechanism that does not involve serotonin or GABA. L-5 hydroxytryptophan (L-5HTP) administered with carbidopa may be useful, but this investigational agent is no longer available, and gastrointestinal side effects limit its tolerability.

Startle and Hyperekplexia Hyperekplexia is a startle syndrome characterized by muscle jerks in response to unexpected stimuli. Families with autosomal dominant

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and recessive inheritance have been described. Two forms of startle have been described. The major form of the illness is characterized by continuous stiffness beginning in infancy and exaggerated startle culminating in falls. Some patients have seizures and low intelligence. In the minor form, there is only excessive startle with hypnic myoclonic jerks. The hereditary form is typically caused by mutations in the gene coding for the α1 subunit of the inhibitory glycine receptor (GLRA1) on chromosome 5. The disorder is also caused by mutations in the β subunit of the inhibitory glycine receptor (GLRB), by mutations in the gephyrin gene (GPHN), and by mutations in SLC6A5, which encodes the presynaptic glycine transporter 2. The SLC6A5 mutations are predominately associated with recessive hyperekplexia, symptoms of which include life-threatening neonatal apnea and breath-holding spells. Startle in patients with hyperekplexia differs from normal startle because it has a lower threshold, is more generalized, and fails to normally habituate with repeated stimuli. Electrophysiological studies in well-characterized cases suggest the origin of the pathological startle in the lower brainstem, possibly the medial bulbopontine reticular formation. The disorder is genetically heterogeneous, with most mutations occurring in patients with the major form of the illness. Symptomatic hyperekplexia has been reported to result from infarct, hemorrhage, or encephalitis. Clonazepam is the treatment of choice, although it may be only partially effective.

Palatal Myoclonus Palatal myoclonus, sometimes also referred to as palatal tremor, is characterized by rhythmic movements of the soft palate. Since the movement consists of repetitive rather than oscillatory contractions of agonists only, it is also classified as segmental myoclonus rather than tremor. There are two types of PM, depending on the presence or absence of a structural lesion of the brainstem or cerebellum. Patients without an underlying structural lesion are considered to have essential PM, and those with underlying structural lesions are considered to have symptomatic PM. Essential and symptomatic PM can be distinguished by clinical features and neuroimaging. Essential PM is very rare. It affects men and women equally. Patients with essential PM complain of audible ear clicks. The movements usually disappear during sleep. In essential PM, the palatal movements are produced by rhythmic movement of the tensor veli palatini muscle. Symptomatic PM is more common than essential PM and affects men more often than women. Symptomatic or secondary PM is not associated with ear clicks because the levator veli palatini rather than the tensor veli palatini is involved. Simultaneous tremor of other regional structures with cranial nerve innervation may be seen. Some patients have oscillopsia from pendular nystagmus. Laryngeal involvement may interrupt speech or cause rhythmic involuntary vocalizations. Rhythmic limb tremor may be seen. In patients with symptomatic PM, hypertrophy of the superior olive is demonstrable on MRI brain scans. Symptomatic PM may be associated with slow rhythmic movement in the face and limbs, called myorhythmia, and is often associated with structural lesions found in the brainstem or cerebellum within the Guillain-Mollaret triangle, which connects the dentate nucleus with the contralateral red nucleus and inferior olive (Baizabal-Carvallo et al., 2015). Many underlying etiologies have been reported: neurodegenerative, infectious, inflammatory, demyelinating, traumatic, ischemic, and even psychogenic. Characteristic pathological changes include enlargement of olivary neurons with vacuolation of the cytoplasm. Astrocytic proliferation with aggregates of argyrophilic fibers may also be seen. The pathophysiology of PM is incompletely understood, but it is believed that in symptomatic PM, damage to the dentato-olivary tract

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BOX 96.5

Myoclonus

Neurological Diseases and Their Treatment

Drugs Associated with

Anesthetics: etomidate, chloralose Antibiotics, anthelmintics, antiviral drugs: penicillin, imipenem, quinolones, piperazine, acyclovir Anticonvulsants: phenytoin, phenobarbital, primidone, valproic acid, carbamazepine, gabapentin, lamotrigine, vigabatrin Amantadine Antihistamines Sodium bicarbonate (baking soda) Benzodiazepine withdrawal Psychotropic medications: tricyclic antidepressants, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, lithium, buspirone, neuroleptics Antineoplastic drugs: chlorambucil, prednimustine, ifosfamide Narcotics: morphine, meperidine, hydromorphone, fentanyl, sufentanil, diamorphine

induces synchronization of cells in the inferior olive. The firing rhythm appears to be determined by membrane properties of the olivary neurons. This rhythm is then propagated through the inferior cerebellar peduncle to the contralateral cerebellar hemisphere, where it interferes with oculomotor, cerebelloreticular, and cerebellospinal systems. Treatment of PM is difficult. Because of the rarity of the condition, there have been no randomized controlled clinical trials of therapeutic agents. Phenytoin, carbamazepine, clonazepam, diazepam, trihexyphenidyl, and baclofen are considered first-line agents in the treatment of PM. Second-line drugs include 5-HTP and presynaptic antidopaminergic drugs such as tetrabenazine. Sumatriptan has been reported to aid a single patient. Injections of botulinum toxin into the tensor veli palatini muscle have been reported beneficial in essential PM.

Spinal Myoclonus Spinal myoclonus is a syndrome of involuntary rhythmic or semirhythmic myoclonic jerks in a muscle or group of muscles. The myoclonic jerks may be unilateral or bilateral. In some cases, they are stimulus sensitive. The jerks relate to spontaneous motoneuron discharge in a limited area, often a single segment of the spinal cord. Propriospinal myoclonus is a more widespread disorder in which myoclonic jerks are propagated up and down the spinal cord from a central generator. Most patients with propriospinal myoclonus have had minor spinal cord trauma with normal MRI findings, but the disorder has been reported in severe spinal cord injury, multiple sclerosis, human immunodeficiency virus, Lyme infection, syringomyelia, spinal cord tumors, and spinal cord infarction. Propriospinal myoclonus has been reported to affect particularly the transition from wake to sleep. An increasing number of cases of propriospinal myoclonus have been documented to be of psychogenic origin.

Toxin- and Drug-Induced Myoclonus A number of drugs and environmental agents with CNS toxicity have been shown to cause myoclonus (Box 96.5). Criteria for drugor toxin-induced myoclonus include verified exposure, temporal association, and exclusion of genetic or other causes. The myoclonus produced by drugs and toxins is often multifocal or generalized, stimulus- and action- or stimulus-sensitive, and accompanied by other suggestive nervous system signs, particularly by encephalopathic signs. Metrizamide and diclofenac may cause segmental myoclonus.

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Treatment requires withdrawal of the causative drug and symptomatic treatment, if required, with clonazepam or levetiracetam. There are many other causes of myoclonus, but autoimmune disorders, such as opsoclonus-myoclonus, NMDAR encephalitis, progressive encephalomyelitis with rigidity and myoclonus, and Hashimoto encephalopathy should be considered, particularly when the onset is subacute (Baizabal-Carvallo and Jankovic, 2018).

TARDIVE DYSKINESIA Classic Tardive Stereotypy TD is a movement disorder that develops in the context of chronic dopamine receptor blockade, usually in patients who are chronically treated with antipsychotics or antiemetics (Savitt and Jankovic, 2018). With the decline in the use of typical antipsychotics and metoclopramide and introduction of atypical antipsychotics there has been a slight decline in the incidence of TD. TD usually requires a minimum of 6 weeks or more of dopamine receptor blockade, but onset as soon as after the first dose has been reported. Reported risk factors include old age, female gender, affective disorder, edentulousness, diabetes mellitus, and prior CNS injury. Although orofacial stereotypy is the most common hyperkinetic movement disorder associated with TD, other hyperkinetic disorders such as chorea, akathisia, dystonia, tics, and myoclonus may be seen. Tardive parkinsonism has also been reported, but some patients with parkinsonism persisting years after withdrawal of the offending neuroleptic have been found to have pathological evidence of PD. The classic appearance of TD is repetitive stereotypic (e.g., chewing) movements of the mouth, tongue, and lower face (oral-buccolingual dyskinesias) (Savitt and Jankovic, 2018). In contrast to HD, the upper face tends to be spared (see Chapter 24) (Jankovic and Roos, 2014). Choreic movements may also affect the trunk and pelvis, causing pelvic thrusting movement and respiratory dyskinesia (Mehanna and Jankovic, 2010). Limb chorea and restlessness (akathisia) may also be seen. The pathophysiology of TD is incompletely understood, but the drugs that cause this syndrome appear to exhibit potent binding to postsynaptic D2 receptors (Savitt and Jankovic, 2018). Denervation supersensitivity of the postsynaptic dopamine receptor has been proposed as a possible mechanism. There are other theories, including oxidative stress and insufficiency of GABA. Evidence is accumulating that suggests that neuroleptics are toxic to the striatum, and apoptotic cell death has been described in animals chronically exposed to neuroleptics. Genetic susceptibility factors that might be involved in increased risk of TD include polymorphisms of the dopamine D3 receptor gene and the 5-HT2C serotonin receptor gene. The most important intervention in TD is to prevent its occurrence. In prospective studies, high-risk individuals treated with atypical rather than typical antipsychotics appear to have a reduced risk of TD compared with historical controls. Because patients may not complain about early or mild movements, the clinician must carefully examine neuroleptic-treated patients for early signs of TD. Neuroleptics should be discontinued if possible. Mild TD may improve with benzodiazepines or baclofen. Deutetrabenazine and valbenazine, dopamine-depleting drugs (VMAT2 inhibitors), have been approved by the US FDA for the treatment of TD (Bashir and Jankovic, 2020; Savitt and Jankovic, 2018).

Tardive Dystonia Tardive dystonia should be differentiated from transient acute dystonic reaction and from the more typical TD. In contrast to TD, which tends to affect more elderly women, young men are more likely to develop tardive dystonia. All of the typical antipsychotics,

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CHAPTER 96 Parkinson Disease and Other Movement Disorders as well as antiemetics with dopamine receptor-blocking properties, have been associated with the development of tardive dystonia (Savitt and Jankovic, 2018). Symptoms begin insidiously after days to decades of neuroleptic therapy. Although rare cases have been reported after a short duration of therapy, the median duration of exposure to neuroleptics at the time of onset is 5.1 years. Tardive dystonia usually presents as focal or segmental dystonia (e.g., blepharospasm) or oromandibular or cervical dystonia, but the most typical presentation is a truncal dystonia with opisthotonic posturing in a young man associated with pronating movements of arms and extension of the elbows. There is a relationship between age at onset and distribution of the dystonic movements, with trunk and leg symptoms in younger persons and face, jaw, and neck involvement in older persons. In comparison with primary focal or segmental dystonia, there is more retrocollis and anterocollis. Dystonic symptoms may improve over a period of 5 years if the offending neuroleptic agent is withdrawn, although recovery is less common than in patients with choreic or stereotypic TD. Young patients with a shorter duration of neuroleptic exposure have the greatest likelihood of remission. As with TD, the primary treatment of tardive dystonia is prevention, but once it has developed, every attempt should be made to rid the patient of the offending neuroleptic. Neuroleptic-dependent patients should be managed with atypical antipsychotics if possible. VMAT2 inhibitors, anticholinergics, benzodiazepines, and baclofen have all been reported to help patients with tardive dystonia. Botulinum toxin injections can be particularly helpful in patients with disabling focal or segmental dystonia such as blepharospasm or cervical and truncal dystonic movements (Jankovic, 2018b). Oral and intrathecal baclofen infusions may also be helpful.

STEREOTYPIES Stereotypies are involuntary or unvoluntary (in response to or induced by inner sensory stimulus or unwanted feeling), coordinated, patterned, repetitive, rhythmic, seemingly purposeless movements or utterances. Stereotypies can be seen in a variety of conditions, such as TD, but when they occur in children they are often seen in the setting of autism or intellectual impairment (Oakley et al., 2015). In this situation typical motor stereotypies include body rocking, head nodding, head banging, hand waving, fluttering of fingers in front of the face, repetitive and sequential finger movements, lip smacking, pacing, skin picking, and various self-injurious behaviors such as biting, scratching, and hitting. Although TD is one the most common causes of adult-onset stereotypies, there are many other causes of coordinated, repetitive movements. One of the most common causes of repetitive movements is the “leg stereotypy syndrome” (Lotia et al., 2018), This is defined as a repetitive, continuous movement present almost exclusively in the legs while the patient is seated. The characteristic features of leg stereotypy disorder include continuous or intermittent flexion– extension, abduction–adduction, movement of proximal legs when seated with feet resting on the floor or flexion–extension of the knees or ankles when legs are crossed in a sitting position. When standing there is often swaying movement of the trunk and shifting of weights from one to the other. Leg stereotypy syndrome must be differentiated from other sensorymotor disorders, such as RLS. Although both conditions are familial the latter is characterized by diurnal pattern, is worse at night, and is associated with unpleasant sensations such as “crawling,” “tingling,” “creeping,” “pulling,” “electric,” “itching,” “burning,” “prickly,” and other sensory phenomenon (Patel

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et al., 2014). Also, in contrast to leg stereotypy syndrome, RLS often requires treatment with medications such as gabapentin, DAs, or even opiates (Wijemanne and Jankovic, 2015).

MISCELLANEOUS MOVEMENT DISORDERS Hemifacial Spasm The prevalence of HFS is 14.5 per 100,000 in women and 7.4 per 100,000 in men, but the prevalence seems to be much higher in Asian populations (Wu et al., 2010; Yaltho and Jankovic, 2011). HFS is characterized by twitching of the muscles supplied by the facial nerve. The disorder usually begins in adulthood, with an average age at onset of 45–52 years. Although there are some familial cases, most are sporadic. In typical cases, twitching first affects the periorbital muscles but spreads to other ipsilateral facial muscles over a period of months to years. The spasms are synchronous in all affected muscles. In approximately 5% of patients, the opposite side of the face becomes affected, but when bilateral, the spasms are never synchronous on the two sides. The spasms of HFS may be clonic or tonic, and often a paroxysm of clonic movements culminates in a sustained tonic contraction. Although the spasms occur spontaneously, they may be precipitated or exacerbated by facial movements or by anxiety, stress, or fatigue. The affected muscles may be weaker than their contralateral counterparts. Some patients have evidence of regional cranial neuropathy, such as altered hearing or trigeminal function. Detailed neuroradiological work-ups using routine and specialized MRI techniques may demonstrate compressing vascular structures in the facial nerve root entry zone in most patients with HFS. More advanced scanning techniques such as high-resolution T1- and T2-weighted spin echo or gradient echo imaging with gadolinium provide maximum visualization of the root entry zone. Yet, serious underlying causes are rare, and many clinicians do not routinely image patients with typical HFS unless the clinical picture is atypical or the patient is being considered for surgery. HFS is an example of peripherallyinduced movement disorder, thought to result from compression of the facial nerve at the root exit zone, usually by vascular structures (Yaltho and Jankovic, 2011). The facial nerve root entry zone generally shows axonal demyelination or nerve degeneration. Vessels commonly implicated are the posterior inferior cerebellar artery, the anterior inferior cerebellar artery, and the vertebral artery. Tumors or other space-occupying lesions are found in approximately 5% of patients. Epidermoid tumors, neuroma, meningioma, astrocytoma, and parotid tumors are most common. There are two main theories of pathogenesis. The first proposes that in the area of compression-induced demyelination, an ephapse, or false synapse, forms. Mechanical irritation or other regional changes induce ectopic activity in the region, which is then conducted antidromically within the nerve fiber. The main competing theory proposes that the aberrant signals arise from the facial nerve nucleus, which is reorganized as a result of deranged afferent information. Traditionally, patients with HFS were treated with anticonvulsants, baclofen, anticholinergics, and clonazepam, but the introduction of botulinum toxin injections revolutionized treatment of the disorder. Botulinum toxin injected into the periorbital subcutaneous tissue produces clinically meaningful improvement in almost 100% of patients, and side effects are mild and transient. Botulinum toxin injections must be administered every 3–6 months. Follow-up of chronically treated patients shows the injections retain efficacy for at least 15 years.

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A number of surgical techniques have been used in HFS. These include removal of the orbicularis oris or other affected muscles, selective destruction of parts of the facial nerve, decompression of the facial canal, and radiofrequency thermocoagulation of the nerve. Intracranial microvascular decompression of the nerve is successful in relieving spasms in up to 90% of patients, but complications such as facial nerve injury and hearing loss occur in as many as 15% of patients.

Painful Legs–Moving Toes Syndrome PLMTS is a very rare condition characterized by pain in the legs and spontaneous movements of the foot and toes. The pain usually precedes the onset of involuntary movements and varies in constancy and intensity. In some cases, the condition is painless. The toe and foot movements are complex, combining flexion, extension, abduction, and adduction in various sequences at frequencies of 1–2 Hz. The movements may be precipitated or aborted by moving or repositioning the foot or toes, but they cannot be simulated voluntarily. Similar movements have been described in the arms, with or without accompanying pain. In most cases, there is an underlying cause, although there is little consistency from case to case. PLMTS has been associated with injuries to the spinal cord and cauda equina, spinal nerve roots, peripheral neuropathy, and soft-tissue or bony limb trauma. EMG studies show that the movements are produced by long bursts of normal motor unit firing with normal recruitment patterns. PLMTS doubtless has a central origin. Central reorganization consequent to altered afferent information from the periphery has been proposed, but a precise location and mechanism of these changes remain unknown. Treatment of PLMTS is very difficult. Many medications have been tried—baclofen, benzodiazepines, anticonvulsants, and antidepressants—but none has emerged as effective. Lumbar sympathetic block or epidural stimulation may give transient relief. Spontaneous resolution is very unusual.

Stiff Person Syndrome SPS is a rare autoimmune movement disorder, characterized by progressive rigidity of axial and proximal appendicular muscles, exaggerated lumbar lordosis, and a stiff gait (Baizabal-Carvallo and Jankovic, 2012, 2018). Intense spasms are superimposed on a background of continuous muscle contraction. Spasms and stiffness improve with sleep and are eliminated by general anesthesia and neuromuscular blocking agents. Clinical criteria for diagnosis include insidious development of limb and axial (thoracolumbar and abdominal) stiffness, clinical and electrophysiological confirmation of co-contraction of agonist and antagonist muscles, episodic spasms superimposed on chronic stiffness, and no other underlying illness that would explain the symptoms. Some authors divide SPS into three syndromes: stiff trunk syndrome, stiff limb syndrome, and rapidly progressive encephalomyelitis with rigidity. EMG examination shows continuous firing of normal motor units. SPS is associated with autoimmune disorders such as type 1 diabetes, thyroiditis, myasthenia gravis, pernicious anemia, and vitiligo. High titers of antibodies to the 65-kD fraction of GAD and to other antigens are present. It is thought that SPS results from dysfunction of descending suprasegmental pathways possibly secondary to immune-mediated inhibition of GABA synthesis. Paraneoplastic SPS has been reported with breast and other cancers.

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Untreated, SPS progresses to extreme disability. Diazepam at doses of 20–400 mg/day is the most effective symptomatic treatment. Clonazepam, baclofen, valproic acid, clonidine, vigabatrin, and tiagabine have also been reported to be effective. Intrathecal baclofen and local intramuscular injections of botulinum toxin have been helpful in some cases. Plasmapheresis, intravenous immunoglobulin (IVIG), and immunosuppression have been reported to have variable effects on the condition. In a recent placebo-controlled crossover study of IVIG, active treatment was associated with clinical improvement and decreases in anti-GAD antibody titers. Newer agents such as rituximab are currently under study for the treatment of SPS.

Functional (Psychogenic) Movement Disorders Functional movement disorders (FMDs), previously referred to as “psychogenic movement disorders,” represent about 5% of patients in a movement disorders clinic, but the relative frequency is increasing as patients with atypical movement disorders, many of whom have FMD, are referred to specialized centers (see Chapter 113). In many cases, the symptoms are abrupt in onset and associated with a specific trigger. Clinically, distractibility is common, as are stimulus sensitivity and entrainment with voluntary activities. Other functional (psychogenic) symptoms are often present. Approximately 25% of patients have a comorbid organic movement disorder. About half have an Axis 1 psychiatric disorder, most often depression. The predominant movement disorders diagnosed as psychogenic (functional) include tremor, often manifested by irregular, distractible shaking of variable amplitude and frequency, dystonia, typically manifested by fixed abnormal posture, myoclonus, parkinsonism (Jankovic, 2011), tics (Baizabal-Carvallo and Jankovic, 2014), and a variety of other movement disorders (Stone et al., 2016; Thenganatt and Jankovic, 2019). The pathophysiology of FMDs is poorly understood (BaizabalCarvallo et al., 2019). Although stressful events on a background of depression and anxiety are common precipitants of FMDs, this link is not always possible to establish in all patients. While usually attributed to some psychiatric causes, several neurobiological abnormalities differentiate patients with FMD from normal controls. These include evidence of strengthened connectivity between the limbic and motor networks, increased activation of areas implicated in self-awareness, self-monitoring, and active motor inhibition such as the cingulate and insular cortex, coupled with decreased activation of the SMA and pre-SMA. Furthermore, the sense of agency defined as the feeling of controlling external events through one’s own action also seems to be impaired in individuals with FMDs. Some studies have correlated a recall of real-life events with abnormalities on functional imaging studies suggesting that the chief mechanism of functional (psychogenic) disorders involves repression of memories and conversion to somatic symptoms (Aybek et al., 2014). Treatment of patients with functional (psychogenic movement disorders) is very challenging and requires tactful disclosure of the diagnosis, followed by insight-oriented and physical therapy, supplemented by treatment of underlying anxiety, depression, and other psychological and psychiatric issues (Thenganatt and Jankovic, 2019; see Chapter 113). The complete reference list is available online at https://expertconsult. inkling.com/.

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97 Disorders of Upper and Lower Motor Neurons Conor Fearon, Brian Murray, Hiroshi Mitsumoto

OUTLINE Disorders of Upper Motor Neurons, 1535 Neuroanatomy of Upper Motor Neurons, 1535 Signs and Symptoms of Upper Motor Neuron Involvement, 1536 Laboratory Evidence of Upper Motor Neuron Involvement, 1537 Primary Lateral Sclerosis, 1537 Hereditary Spastic Paraplegia, 1538 Human T-Lymphotropic Virus Type 1-Associated Myelopathy, or Tropical Spastic Paraparesis, 1543 Human T-Lymphotropic Virus Type 2-Associated Myelopathy, 1543 Adrenomyeloneuropathy, 1543 Plant Excitotoxins, 1544 Disorders of Lower Motor Neurons, 1544 Neuroanatomy of Lower Motor Neurons, 1544 Clinical Features of Lower Motor Neuron Involvement, 1544 Laboratory Evidence of Lower Motor Neuron Involvement, 1545 Acute Poliomyelitis and Other Viral Acute Flaccid Paralyses, 1545 Postpolio Syndrome/Progressive Postpoliomyelitis Muscular Atrophy, 1547 Multifocal Motor Neuropathy, 1548

Benign Focal Amyotrophy, 1548 Spinal Muscular Atrophy, 1549 Kennedy Disease (X-Linked Recessive Bulbospinal Neuronopathy), 1553 Progressive Muscular Atrophy, 1554 Subacute Motor Neuronopathy in Lymphoproliferative Disorders, 1555 Postirradiation Lower Motor Neuron Syndrome, 1556 Disorders of Both Upper and Lower Motor Neurons, 1556 Amyotrophic Lateral Sclerosis, 1556 Familial Amyotrophic Lateral Sclerosis, 1564 Amyotrophic Lateral Sclerosis–Parkinsonism-Dementia Complex (Western Pacific Amyotrophic Lateral Sclerosis), 1566 Spinocerebellar Ataxia Type 3 (Machado-Joseph Disease), 1566 Adult Hexosaminidase-A Deficiency, 1566 Allgrove Syndrome (Four-A Syndrome), 1567 Adult Polyglucosan Body Disease, 1567 Paraneoplastic Motor Neuron Disease, 1567 Human Immunodeficiency Virus Type 1-Associated Motor Neuron Disorder, 1567

It is important for the practicing clinician to make the distinction between the term motor neuron disease (MND) and motor neuron diseases (MNDs). The intention of the first term, coined by Brain in 1969, is to refer to a specific disorder of both upper and lower motor neurons, otherwise known as amyotrophic lateral sclerosis (ALS). The second term refers to the broader family of disorders that may affect the upper and/or lower motor neuron system as well as nonmotor systems. Within this heterogeneous family are included familial and sporadic disorders, inflammatory and immune disorders, and others of undetermined cause. Many are distinct entities, but some (e.g., primary lateral sclerosis [PLS], progressive muscular atrophy [PMA]) may be variations of a single multisystem disorder that predominantly involves motor neurons. This chapter reviews the causes, diagnosis, and treatment of the motor neuron diseases according to whether the disorder affects upper motor neurons (UMNs), lower motor neurons (LMNs), or both UMNs and LMNs.

innervate skeletal muscles. The UMNs are rostral to the LMNs and exert direct or indirect supranuclear control over the LMNs (Box 97.1).

DISORDERS OF UPPER MOTOR NEURONS Neuroanatomy of Upper Motor Neurons The UMN is a motor neuron, the cell body of which lies within the motor cortex of the cerebrum, and the axon of which forms the corticobulbar and corticospinal tracts. The LMNs, lying in the brainstem motor nuclei and the anterior horns of the spinal cord, directly

Motor Cortex In the cerebral cortex, UMNs are located in the primary motor cortex (Brodmann area 4) and the premotor areas (Brodmann area 6), which are subdivided into the supplementary motor area (sometimes called the secondary motor cortex) and the premotor cortex, respectively. Betz cells (giant pyramidal neurons) are a distinct group of large motor neurons in layer 5 of the primary motor cortex and represent only a small portion of all primary motor neurons with axons in the corticospinal tracts. Individual motor neurons in the primary motor cortex initiate and control the contraction of small groups of skeletal muscles subserving individual movements. The entire motor area of the cerebral cortex controls the highest levels of voluntary muscle movement, including motor planning and programming of muscle movement. Corticospinal and corticobulbar tracts. Axons from the motor areas form the corticospinal and corticobulbar tracts. Axons arising from neurons in the primary motor cortex constitute only one-third of all the corticospinal and corticobulbar tracts. Among these, Betz cell axons make up 3%–5% of the tract, and the remaining fibers from the primary motor cortex arise from other neurons in layer 5 of the primary motor cortex. Another one-third of the axons in these tracts derive from Brodmann area 6, which includes the supplementary motor and

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the lateral premotor cortex. The remaining third derives from the somatic sensory cortex (areas 1, 2, and 3) and the adjacent temporal lobe region. The corticobulbar tract projects bilaterally to the motor neurons of cranial nerves V, VII, IX, X, and XII. Most corticospinal fibers (75%–90%) decussate in the lower medulla (pyramidal decussation) and form the lateral corticospinal tract in the spinal cord (the pyramidal tracts). The remaining fibers descend in the ipsilateral ventral corticospinal tract. The lateral corticospinal tract projects to ipsilateral spinal motor neurons and their interneurons that control extremity muscle contraction, whereas the anterior corticospinal tract ends bilaterally on ventromedial motor neurons and interneurons that control the axial and postural muscles. These corticospinal axons provide direct glutamatergic excitatory input to alpha motoneurons. Brainstem control. Several brainstem nuclei exert supranuclear influence on the LMN population in the spinal cord through highly complex projections. The fibers originating in the medial and inferior vestibular nuclei in the medulla descend in the medial vestibulospinal tract and terminate both on medial cervical and thoracic motor neurons and on interneurons. They excite ipsilateral motor neurons but inhibit contralateral neurons. The lateral vestibulospinal tracts originating in the lateral vestibular nucleus (Deiters nucleus) activate the extensor motor neurons and inhibit the flexor motor neurons in all limbs. The brainstem reticular formation also strongly influences the spinal motor neurons, exerting widespread polysynaptic inhibitory input on extensor motor neurons and excitatory input on flexor motor neurons. The reticulospinal tracts modulate various reflex actions during ongoing movements. The brainstem reticular formation receives supranuclear control from the motor cortex via the cortical reticulospinal pathway to act as a major inhibitor of spinal reflexes and activity. Therefore, a lesion of the corticoreticular pathway can disinhibit reticulospinal control of the LMNs. The tectospinal tract originates in the superior colliculus and controls eye and head movement. Variations in the balance between inhibitory input (mediated by the dorsal reticulospinal tract) and facilitatory input (mediated by the medial reticulospinal tract) alter muscle tone. To some extent, the vestibulospinal tract alters tone by input to muscle stretch receptors. Limbic motor control. The limbic system is involved in emotional experience and expression and associated with a variety of autonomic, visceral, and endocrine functions. It strongly influences the somatic motor neurons. The emotional status and experience of an individual determines overall spinal cord activity, and the limbic motor system also influences respiration, vomiting, swallowing, chewing, and licking

Upper Motor Neurons and Their Descending Tracts

BOX 97.1

The motor areas The primary motor neurons (Betz giant pyramidal cells and surrounding motor neurons) The premotor areas (the supplementary motor area and premotor cortex) Corticospinal and corticobulbar tracts Lateral pyramidal tracts Ventral (uncrossed) pyramidal tracts Brainstem control Vestibulospinal tracts Reticulospinal tracts Tectospinal tracts Limbic motor control F ECF

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(at least in animal studies). Furthermore, the generation of signs of pseudobulbar hyperemotionality (pseudobulbar affect, emotional incontinence) in ALS is closely related to an abnormal limbic motor control, particularly in the periaqueductal gray and nucleus retroambiguus. The latter nuclei project to the somatic motor neurons that innervate pharyngeal, soft palatal, intercostal, diaphragmatic, abdominal, and probably laryngeal muscles. Pseudobulbar hyperemotionality symptoms may appear when UMN control over these motor nuclei is impaired, and thus limbic motor control is disinhibited. There appears to be some degree of emotional regulation by the cerebellum. The “cerebellar cognitive affective syndrome” can arise when stroke, tumor, or infection interrupts connections between the cerebellum and cerebral association and paralimbic regions (Schmahmann and Sherman, 1998).

Signs and Symptoms of Upper Motor Neuron Involvement Loss of Dexterity

Loss of dexterity is one of the most characteristic signs of UMN impairment. Voluntary skillful movements require the integrated activation of many interneuron circuits in the spinal cord; such integration is ultimately controlled by the corticospinal tract and thus by UMNs. Loss of dexterity may express itself as stiffness, slowness, and clumsiness in performing any skillful motor actions. Asking the patient to perform rapid repetitive motions such as foot or finger tapping assesses loss of dexterity at the bedside. It is useful to assess both sides of the body, as many motor neuron disorders are asymmetrical (Box 97.2).

Loss of Muscle Strength (Weakness) The degree of muscle weakness resulting from UMN dysfunction is generally mild. Extensor muscles of the upper extremities and flexor muscles of lower extremities may become weaker than their antagonist muscles because the UMN lesion disinhibits brainstem control of the vestibulospinal and reticulospinal tracts.

Spasticity Spasticity is the hallmark of UMN disease, but its pathophysiology is complex and controversial. It seems to reflect altered firing of alpha motoneurons and interneurons within the spinal cord, together with increased activity of group II nerve fibers derived from muscle spindles. An excess level of excitatory input to gamma motoneurons exists via excess synaptic levels of excitatory neurotransmitters such as serotonin, norepinephrine, and glutamate. In addition, there is reduced inhibitory glycinergic and γ-aminobutyric acid (GABA)ergic neurotransmission. The result is a state of sustained increase in muscle tension when the muscle lengthens. Clinically, muscles exhibit a sudden resistive “catch” midway during passive movement of the limb. However, when a sustained passive stretch is continued, spastic muscles quickly release the tension and relax, an event often described

Signs and Symptoms of Upper Motor Neuron Involvement

BOX 97.2

Loss of dexterity Loss of muscle strength (mild weakness) Spasticity Pathological hyperreflexia Pathological reflexes (Babinski, Hoffmann sign, loss of abdominal reflexes) Increased reflexes in an atrophic limb (probable upper motor neuron sign) Pseudobulbar (spastic bulbar) palsy (emotional lability, brisk jaw jerk, hyperactive gag, forced yawning, snout reflex, suck reflex, slow tongue movements, spastic dysarthria) 02 .4.(1( 4 (

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CHAPTER 97 Disorders of Upper and Lower Motor Neurons as the “clasp-knife phenomenon.” In muscles that are severely spastic, passive movement becomes more difficult and even impossible. Sustained increases in muscle tone lead to a slowing in motor activities.

Pathological Hyperreflexia and Pathological Reflexes Pathological hyperreflexia is another crucial manifestation of UMN disease. The Babinski sign (extensor plantar response) is perhaps the most important sign in the clinical neurological examination and is characterized by extension of the great toe (often, but not universally, accompanied by fanning of the other toes) in response to stroking the outer edge of the ipsilateral sole upward from the heel with a blunt object. This sign may only evolve at a later stage of disease and may be absent in the setting of marked atrophy of the toe extensor muscles.

1537

Transcranial Magnetic Stimulation Transcranial magnetic stimulation (TMS) is an electrophysiological technique that has detected cortical hyperexcitability/impaired inhibition as well as cortical motor neuron and long-tract degeneration in ALS. The stimulus is a brief, high-intensity electromagnetic pulse generated from a series of capacitors and discharged through wire coils applied at the scalp over the motor cortex and the evoked response measured at skeletal muscle. Several different techniques are under investigation, including single-pulse TMS, cortical silent period measurement, paired pulse TMS, and repetitive TMS (Geevasinga et al. 2019). Overall, this promising, noninvasive tool requires further evaluation as a marker of UMN dysfunction. Recent evidence suggests that it may be useful in combination with other tools such as DTI.

Pseudobulbar (Spastic Bulbar) Palsy

Primary Lateral Sclerosis

Pseudobulbar palsy (or spastic bulbar palsy) develops when there is disease involvement of the corticobulbar tracts that exert supranuclear control over those motor nuclei that control speech, mastication, and deglutition. The prefix pseudo distinguishes this condition from true bulbar palsy that results from pure LMN involvement in brainstem motor nuclei. Articulation, mastication, and deglutition are impaired in both pseudobulbar and bulbar palsies, but the degree of impairment in pseudobulbar palsy is generally milder. Spontaneous or unmotivated crying and laughter uniquely characterize pseudobulbar palsy. This is also termed emotional lability, hyperemotionality, labile affect, or emotional incontinence and is often a source of great embarrassment to the patient.

PLS, first described by Erb in 1875, is a rare UMN disease variant that accounts for 2%–4% of all cases of ALS and is traditionally distinguished by a lack of LMN involvement. In fact, the latter feature would lead some to argue that PLS is an entity that is distinct from ALS (Kolind et al., 2013). The Pringle criteria for PLS stipulated that disease be restricted to the UMN system for at least 3 years from the time of clinical onset (Pringle et al., 1992), but a figure of 4 years is now proposed during which there is neither clinical nor neurophysiological evidence of LMN involvement. In a recent study comparing the evolution of disease in PLS versus UMN-predominant ALS and typical ALS, the median time to development of electromyographic (EMG). LMN features after onset in those with an evolving ALS was 3.17 years; in those patients, clinical signs of LMN disease occurred on average about 6 months later. Nonetheless, later development of LMN signs may occur and require reclassification as ALS in some cases, which therefore necessitates constant longitudinal review of each case (Gordon et al., 2009). Indeed, it is possible to divide PLS patients into subgroups based on clinical and molecular characteristics. A recent study identified two broad clinical groups presenting with PLS; those with bulbar/dysphagia and those with urinary urgency. Furthermore, there were PLS-like presentations due to mutations in C9Orf72 but also in PARK2, SPG7, and DCTN1 (Mitsumoto et al., 2015). PLS typically presents in patients in their early 50s (about a decade younger than typical MND/ALS patients) as a very slowly evolving spastic paraparesis that spreads to the upper limbs and eventually causes pseudobulbar palsy. In rare instances, onset is in the bulbar system or follows a slowly ascending or descending hemiplegic pattern (Mills hemiplegic variant), but a bulbar-onset presentation should make the clinician wary of later LMN signs elsewhere. Other features include cramps and fasciculations, but such complaints are neither prominent nor universal. Bladder dysfunction is rare and, if it occurs at all, tends to be a late feature. Although muscle weakness is present, the main deficits are due to spasticity in dexterity and gait. The rate of progression can be exceedingly slow, often progressing over many years to the point where the patient manifests a robotic gait, debilitating generalized spasticity, and prominent pseudobulbar palsy. Muscle atrophy, if it occurs at all, is a very late feature. No clinically detectable sensory changes occur. Neuropsychological test batteries may define subtle cognitive deficits due to frontal cortical involvement, but dementia is not a prominent feature. A few patients may exhibit abnormal saccadic voluntary eye movements. Corticobasal syndrome can develop rarely in patients who initially present with a pure upper motor neuron syndrome (Johnson et al., 2015). Breathing is usually unimpaired in PLS, and as a consequence, forced vital capacity (FVC) is not affected (Gordon et al., 2009).

Laboratory Evidence of Upper Motor Neuron Involvement Several promising imaging and electrophysiological techniques are under investigation as potential markers of UMN involvement in neurological disease. However, a thorough bedside examination is the easiest and most effective means to detect UMN disease.

Neuroimaging The use of brain magnetic resonance imaging (MRI) in ALS is largely to exclude other conditions but sometimes shows abnormal signal intensity in the corticospinal and corticobulbar tracts as they descend from the motor strip via the internal capsules to the cerebral peduncles. In ALS, signal changes, best appreciated on proton density images of the internal capsules, probably represent Wallerian degeneration; similar changes also appear on conventional T2-weighted and fluidattenuated inversion recovery (FLAIR) sequences. However, these changes do not appear to be sufficiently sensitive, and efforts continue to evaluate other potential MRI techniques such as diffusion tensor imaging (DTI) and high-field volumetric MRI, which may serve as markers of UMN disease (Foerster et al., 2013).

Magnetic Resonance Spectroscopy Imaging Proton density magnetic resonance spectroscopy (1H-MRS) is a noninvasive nuclear magnetic resonance technique that combines the advantages of MRI with in vivo biochemical information. A significant reduction of N-acetylaspartate, a neuronal marker, relative to creatine or choline (used as internal standards) exists in the sensorimotor cortices of patients with ALS who have UMN signs. Alterations in the measured levels of these metabolites using 1H-MRS are useful in the detection of UMN dysfunction early in the evolution of ALS and are useful for monitoring progression over time. MRS still requires further technological improvements before it comes into widespread use.

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The prognosis is significantly better than for MND/ALS: one series had a median disease duration of 19 years and another series exhibited a range of survival from 72 to 491 months (Murray, 2006). The underlying pathogenesis of PLS remains undefined. Pathological changes include a striking loss of Betz cells in layer 5 of the frontal and prefrontal motor cortex (and other smaller pyramidal cells) together with laminar gliosis of layers 3 and 5 and degeneration of the corticospinal tracts. Spinal anterior horn cells are characteristically unaffected.

Diagnosis The diagnosis of PLS is essentially one of exclusion (Table 97.1). Rare reports of UMN-onset ALS exist where the interval between onset of UMN signs and subsequent LMN signs has been up to 27 years. As such, it is vital to reassess patients diagnosed with PLS, as late signs of LMN involvement may occur that would reclassify their disorder as UMN-onset ALS. Appropriate testing must exclude all definable causes for generalized UMN involvement. These include structural abnormalities (Chiari malformation and intrinsic and extrinsic spinal cord lesions) and myelopathies such as multiple sclerosis (MS) spondylotic cervical myelopathy, human immunodeficiency virus (HIV) myelopathy, human T-lymphotropic virus type 1 (HTLV-1) myelopathy, Lyme disease, syphilis, or adrenomyeloneuropathy. Spondylotic cervical myelopathy and MS are probably the most common causes among these disorders. The family history must be negative to rule out hereditary spastic paraplegia (HSP)/familial spastic paraparesis, spinocerebellar ataxia (SCA), hexosaminidase-A (Hex-A) deficiency, familial ALS (FALS), or adrenomyeloneuropathy. It is now apparent that some forms of HSP, including spastin and paraplegin mutation-associated HSP, may lack a family history; it is worthwhile to carry out genetic testing for HSP in patients presenting with symptoms and signs that are restricted to the lower extremities (Brugman et al., 2009). Paraneoplastic syndromes (especially in association with breast cancer) and Sjögren syndrome may clinically resemble PLS. Thus, it is important to consider paraneoplastic diseases, particularly in an older woman presenting with a pure upper motor syndrome and other genetic mimics.

Treatment No specific pharmacotherapy is available, and treatment therefore focuses on symptom control and supportive care. However, antispasticity drugs such as the GABA-B agonist baclofen and the central α2-agonist tizanidine may be tried for symptomatic treatment. Severe spasticity sometimes requires the insertion of an intrathecal baclofen

TABLE 97.1

pump. Tricyclic antidepressants, selective serotonin reuptake inhibitors, or dextromethorphan/quinidine may control pseudobulbar affect lability (Brooks et al., 2005).

Hereditary Spastic Paraplegia HSP (or familial spastic paraparesis) is a genetically and clinically heterogeneous group of disorders rather than a single entity. The clinical feature common to all cases is progressively worsening spasticity of the lower extremities, often with variable degrees of weakness. The characteristic pathology is retrograde degeneration of the longest nerve fibers in the corticospinal tracts and posterior columns due to mutations affecting vesicular trafficking, axonal transport, lipid metabolism, mitochondrial dynamics, and myelination. Its estimated prevalence is 3–10 per 100,000, but its worldwide prevalence may actually be underestimated because of the benign nature of the disease in many families (Blackstone, 2012). It may be inherited in an autosomal dominant, autosomal recessive, or X-linked fashion, but it should be borne in mind that a number of cases will lack a family history, as stated below (Depienne et al., 2006, Lan et al., 2015). Although most cases present in the second to fourth decades, onset is from infancy into the eighth decade. The clinical syndrome is broadly divisible into the pure form and the complicated form. In the pure form, patients develop only lower-extremity spasticity, but some of these cases eventually become complicated. However, the complicated form may also include optic neuropathy, pigmentary retinopathy, deafness, ataxia, ichthyosis, amyotrophy, peripheral neuropathy, dementia, autoimmune hemolytic anemia/thrombocytopenia (Evans syndrome), extrapyramidal dysfunction, cerebellar dysfunction, ptosis, ophthalmoparesis, intellectual disability, and bladder dysfunction (Video 97.1). There is an ever-expanding list of genes and genetic loci in the HSP family. Over 70 genetic subtypes have been described (de Souza et al., 2017; Table 97.2). Novel techniques such as exome sequencing are valuable in discovering new genes. Inheritance of most pure HSP is autosomal dominant, whereas complicated forms are more often autosomal recessive. For example, approximately 40% of autosomal dominant pure HSP worldwide is due to mutations of the SPAST gene on chromosome 2p22–21, which encodes spastin, a 616-amino acid protein. Mutations of various types (missense, nonsense, frameshift, splice site) may affect this gene (McDermott, 2006). Spastin is a highly conserved member of the AAA family of proteins (adenosine triphosphatase [ATPase] associated with various cellular activities). The exact role of mutant spastin in the pathogenesis of HSP is not known, although a disturbance in maintenance of the microtubule cytoskeleton may exist, thus disrupting axonal transport. More than half of all cases do not

Disorders of Upper Motor Neurons and Their Key Characteristics

Disorders

Key Characteristics

Primary lateral sclerosis Hereditary spastic paraplegia

A diagnosis of exclusion Heredity, usually autosomal dominant, spastin gene mutation, other mutations (see text), “sporadic” Slowly progressive myelopathy, endemic, and positive HTLV-1 Amerindian, IV drug abuser, concomitant HIV X-linked recessive inheritance, adrenal dysfunction, myelopathy, very long-chain fatty acid assay History of consumption of chickling peas Eastern African, cassava root consumption

HTLV-1-associated myelopathy HTLV-2-associated myelopathy Adrenomyeloneuropathy Lathyrism Konzo

HIV, Human immunodeficiency virus; HTLV, human T-lymphotropic virus; IV, intravenous.

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TABLE 97.2 Phenotype (OMIM Reference)

Hereditary Spastic Paraplegia Known Phenotype-Genotype Disorders Proposed Mechanism

Mode of Key Clinical/Radiographic Inheritance Features

Gene OMIM Reference

Gene

Location

Spastic paraplegia 1/MASA syndrome/ CRASH syndrome (#303350) Spastic paraplegia 2 (#312920)

L1CAM

Xq28

Neuronal migration, X-linked myelination production

Mental retardation, aphasia, shuffling gait, short stature, and adducted thumbs, corpus callosum hypoplasia, hydrocephalus

*308840

PLP1

Xq22.2

Myelin production

X-linked

*300401

Spastic paraplegia 3A (#182600)

ATL1

14q22.1

Membrane trafficking

AD

Spastic paraplegia 4 (#182601)

SPAST

2p22.3

Microtubule dynamics

AD

Spastic paraplegia 5A (#270800)

CYP7B1

8q12.3

Lipid metabolism

AR

Spastic paraplegia NIPA1 (SPG6) 6/Familial spastic paraparesis (#600363) Spastic paraplegia SPG7, (PGN 7 (#607259) CMAR, CAR)

15q11.2

Membrane transport/lysosomal degradation

AD

Onset in childhood, highly variable phenotype including cerebellar signs/ optic atrophy/contractures/mental retardation Early-onset (often before age 5–10), slowly progressive, pes cavus, sphincter disturbance. Variable age at onset, symptom severity and rate of symptom progression. Pes cavus, sphincter disturbance, mild dysarthria Variable age at onset, mostly pure but variable cerebellar involvement, optic atrophy, reduced vibration/proprioception Insidious onset in 2nd–3rd decade, variable severity, seizures, tremor

16q24.3

Mitochondrial dysfunction

Spastic paraplegia 8 (#603563) Spastic paraplegia 9A (#601162) Spastic paraplegia 10 (#604187)

KIAA0196

8q24.13

ALDH18A1

10q24.1

KIF5A

12q13.3

Spastic paraplegia 11 (#604360)

SPG11

15q21.1

Spastic paraplegia 12 (#604805)

RTN2

19q13.32

Spastic paraplegia HSPD1 (SPG13, 2q33.1 13 (#605280) HSP60, HLD4) 14q24.1 Spastic paraplegia ZFYVE26 15/Spastic paraplegia and retinal degeneration/ Kjellin syndrome (#270700) BSCL2 11q12.3 Spastic paraplegia 17/Silver spastic paraplegia (#270685)

Onset in 3rd–5th decade, variable AR, some heterozygous cerebellar signs/optic atrophy/eye movement abnormalities/attention mutations deficits, cortical/cerebellar atrophy Protein aggregation AD Onset 18–60 years, upper limb spasticity, amyotrophy, severe phenotype Amino acid metab- AD Juvenile or adult, ALS-like, short stature, olism cataracts, pes cavus. Membrane transport AD Onset 3rd–4th decade, with or without axonal sensorimotor neuropathy. Can be associated with amyotrophy, parkinsonism, cerebellar ataxia Onset in adolescence, mental Unknown, presumed AR impairment, cerebellar ataxia, membrane transport parkinsonism, amyotrophy, thin corpus callosum, “ears-of-the-lynx sign” Tubular endoplasAD Onset 1st–2nd decade, pure phenotype, mic reticulum netrapidly progressive work dysfunction Mitochondrial pro- AD Variable age at onset, pure phenotype, tein instability severe spasticity Unknown, presumed AR Onset in 1st–2nd decade, variable intellectual disability/dysarthria/retimembrane transport nal degeneration, distal amyotrophy, parkinsonism, seizures, axonal neuropathy, thin corpus callosum, cerebral atrophy, white matter hyperintensities Tubular endoplasAD Variable age at onset, distal amyotrophy mic reticulum network dysfunction

*606439

*604277

*603711

*608145

*602783

*610657 *138250 *602821

*610844

*603183

*118190 *612012

*606158

Continued

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TABLE 97.2 Phenotype (OMIM Reference)

Neurological Diseases and Their Treatment

Proposed Mechanism

Mode of Key Clinical/Radiographic Inheritance Features

Gene OMIM Reference

8p11.23

Endoplasmic reticulum-associated degradation pathway

AR

*611605

SPG20

13q13.3

Microtubule dynamics

AR

Spastic paraplegia 21/Mast syndrome (#248900)

SPG21

15q22.31

Dysregulation of CD4 activity

AR

Spastic paraplegia 23

DSTYK

1q32.1

Unknown

AR

Spastic paraplegia 26 (#609195)

B4GALNT1

12q13.3

Sphingolipid metab- AR olism

Spastic paraplegia 28 (#609340) Spastic paraplegia 30 (#610357) Spastic paraplegia 31 (#610250)

DDHD1

14q22.1

Lipid metabolism

KIF1A

2q37.3

REEP1

2p11.2

Microtubule AR dynamics AD Tubular endoplasmic reticulum network dysfunction

Spastic paraplegia 33 (#610244)

ZFYVE27

10q24.2

Spastic paraplegia 35/Fatty acid hydroxylaseassociated neurodegeneration (#612319)

FA2H

16q23.1

Spastic paraplegia 39/NTE-related motor neuron disorder (#612020) Spastic paraplegia 42 (#612539)

PNPLA6

19p13.2

Unknown, presumed AR lipid/myelination related

SLC33A1

3q25.31

Spastic paraplegia 43 (#615043)

C19orf12

19q12

Glycoprotein and ganglioside metabolism in Golgi apparatus Mitochondrial transmembrane protein, function unknown

Gene

Location

Spastic paraplegia 18 (#611225)

ERLIN2

Spastic paraplegia 20/Troyer syndrome (#275900)

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AD

AR

Onset in infancy, severe psychomotor retardation, joint contractures, global muscle weakness and atrophy, high arched palate, kyphosis/scoliosis, speech absent or limited, occasional seizures Onset in early childhood, distal amyotrophy and contractures, short stature, hypertelorism, maxillary overgrowth, tongue dyspraxia Onset 2nd–3rd decade, presenile dementia, parkinsonism, cerebellar signs, thin corpus callosum and white matter abnormalities Vitiligo, hyperpigmentation, lentigines, facial features, mental retardation, mild neuropathy Onset in 1st -2nd decades of life, slowly progressive, distal amyotrophy, intellectual disability, axonal sensorimotor neuropathy, dysarthria, variable cerebellar signs, extrapyramidal signs, cortical atrophy, and white matter hyperintensities Onset in childhood or adolescence, slowly progressive pure phenotype Onset 1st–2nd decade, variable cerebellar involvement/peripheral neuropathy Bimodal age of onset (usually 1st–2nd decade), variable severity, mostly pure HSP, occasionally complicated (e.g., bulbar dysfunction, distal amyotrophy) Adult onset, pure phenotype

*607111

*608181

*612666

*601873

*614603 *601255 *609139

*610243

*611026 Onset in 1st decade, dysarthria, mild cognitive decline, variable dystonia/ optic atrophy/seizures, leukodystrophy and occasional evidence of neurodegeneration with brain iron accumulation, atrophy of cerebellum/brainstem/ corpus callosum Childhood onset, distal upper and lower *603197 extremity wasting, cerebellar signs, spinal cord atrophy

AD

Variable age at onset, pure phenotype

AR

Onset in 1st decade, decreased vibration, *614297 distal muscle atrophy, reduced reflexes, contractures

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CHAPTER 97 Disorders of Upper and Lower Motor Neurons

TABLE 97.2 Phenotype (OMIM Reference)

Hereditary Spastic Paraplegia Known Phenotype-Genotype Disorders—cont’d Proposed Mechanism

Mode of Key Clinical/Radiographic Inheritance Features

Gene OMIM Reference

Disruption of oligodendrocyte homeostasis

AR

*608803

Gene

Location

Spastic paraplegia 44 (#613206)

GJC2

1q42.13

Spastic paraplegia 45 (#613162)

NT5C2

Spastic paraplegia 46 (#614409)

GBA2

10q24.32-q24.33 Purine/pyrimidine AR (10q24.3-q25.1) nucleotides metabolism 9p13.3 Sphingolipid metab- AR olism

Spastic paraplegia 47 (#614066)

AP4B1

1p13.2

Membrane transport AR

Spastic paraplegia 48 (#613647) Spastic paraplegia 49 (#615031)

AP5Z1

7p22.1

TECPR2

14q32.31

Membrane transAR port/DNA repair Interruption of intra- AR cellular autophagy pathway

Spastic paraplegia 50 (#612936)

AP4M1

7q22.1

Membrane transport AR

Spastic paraplegia 51 (#613744)

AP4E1

15q21.2

Membrane transport AR

Spastic paraplegia 52 (#614067)

AP4S1

14q12

Membrane transport AR

Spastic paraplegia 53 (#614898)

VPS37A

8p22

Endosomal sorting

AR

Spastic paraplegia 54 (#615033)

DDHD2

8p11.23

Lipid metabolism

AR

Onset of mild symptoms in 1st–2nd decade with progression in adulthood, cerebellar signs, hearing loss, seizures, hypomyelinating leukodystrophy and thin corpus callosum Onset before age 2, intellectual disability, contractures, optic atrophy, dysplastic corpus callosum Onset in childhood cerebellar involvement, variable cognitive impairment/ cataracts/kyphoscoliosis/testicular atrophy, variable cerebral, cerebellar, and corpus callosum atrophy Onset at birth, severe mental retardation with poor or absent speech development, stereotyped laughing, spastic tongue protrusion, variable dysmorphic features Adult onset, pure phenotype, mild cervical spine hyperintensities Onset in the first 2 years of life, moderate to severe intellectual disability, dysmorphic features, episodes of central apnea, thin corpus callosum, cerebral and cerebellar atrophy Neonatal hypotonia, severe mental retardation, dysmorphism, speech absent or limited, pseudobulbar signs, ventriculomegaly, white-matter abnormalities, and variable cerebellar atrophy Presents with neonatal hypotonia, severe intellectual disability, speech absent or limited, dysmorphic features, seizures, stereotypic laughing, contractures, ventriculomegaly, cerebral/cerebellar atrophy, and leukodystrophy Presents at birth with neonatal hypotonia, severe intellectual disability, speech absent or limited, talipes equinovarus, decreased shank muscle mass, short stature, dysmorphic features and microcephaly, stereotypic laughing Onset in infancy, mild-moderate cognitive impairment, dystonia, pectus carinatum, marked kyphosis Onset of spasticity by age 2 years, intellectual disability, short stature, foot contractures, dysarthria, dysphagia, variable optic hypoplasia, strabismus, telecanthus, thin corpus callosum and periventricular white-matter lesions, MR spectroscopy shows an abnormal lipid peak

*600417

*609471

*607245

*613653 *615000

*602296

*607244

*607243

*609927

*615003

Continued

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Hereditary Spastic Paraplegia Known Phenotype-Genotype Disorders—cont’d

TABLE 97.2 Phenotype (OMIM Reference)

Neurological Diseases and Their Treatment

Proposed Mechanism

Mode of Key Clinical/Radiographic Inheritance Features

Gene OMIM Reference

12q24.31

Mitochondrial dysfunction

AR

*613541

CYP2U1

4q25

Spastic paraplegia 57 (#615658)

TFG

3q12.2

Spastic paraplegia 61 (#615685)

ARL6IP1

16p12.3

Unknown, gene AR may play a role in immune functions Endoplasmic AR reticulum and microtubule function Protein transport AR

Spastic paraplegia 62 (#615685) Spastic paraplegia 63 (#615686)

ERLIN1

10q24.31

AMPD2

1p13.3

Spastic paraplegia 64 (#615683)

ENTPD1

Spastic paraplegia 72 (#615625)

Spastic paraplegia 73 (#616282) Spastic paraplegia 74 (#616451)

Gene

Location

Spastic paraplegia 55 (#615035)

C12orf65

Spastic paraplegia 56 (#615030)

Endoplasmic reticulum function Purine nucleotide metabolism

AR

10q24.1

Purine nucleotide metabolism

AR

REEP2 (SGC32445, C5orf19)

5q31.2

CPT1C

19q13.33

IBA57

1q42.13

AD or AR Shaping of endoplasmic reticulum, membrane interactions Altered lipid metab- AD olism Mitochondrial AR dynamics

AR

Onset in 1st decade, axonal peripheral neuropathy, optic atrophy, strabismus, mental retardation, arthrogryposis of small joints, thin corpus callosum Onset birth to 8 years, upper limb involvement, dystonia, thin corpus callosum, basal ganglia calcification Early onset, optic atrophy, wasting of hand and leg muscles and contractures, axonal demyelinating sensorimotor neuropathy Present in first 2 years of life, sensorimotor neuropathy, severe mutilating acropathy Cerebellar ataxia, distal amyotrophy

*610670

*602498

*607669

*611604

Present in first 2 years of life, short *102771 stature, white-matter changes, thin corpus callosum Onset in childhood, intellectual disability, *601752 microcephaly, delayed puberty, dysarthria Onset in early childhood, slowly progres- *609347 sive, postural tremor

Onset in early adulthood, slowly progres- *608846 sive, mild amyotrophy Onset in first decade, slowly progressive, *615316 optic atrophy, distal amyotrophy

AD, Autosomal dominant; AR, autosomal recessive.

manifest symptoms and signs until after age 30 years. Although this is normally a pure HSP, complicated forms occur, and some cases can develop a late-onset cognitive decline. Pathologically, degeneration of the longest corticospinal tracts and, to a lesser degree, the posterior columns of the spinal cord is seen. Mutations in the SPG3A gene on 14q11–q21 encoding the novel protein, atlastin, give rise to another autosomal dominant, often early-onset (15 years) after the acute poliomyelitis infection. These patients then experience progressive symptoms of new muscle weakness and new atrophy in previously affected muscles or sometimes in muscles apparently not affected by the original poliomyelitis; this deterioration occurs over a protracted timeframe of at least 1 year. EMG examination reveals that muscles thought to be clinically unaffected by acute poliomyelitis often have evidence of previous disease (characterized by chronic neurogenic motor unit potential (MUP) changes with or without some acute denervation). Weakness can involve limbs and/or bulbar musculature. Muscle cramps and fasciculations may accompany new weakness, but they are often present in stable muscles also. Generalized fatigue is characteristic and can be the most disabling accompaniment, often called the polio wall. Other common symptoms include pain, sleep disturbances, cold intolerance, depression, hypoventilation (manifesting as dyspnea), dysphagia, and dysarthria. The proposal is that these new symptoms should have persisted for a full year if one is to consider the diagnosis of postpolio syndrome. The neurological examination reveals focal and asymmetrical muscle weakness and atrophy, but it may be difficult to determine whether the weakness and atrophy is new and progressive or remote and static. Fasciculations can be unusually coarse and large in keeping with the giant motor units detectable during EMG examination.

Laboratory Features

Medical history: Recovery from acute poliomyelitis A long, stable course—at least 10 years Signs and symptoms: Progressive weakness, usually in previously affected muscles Accompanying overstressed muscle pains and arthralgia Laboratory studies: EMG is helpful to identify evidence of previous polio infection No test is specific for PPMA Diagnosis: Exclusion of other treatable diseases Treatment: Symptomatic and supportive care

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Because EMG provides definitive evidence of remote poliomyelitis and can help exclude diseases mimicking PPMA, it is an indispensable test when suspecting PPMA, though it cannot confirm the diagnosis. In patients with PPMA, the motor nerve conduction studies may be abnormal (low maximum CMAP amplitudes) when recorded from affected muscles. The needle electrode examination of affected weak muscles typically shows a reduced number of motor units and chronic neurogenic MUPs. Giant motor units may be present, indicative of chronic denervation and reinnervation. Modest numbers of fibrillation potentials and occasional fasciculations may occur in affected muscles, but such electrophysiological evidence of acute muscle fiber injury is not necessary to make the diagnosis. Sensory nerve conduction studies are normal. The muscle biopsy specimen usually shows acute and chronic neurogenic atrophy and often marked group muscle fiber atrophy and fiber-type grouping; however, these biopsy findings are not diagnostic of PPMA.

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Diagnosis A history of clinical stability for at least 10 years after recovery from acute poliomyelitis is a prerequisite for considering the diagnosis of PPMA. When this requirement is satisfied, PPMA is then a diagnosis of exclusion. Exclude all potential diseases causing progressive, focal, and asymmetrical weakness. Myelopathy, radiculopathy, electrolyte abnormalities, endocrine diseases, diabetic amyotrophy, connective tissue disorders, entrapment neuropathies, inflammatory myositis, inflammatory neuropathy, and vasculitis are among the diseases to exclude by appropriate laboratory studies. The symptoms of progressive focal muscle weakness in PPMA may raise the possibility of the PMA variant of ALS. Approach this diagnosis with great caution in the setting of a history of prior paralytic polio.

Treatment No specific pharmacotherapy for postpolio syndrome exists. Care focuses on symptom relief (Gonzalez et al., 2010). A randomized controlled trial of IVIG (2 courses of IVIG at a dose of 90 g per course over 3 days, with a 3-month interval) reported a significant improvement in muscle strength but not quality of life in 135 patients (Gonzalez et al., 2006). Other agents have also been studied but at present there is insufficient evidence to support use of any of these (IVIG included) in postpolio syndrome (Koopman, 2015; Patwa et al., 2012). The care plan should focus on avoiding fatiguing activities that aggravate symptoms, modifying activities to conserve energy, weight reduction for those who are overweight, and treating underlying medical disorders that reduce overall well-being. Careful screening and treatment for possible sleep apnea and depression are important. Those patients who have worsening of preexisting ventilatory muscles may require noninvasive positive-pressure ventilation (NIPPV) or noninvasive bilevel positive airway pressure (BiPAP) ventilation. Physical therapy should focus on nonfatiguing aerobic exercise, modest isometric/isokinetic exercise, and range-of-motion stretching maneuvers. The goal should be to maintain exercise in affected muscles but not to the point of overuse, while also limiting the disuse of unaffected muscles. Low-impact exercise in warm water can be particularly helpful and also appears to help control fatigue and pain. In patients with more serious functional decline, prescribe appropriate assistive devices to maintain activities of daily living. Pulmonologists must evaluate those who develop respiratory insufficiency to rule out primary pulmonary disease and to prevent/treat chest infections. Patients whose employment or lifestyle involves significant physical exertion need to modify their work duties and other activities.

Multifocal Motor Neuropathy A complete description of multifocal motor neuropathy is in Chapter 106. The condition is believed to be autoimmune in nature, and most cases have evidence of focal demyelination in the peripheral nerves (multifocal motor neuropathy with conduction block [MMNCB]) similar to that in chronic inflammatory demyelinating peripheral neuropathy. The clinical presentation, however, is with pure LMN involvement. The condition enters into the differential diagnosis of benign focal amyotrophy and the PMA variant of ALS. It is important to search for this condition since it is treatable by high-dose immunoglobulin infusions or other immunotherapy.

Benign Focal Amyotrophy The terms benign focal amyotrophy, brachial monomelic amyotrophy, benign calf amyotrophy, Hirayama disease, or juvenile segmental muscular atrophy are used to describe disorders characterized by LMN disease

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clinically restricted to one limb. The etiology is unknown. Autopsy studies have shown the affected region of spinal cord flattened, the anterior horn markedly atrophied and gliotic, and a reduction in the numbers of both large and small motor neurons. Based upon neuroradiological studies, Hirayama, who established the disease entity, has proposed a mechanically induced limited form of ischemic cervical myelopathy, being the result of local compression of the dura and spinal cord against vertebrae during repeated neck flexion/extension, in turn due to disproportionate growth between the contents of the dural sac and the vertebral column (Hirayama, 2008; Hirayama and Tokamaru, 2000). However, surgical decompression has not altered the course of the disease, and this theory is no longer widely held. Another school of thought is that this is a segmental, perhaps genetically determined, SMA, but the actual cause is still unknown. The disease usually begins in the late teens, but many cases can present in the fourth decade. More than 60% of patients are men. Although originally described in Indian and Japanese patients, the disorder is now recognizable around the world. The most common presentation is one of an idiopathic, slowly progressive, painless weakness and atrophy in one hand or forearm. The distribution of muscle weakness varies markedly from case to case, but a characteristic feature is that the condition remains limited to only a few myotomes in the affected limb. The most common pattern is unilateral atrophy of C7–T1 innervated muscles, with sparing of the brachioradialis (the “oblique atrophy” pattern). Muscle stretch reflexes are invariably hypoactive or absent in the muscles innervated by the involved cord segment but are normal elsewhere. UMN signs are not present, and if they are, one should consider the onset of ALS instead. Approximately 20% have hyperesthesia to pinprick and touch, usually located on the dorsum of the hand. The cranial nerves, pyramidal tracts, and the autonomic nervous system are normal. Weakness and atrophy may progress steadily for the initial 2–3 years, but most patients have stabilized within 5 years. The arm is the affected limb in approximately 75% of the patients and the leg in the remaining 25% (benign calf amyotrophy). Spread may occur to the contralateral limb in about 20% of cases (Gourie-Devi and Nalini, 2003), and rare patients later develop an ALS-like picture. No pathognomonic laboratory or electrodiagnostic tests exist for this condition; their main purpose is to exclude alternative diagnoses. Motor nerve conduction studies are either normal or reveal only reduction in the maximum CMAPs; a modest reduction in SNAPs occurs in up to one-third of patients. The EMG examination may show some fibrillation and fasciculation potentials, and chronic neurogenic motor unit changes are prominent. The C5–T1 myotomes are most commonly involved when the arms are affected. Careful EMG examination may reveal mild neurogenic changes on the asymptomatic contralateral side. The serum creatine kinase (CK) concentration may be modestly elevated, but other routine laboratory test results are normal. Cervical MRI may reveal segmental spinal cord atrophy or occasionally an area of increased signal on T2-weighted scans of the cervical spinal cord enlargement. “Incidental” spondylosis and cervical spinal canal stenosis detected by MRI require careful evaluation before the diagnosis of benign focal amyotrophy is established.

Differential Diagnosis Two diseases require distinction from benign focal amyotrophy: ALS, which is almost always a relentlessly progressive terminal disease, and MMNCB, which is a treatable peripheral motor neuropathy. A small proportion of ALS presents as an LMN monomelic disease, albeit in an older patient population. It is only with follow-up examination that the more widespread anterior horn cell disorder becomes apparent and UMN signs appear. Deep tendon reflexes are almost always hyperactive early in the evolution of ALS. Furthermore, the electrodiagnostic

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CHAPTER 97 Disorders of Upper and Lower Motor Neurons finding of generalized widespread acute and chronic motor neuron loss distinguishes ALS from the segmental motor neuron involvement of benign focal amyotrophy. The slowly progressive focal weakness that is distinctive of benign focal amyotrophy may also be the presenting picture of MMNCB, but detailed motor nerve conduction studies and serum tests for elevated titers of anti-GM1 antibodies can differentiate these two conditions. Cervical or lumbosacral radiculopathy may also appear in a manner somewhat akin to benign focal amyotrophy. However, radicular pains and sensory impairment are typical of radiculopathies. Neuralgic amyotrophy/ Parsonage-Turner syndrome typically begins with severe pain before the onset of weakness and wasting in the distribution of predominantly motor nerves derived from the brachial plexus. It may also involve selected sensory nerves. Most cases are monophasic and do not progress over years, as does benign focal amyotrophy, although hereditary neuralgic amyotrophy can present as recurrent bouts of brachial plexopathy. Cervical syringomyelia or a benign tumor involving nerve roots or the spinal cord may also cause progressive weakness in a monomelic fashion. Careful EMG studies and neuroimaging should differentiate these diseases.

Treatment The term benign in benign focal amyotrophy distinguishes it from malignant motor neuron disease, as seen in ALS. This condition is not life threatening, but it nevertheless severely impairs motor function in the involved extremity (although most patients adapt very well to their disability). Supportive care consists of physical and occupational therapy and effective use of assistive devices (splinting and braces). Tendon transfers are a consideration in selected patients with focal weakness in a muscle group whose function is crucial for certain activities of daily living.

Spinal Muscular Atrophy SMA is a group of disorders caused by degeneration of anterior horn cells and, in some subtypes, of bulbar motor neurons. Almost all cases are genetically determined, with most being autosomal recessive due to homozygous deletions of the survival motor neuron (SMN) gene on chromosome 5. Traditionally, SMA is classified as one of the four types based on the age at onset: SMA type 1 (infantile SMA or WerdnigHoffmann syndrome), SMA type 2 (intermediate SMA), SMA type 3 (juvenile SMA or Kugelberg-Welander disease), and SMA type 4 (adult-onset SMA, pseudomyopathic SMA). A very severe prenatal form of SMA (type 0 SMA) can manifest prenatally with reduced fetal movements and respiratory distress at birth. It is also important to consider the maximum function that a child achieves in terms of sitting and walking; this is of prognostic significance. In the less severe

forms of the disease, there can be periods where the child will improve or plateau, but long-term studies have demonstrated a net deterioration (Russman, 2007) (Table 97.3). The estimated incidence of infantile and juvenile recessive SMA is 1 in 6000 to 10,000 live births, with an approximate carrier frequency of 1 in 35 of the general population, making it a leading genetic cause of infant mortality, although the carrier frequency is lower in people of sub-Saharan African origin (Sangaré et al., 2014). True adult-onset disease accounts for probably less than 10% of all cases of SMA, with an estimated prevalence of 0.32 in 100,000. The mean age at onset is the mid-30s but ranges from 20 to the late 40s. Up to 95% of all childhood cases are due to deletion of the survival motor neuron (SMN1, telomeric SMN, SMNT) gene located on chromosome 5q11.2–13.3. The remaining cases are due to small SMN mutations (rather than full deletions). SMN1 is located within an inverted gene duplication, the other half of which is occupied by the almost identical SMN2 (centromeric SMN, SMNC) gene. The SMN1 protein product is functionally absent in the vast majority (95%–98%) of cases of SMN-mutated SMA, and small amounts are present in the remaining few percent. The SMN2 protein is present in all patients, but the copy number can vary considerably. Only 1%–2% of childhood-onset SMA is unrelated to the SMN locus on chromosome 5. SMN1 protein is a 38-kDa polypeptide important in the processing of the primary transcripts of other genes. Although a ubiquitous protein, expression is great within spinal motor neurons, and this may be why the disorder manifests as a motor neuron disease. It is associated with both nuclear and cytoplasmic complexes involved in messenger RNA (mRNA) splicing and interacts with other proteins that are important in the regulation of ribosomal RNA processing and modification. Within the nucleus, SMN1 forms macromolecular complexes with other nuclear proteins important in the assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs). It is thus possible that SMA develops because of disruption in mRNA transport and/or SMN-dependent snRNP biogenesis. SMN2 protein is almost identical to SMN1 protein but only has about 10% of the activity of SMN1 protein because of a C-to-T transition within exon 7 that alters splicing. The full-length SMN1 transcript has all 9 exons, whereas 90% of the transcripts from SMN2 lack exon 7. Thus, only 10% of the SMN2 output is the full-length SMN transcript, the remainder being unstable and rapidly degraded. Therefore, despite the near-identical nature of the two proteins, SMN 2 cannot compensate fully for loss of SMN1. Motor neuron health requires at least 23% full-length SMN protein. The SMN genome is rather unstable and, as a consequence, increased copy numbers of SMN2 are possible through a process of gene conversion from SMN1 to SMN2. This has major implications for

TABLE 97.3

Childhood and Adult Spinal Muscular Atrophies

SMA Type

Age at Onset

0. Prenatal

Prenatal

1. Infantile SMA (Werdnig-Hoffmann) 2. Intermediate SMA 3. Juvenile (Kugelberg-Welander) 4. Adult-onset SMA (pseudomyopathic SMA)

Birth to 6 months

Maximum Function Achieved Survival/Prognosis

Before 18 months After 18 months After 5 years (most >30 years)

1549

Inheritance

Defective Gene

Needs respirator support at birth Sits with support

Fatal at birth without respirator support Death by age 2 years

AR

SMN gene

AR

SMN gene

Sits independently Walks independently: approx. 25 steps Walks normally

No walking, adulthood Adulthood

AR AR

SMN gene SMN gene

Slow progression Proximal or distal

AR, AD “Sporadic”

SMN gene VAPB, dynactin unknown, distal overlap with HMN-V

AD, Autosomal dominant; AR, autosomal recessive; HMN-V, hereditary motor neuropathy type V; SMA, spinal muscular atrophy; SMN, survival motor neuron; VAPB, vesicle-associated membrane protein B. . F ECF

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the clinical phenotype: the infantile form is very severe because most of these children have no SMN1 and only two copies of SMN2, thus producing about 9% of full-length functional transcript, whereas multiple copies of SMN2 (3–5) are associated with mild SMA (Hirth et al., 2005; Kostova et al., 2007; Monani, 2005). A study from Japan showed that the type of SMA mutation itself is also an independent determinant of severity (Yamamoto et al., 2014). Most (about 70%) adult-onset type 4 SMA is autosomal recessive, is allelic with SMA types 1, 2, and 3, and is due to mutations or deletions in the SMN1 gene. Gene conversion events occur in some cases with SMA type 4 whereby SMN1 is “converted” to SMN2. The remaining adult-onset SMA cases are autosomal dominant, autosomal recessive (but not linked to chromosome 5), or are apparently sporadic. One rare form of adult-onset SMA described in a large Brazilian family was caused by a missense mutation in the vesicle trafficking protein, vesicle-associated membrane protein (VAPB). This can present with typical ALS or with a late-onset SMA (Nishimura et al., 2004).

Clinical Features Spinal muscular atrophy type 1, infantile form (WerdnigHoffmann disease). SMA type 1 begins within the first few months of life. By definition, children with this disease are never able to sit without support. Symptoms include severe hypotonia, a weak cry, and respiratory distress. These children are unable to lift their heads when placed prone and demonstrate severe head lag when pulled from a supine to a seated position (Fig. 97.1). The baby’s posture at rest also takes a characteristic “frog-leg” position, with the thighs externally rotated and abducted and the knees flexed (a “floppy” baby). Limb weakness is severe, generalized, and worse proximally. The infant is unable to sit and raise its arms or legs from the examining table, but there may be antigravity movements of the hands and flickering movements of the feet. Muscle stretch reflexes are usually absent, and the sensory examination is normal. Observation of the fingers

may reveal fine, small-amplitude involuntary movements called minipolymyoclonus that are due to dense fasciculations. Contractures usually do not develop in the early phases but may develop after several months of immobilization. Bulbar muscle weakness makes feeding laborious, causes a continuous gurgling, and eventually leads to aspiration pneumonia. Fasciculations of the tongue occur in about 50% of affected infants. In contrast to bulbar and extremity muscles, the facial muscles are only mildly weak, giving these children an alert expression. Extraocular movements are always normal. Intercostal muscles are severely weak, but diaphragmatic strength preserves until late in the disease. This dysequilibrium of ventilatory muscle function causes outward flaring of the lower ribcage and gives rise to a bell-shaped chest deformity. Death from respiratory failure, pneumonia, and malnutrition usually occurs before age 2 years. A rare form of atypical infantile SMA, spinal muscular atrophy with respiratory distress (SMARD) (Viguier et al., 2019), is associated with respiratory distress, cardiomyopathy, and lactic acidosis. This disorder is not due to SMN1 deletion but caused by mutations in the gene for immunoglobulin mu-binding protein 2 (IGHMBP2). It is interesting that this gene has homology to SETX, the gene responsible for ALS4, which can cause a familial form of distal amyotrophy, oculomotor apraxia–cerebellar ataxia, or juvenile ALS.

Spinal muscular atrophy type 2, intermediate form (chronic spinal muscular atrophy). The signs and symptoms of SMA type 2 usually begin between the ages of 6 and 18 months. Delayed motor milestones are often the first clue to neurological impairment, with more prominent leg weakness then arm weakness. A fine hand tremor due to minipolymyoclonus suggests the diagnosis. The distribution, pattern, and progression of weakness is similar to that found in SMA type 1, but type 2 disease is quantitatively much milder, and progression is slower. Most children eventually are able to roll over and sit unsupported, but they rarely achieve independent walking. Weakness of trunk muscles produces a characteristic rounded kyphosis

C

A

B

D

Fig. 97.1 A 6-Month-Old Baby with Werdnig-Hoffmann Disease. A, The baby has a typical “frog leg” posture; mouth is triangular, and facial expression suggests facial weakness. B, On sitting, the baby cannot sustain his head upright. C, When the baby is pulled by the arms, the head falls back. D, When the body is held supine, the head and extremities drop by force of gravity, and there is no active body motion. (Courtesy Neil Friedman, Cleveland Clinic.)

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CHAPTER 97 Disorders of Upper and Lower Motor Neurons in the seated position, and, as the shoulders weaken, the child becomes less mobile and eventually wheelchair confined. Contractures of the hips and knees, clubfoot deformities, severe scoliosis, and dislocation of the hips may eventually develop. The long-term prognosis varies markedly; some die in childhood because of respiratory failure, but many others survive into the third or fourth decade of adulthood. Another rare childhood-onset form of SMA that is distinct from SMA type 2 is Fazio-Londe disease. This is a form of sporadic autosomal dominant or autosomal recessive progressive facial and bulbar palsy of late childhood. Affected children are normal at birth but develop progressive bulbar palsy (PBP) and eventual respiratory failure in the second decade of life, with little or no evidence of involvement of other motor neurons and with usually normal extraocular motility. The differential diagnosis includes a structural brainstem lesion, myasthenia gravis, and the Miller Fisher variant of Guillain-Barré syndrome (GBS).

Spinal muscular atrophy type 3, juvenile form (KugelbergWelander disease). The onset of the juvenile form of SMA is typically

after 18 months of age (usually between 5 and 15 years) and presents with difficulty in walking. Patients with onset before the age of 3 years are subclassified as SMA type 3a and those after age 3 years as SMA type 3b. The disorder has an appearance not unlike a limb-girdle muscular dystrophy. As weakness in hip-girdle muscles increases, the child develops a waddling (Trendelenburg) gait, with a protuberant abdomen due to an exaggerated lumbar lordosis, and trouble climbing stairs. As weakness progresses, the Gowers maneuver is used to arise from lying supine on the floor. Pseudohypertrophy of the calf muscles sometimes occurs, but this may be an illusion resulting from relative preservation of calf muscles as compared to thigh muscles. Eventually, wasting and weakness of the neck, shoulders, and arms develop, but, as with SMA type 2, weakness in the lower extremities is nearly always more severe than in the upper extremities. Fasciculations are more prominent than in SMA types 1 and 2, and a fine action tremor is common. Tendon reflexes uniformly reduce and are lost, and the sensory examination is normal. The clinical course of SMA type 3 is one of slowly progressive limb-girdle weakness, but there may be long periods of stability that last for years. The eventual degree of disability is difficult to predict, but if onset is after the age of 2 years, it is likely that the patient will remain ambulatory into the fifth decade of life and enjoy a normal lifespan. Spinal muscular atrophy type 4, adult-onset. Most cases of autosomal recessive, 5q-associated, adult-onset SMA appear to affect proximal muscles. The characteristic clinical presentation is that of a slowly progressive limb-girdle weakness leading to difficulty in walking, climbing stairs, and rising from a chair or the floor. Fasciculations are an important finding and occur in 75% of patients. Quadriceps muscle weakness is often a prominent feature. Muscle cramps occur but are not prominent. Bulbar signs, bony deformities such as scoliosis, and respiratory weakness are rare. Many cases have a distribution of weakness reminiscent of the limb-girdle muscular dystrophies, leading to the older term, pseudomyopathic SMA (Fig. 97.2). Many cases of autosomal dominant adult-onset SMA (also known as Finkel-type SMA) are clinically similar to the recessive form described earlier. Finkel-type SMA usually begins in the third decade of life, is proximal in distribution, is very slowly progressive, and involves the legs before the arms. Most patients remain ambulatory for decades after clinical onset. One of the autosomal dominant missense mutations causing adult-onset Finkel-type SMA affects VAPB. It is interesting that some patients with this mutation develop the clinical features of ALS rather than SMA (Nishimura et al., 2004). DYNCH1H1 and BIC2D (both autosomal dominant) can cause a phenotype of lower extremity predominant SMA (SMALED) (Beecroft et al., 2017; Wan et al., 2019 ). TRP4V-associated disease is very variable but can include

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a scapuloperoneal-type presentation (Biasini et al., 2016). CHCHD10 autosomal dominant disorders are also highly variable and can be ALS-like, frontotemporal-type dementia (FTD)-like, myopathy-like, or SMA-like (Penttila et al., 2015). A relatively new class of adult-onset SMA has recently emerged and is sometimes referred to as SMA-5 to help distinguish a distal rather than proximal pattern of slowly PMA. The classification of these rare disorders is rather vague, and considerable overlap with distal CMT (see later discussion) exists. Several patterns of inheritance occur, including autosomal dominant, autosomal recessive, and X-linked recessive. Some lack any apparent pattern of inheritance. Distal-predominant adult-onset SMA and some of the neuronal forms of CMT disease appear to overlap both clinically and genetically: indeed, the difference may be purely semantic. Motor-predominant CMT variants such as hereditary motor neuronopathy type 5 (HMN-5), itself a heterogeneous group of conditions, present with a slowly progressive LMNpredominant disorder affecting distal limb muscles. Mutations in the glycyl-tRNA synthetase (GARS) gene, for example, were identifiable in multiple families around the world. Patients usually present with very indolent symmetrical or asymmetrical weakness, clumsiness, and wasting of intrinsic hand muscles (with a particular predilection for thenar muscles) in the absence of any proximal weakness or sensory findings. There is little functional disability (Del Bo et al., 2006; Dubourg et al., 2006). Mutations in the p150Glued subunit of the dynactin gene, a microtubule protein important in axonal transport, cause another distal-predominant atrophic disorder that also has a predilection for thenar muscles. Unlike the GARS-associated disorder, involvement of the face and vocal cords may occur (Puls et al., 2005).

Laboratory Studies The first-line investigation in autosomal recessive proximal SMA (types 0–4) is molecular genetic analysis to identify homozygous deletions in the SMN gene on chromosome 5q and, if confirmed, no further work-up is necessary. However, if a homozygous deletion of SMN1 is not detectable in a patient with a clinical picture consistent with SMA, one can assay for the combination of a deleted SMN allele on one gene and a point mutation on the other. PCR is able to distinguish the single nucleotide change in exon 7 that determines SMN2 from SMN1. It requires measurement because it has prognostic importance. Serum CK may be elevated up to 10 times normal levels in SMA type 3 but is typically normal in the infantile and intermediate types. EMG is valuable in supporting the diagnosis, although it may be technically limited in children by the need to carry out the test under conscious

Fig. 97.2 Patient with mild adult-onset proximal spinal muscular atrophy and marked shoulder-girdle muscle atrophy. Note subluxation at both shoulder joints and marked deltoid muscle atrophy.

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sedation. CMAPs may be reduced in amplitude, but conduction velocities and sensory nerve conduction study results are normal. The needle electrode examination may reveal evidence of acute denervation (fibrillation potentials and positive sharp waves) along with fasciculation potentials and evidence of chronic motor unit remodeling due to a chronic process of denervation and reinnervation. Reduced recruitment of large polyphasic motor units is therefore characteristic, although sedation hampers full voluntary activation. Complex repetitive discharges are an electrodiagnostic feature of SMA type 3. Muscle biopsy reveals a highly characteristic pattern called grouped fascicular atrophy (especially in typical Werdnig-Hoffmann SMA): entire fascicles or groups of fascicles are atrophied, whereas neighboring fascicles (often made up entirely of type 1 fibers) are composed of hypertrophied fibers. It is important to remember that myopathic changes, including fiber size variability, fiber splitting, internal nuclei, and fibrosis, complicate long-standing denervating disorders such as childhood and juvenile SMA. While serum CK and aldolase are often normal in adults with SMA type 4, they may be elevated to levels less than 10-fold the normal values. Motor nerve conduction studies reveal normal conduction velocities and reduced CMAPs in the presence of normal SNAPs. Needle electrode studies show marked chronic neurogenic motor unit changes, which are modest if any evidence of acute denervation. Myopathic changes due to secondary myopathic degenerative changes in motor units are also common. Fasciculation potentials may occur in involved muscles. When molecular genetic testing fails to help with diagnosis, it can be very useful to get a muscle biopsy, which typically shows evidence of a markedly chronic denervation similar to that described in SMA type 3 but with more frequent changes of secondary myopathy.

Differential Diagnosis For infantile SMA type 1, one must exclude all other causes of infantile hypotonia. This includes Pompe disease, centronuclear myopathy, nemaline myopathy, congenital muscular dystrophy, central core disease, and congenital or infantile myotonic dystrophy. For older children with suspected types 2 and 3 SMA, the differential diagnoses include myasthenia gravis, various muscular dystrophies, inflammatory myopathies, and a variety of structural, metabolic, and endocrine myopathies. Clinical, laboratory, and muscle biopsy features usually distinguish these disorders with relative ease. Limb-girdle muscular dystrophy may be difficult to distinguish from adult-onset proximal SMA; it can be autosomal recessive, is often adult-onset, and affects predominantly proximal muscles. The pattern of muscle weakness often points to the diagnosis; for instance, in adult-onset SMA, the triceps muscles may be weaker than the biceps, the opposite of the situation in limb-girdle muscular dystrophy. Muscle biopsy in limb-girdle muscular dystrophy reveals a primary myopathy rather than a neurogenic process, but one should be aware that some degree of secondary myopathic changes can occur in long-standing SMA. Immunohistochemistry and Western blotting on muscle biopsy are able to distinguish SMA from dystrophinopathies, sarcoglycanopathies, calpainopathies, and dysferlinopathies. Other myopathies considered include polymyositis and adult-onset acid maltase deficiency. Chronic inflammatory demyelinating polyneuropathy (CIDP) may mimic SMA because of chronic proximal muscle weakness, but the tendon reflexes are usually diffusely absent in CIDP, whereas some are preserved in SMA. Electrodiagnostic studies in CIDP reveal a demyelinating polyradiculoneuropathy, and CSF protein levels are increased. Hexosaminidase-A deficiency in adults has a similar phenotype to adult-onset SMA, but several nonmotor symptoms typically arise. In the absence of a family history of SMA, it can be most difficult to distinguish adult-onset distal-predominant SMA from the PMA variant

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of ALS. However, adult-onset SMA progresses very slowly, whereas PMA progresses relatively rapidly (albeit slower than classic ALS). Furthermore, muscle biopsy and EDX assessment in adult-onset SMA reveals a markedly chronic disease, whereas PMA findings are consistent with more subacute denervation and thus more modest evidence of neurogenic motor unit remodeling.

Treatment A major breakthrough in specific treatment of SMN1 gene SMA has been made with the approval of intrathecal antisense oligonucleotide (ASO) therapy (nusinersen) in SMA types 1, 2, and 3a. Indeed, the potential for this therapy to transform Werdnig-Hoffmann disease from a universally fatal disorder to a slow chronically progressive disease must be considered a medical triumph. ASOs are complementary to “sense” strand nucleic acids to which they bind and control gene expression: nusinersen binds to the intronic splicing sequencer N1 (ISS-N1) and thus promotes exon 7 production in the final transcript (the production of full-length protein from SMN2). The treatment improves rates of survival/freedom from use of a ventilator at 24 months. In those with later-onset disease, there are demonstrable improvements in motor function (Michelson et al., 2018). Intrathecal administration can be challenging in the older age groups due to scoliosis and respiratory difficulties and a multidisciplinary approach is recommended (Wurster et al., 2019). An issue with this treatment is the expense of the ASO therapy itself; cost–benefit analyses are important when considering this form of therapy (Zuluaga-Sanchez et al., 2019). Additional treatment focuses on supportive care, including physiotherapy, respiratory care, nutritional support, orthotics, and orthopedic interventions. Typical Werdnig-Hoffmann disease is almost uniformly fatal by age 2 years. However, because some affected infants survive beyond infancy and live into childhood, aggressive management including physiotherapy and respiratory therapy is essential in all cases. The management objectives in young children with the intermediate form are twofold: (1) maintain active mobility and independence as long as possible and (2) prevent the development of contractures and kyphoscoliosis. Any devices, even a scooter board, should be considered to maintain mobility. Because all patients invariably become wheelchair confined, the use of an electric-powered wheelchair is required. However, the timing of wheelchair use is critical because it hastens the development of contractures and scoliosis. Stretching exercises in major joints should be part of the patient’s daily routine. Patients with SMA have normal or increased intelligence. They attend school and as adults often live and work outside the home. A well-coordinated multidisciplinary approach is essential when attempting to optimize residual function, especially during periods of disease progression. Physical therapy, occupational therapy, orthopedic evaluation, and emotional support are essential. Maintaining an upright position delays the development of scoliosis. Therefore, a specialized evaluation for a wheelchair at a comprehensive seating clinic is critical. A back brace potentially delays the development of scoliosis. However, bracing remains controversial because it does little to retard the onset or progression of scoliosis and may actually impair function in some patients by reducing spinal flexibility and respiratory vital capacity. Potential benefits from bracing include reduced back discomfort and the ability to sit for longer periods. Progressive scoliosis eventually requires surgical correction in most patients with juvenile SMA. In general, delay surgery until growth ceases. However, in some patients who have never ambulated or who lost ambulation very early, consider surgical intervention for severe scoliosis even before growth ceases. Improved aesthetics, balance, and

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CHAPTER 97 Disorders of Upper and Lower Motor Neurons seating comfort are among the benefits; however, lack of body flexibility, reduced pulmonary function, and general decline in overall motor function may occur after surgery. Pros and cons for scoliosis surgery must be openly discussed with the patient, although for most, the benefits outweigh the disadvantages. Preoperative and postoperative physical and occupational therapy assessments are critical steps for the patient who contemplates spinal fusion for progressive scoliosis in SMA.

Genetic Counseling and Prenatal Diagnosis SMA is one of the most devastating diseases of childhood, and the parents of affected children and their relatives should receive genetic counseling, including determination of carrier status of SMN genes. The available carrier detection tests determine the SMN1 and SMN2 gene dosages and are best carried out in a family where an SMN deletion has been found previously in an affected individual or for an individual who is about to marry a known carrier. Noncarriers will have a single copy of the normal SMN1 on each chromosome, whereas carriers will have only one normal and one deleted SMN gene. Determination of the SMN2 gene dosage in the setting of an SMN deletion is of particular prognostic importance: the more copies of SMN2, the better the prognosis.

Kennedy Disease (X-Linked Recessive Bulbospinal Neuronopathy) In 1968, Kennedy and colleagues reported a new X-linked recessive SMA with bulbar involvement and gynecomastia. The primary pathology was thought to be in the LMNs, but sensory system involvement was later recognized, which led to the term bulbospinal neuronopathy. Molecular genetics research has shown Kennedy disease to be a trinucleotide repeat expansion disease. Though rare, it is more common than adult-onset SMA (Box 97.5).

Pathogenesis In 1991, La Spada and colleagues found the gene abnormality responsible for Kennedy disease: a cytosine-adenine-guanine (CAG) trinucleotide repeat expansion on the androgen receptor gene located on the X chromosome. In normal individuals, the repeats range from 17 to

Characteristic Features of Kennedy Disease

BOX 97.5

CAG, Cytosine-adenine-guanine.

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26 in this coding region, whereas in patients with Kennedy disease, the repeats range from 40 to 65. Two independent components exist for the symptoms of Kennedy disease, one androgen dependent and the other androgen independent. The gynecomastia and testicular atrophy seen in Kennedy disease may be associated with the classic function of the androgen receptor, and thus the severity of symptoms might relate directly to the receptor’s affinity for androgen. Studies of cultured scrotal skin fibroblasts found that direct high-affinity dihydrotestosterone binding decreases in some patients. The abnormal expansion of CAG repeats involves the first exon, an amino-terminal transactivating domain of the androgen receptor protein. The expansion of the CAG repeat in an androgen receptor causes a linear decrease in the transactivation function but does not completely eliminate androgen receptor activity. The residual androgen receptor activity is sufficient to ensure normal development of male primary and secondary sexual characteristics, as evidenced by the fact that affected men are phenotypically male and usually fertile. The subtle decline of androgen receptor transactivation may eventually lead to the loss of integrity of certain tissues that require continuously high androgen levels. Androgens are crucial for normal male development of motor neurons in the rat spinal bulbocavernosus nucleus and for regenerating facial motor neurons in rats and hamsters. Therefore, continuous androgen receptor function may be crucial to maintain normal motor neuron function throughout life. As with most other trinucleotide repeat expansion disorders such as Huntington disease and several spinocerebellar ataxias, the trinucleotide repeat expansion mutation appears to confer a toxic gainof-function on the gene product rather than a loss of function. In fact, complete absence of the androgen receptor leads to an entirely different disorder called androgen-insensitivity syndrome. The mutant androgen receptor leads to an altered receptor–DNA interaction or receptor–protein interaction that interferes with neuronal function. The CAG repeat encodes an unusually long polyglutamine tract in the androgen receptor protein, which appears to alter the normal protein moiety, resulting in mutant protein aggregation. This may in turn interfere with proteasomal breakdown of other cellular proteins and/ or interfere with tubulin-mediated cellular transport. Mutant protein may also interfere with mitochondrial function and transcription regulation and contribute to endoplasmic reticulum stress (Cortes and La Spada, 2018).

Clinical Features

Pathogenesis: X-linked recessive inheritance Abnormal CAG expansion in the gene encoding androgen receptor protein Neurological manifestations: Slowly progressive limb-girdle muscle weakness Early tremor Slowly progressive moderate bulbar dysfunction Muscle cramps and prominent fasciculations Facial fasciculations Systemic manifestations: Gynecomastia (60%–90%) Endocrine abnormalities (testicular atrophy, feminization, infertility) Diabetes mellitus Laboratory studies: Markedly abnormal sensory nerve conduction studies Elevated serum creatine kinase Abnormal sex hormone levels Abnormal CAG repeats in the androgen receptor gene

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As is often seen in an X-linked syndrome, this is a disorder of men, who remain largely asymptomatic until after age 30 years. Hand tremor and subtle speech disturbance are early features that are followed by LMN muscle weakness, initially involving either the proximal hip extensor or shoulder girdle muscles, and associated with decreased or absent reflexes, muscle atrophy, and occasionally calf pseudohypertrophy. Kennedy disease usually causes no respiratory muscle weakness. Coarse muscle fasciculations can be prominent in the extremities and trunk and muscle cramps can be a first symptom in many (Rhodes et al., 2009). Facial and perioral fasciculations are present in more than 90% of patients (Video 97.3). The tongue shows chronic atrophy, often as a longitudinal midline furrow. However, despite weakness of facial and tongue muscles, significant bulbar symptoms are usually a relatively late feature. Neurological examination of the sensory system may reveal only modest impairment. Progression is slow, with most cases remaining independent of assist devices until late into the fifth decade of life (Atsuna et al., 2006). If bulbar dysfunction is severe, the prognosis becomes less favorable. Partial androgen insensitivity is an important element of this condition, and gynecomastia is one of the unique features of Kennedy disease that can be found in 60%–90% of

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patients (Fig. 97.3). Other endocrine abnormalities include testicular atrophy, infertility (40%), and diabetes mellitus (10%–20%). It is now recognized that female carriers may manifest subtle neurological deficits such as late-onset bulbar dysfunction. This disorder often exhibits genetic anticipation—that is, the greater the number of repeats, the younger the age at onset. However, the number of repeats has no correlation with other features such as severity of weakness, serum CK level, and presence or absence of gynecomastia, impotence, or sensory neuronopathy. Furthermore, there is marked variation in phenotypical expression within and among families.

Laboratory Studies Molecular genetic testing is available to identify the abnormal expansion of the CAG repeat in the exon 1 of the androgen receptor gene on the X chromosome. CK levels may be elevated as high as 10 times normal. Serum androgen levels are either normal or decreased, whereas estrogen levels are elevated in some patients. The estrogen-to-androgen ratio increases in some patients, but there is no consistent finding regarding sex hormone levels, and evidence of partial androgen resistance may not develop for several years after disease onset. Motor nerve conduction study results are generally normal, although one-third of the patients have reduced amplitudes of CMAPs. EMG examination of these patients is always abnormal and shows modest acute but prominent chronic denervation changes in motor units. EDX reveals a sensory neuronopathy in 95% of patients (Ferrante and Wilbourn, 1997). Another unique change is the presence of prominent fasciculation potentials in the face (especially in the perioral region) and limbs. Muscle biopsy shows modest denervation, prominent reinnervation, and fiber-type grouping similar to that seen in other forms of adult-onset SMA. Sural nerve biopsy usually reveals a loss of myelinated fibers.

Differential Diagnosis The clinical features (e.g., progressive limb-girdle weakness, bulbar signs, muscle cramps, prominent fasciculations) resemble those of ALS, but a careful physical examination should provide sufficient clues to distinguish one from the other. The most characteristic features are gynecomastia, perioral fasciculations, calf pseudohypertrophy, and hand tremor. Generally, ALS progresses rapidly, whereas Kennedy disease is a largely indolent disorder. The EDX in Kennedy disease shows abnormal sensory nerve conduction studies, which is unusual for any motor neuron disease. Kennedy disease may also be easily mistaken for adult-onset SMA because of the slowly progressive limb-girdle weakness in both, but bulbar involvement and gynecomastia are unlikely features of SMA. Hereditary sensorimotor neuropathy, limb-girdle dystrophy, or facioscapulohumeral muscular dystrophy also may mimic Kennedy disease. Careful clinical examination, EDX studies, and muscle or nerve biopsy distinguishes these disorders. Ultimately, a molecular gene study to identify the abnormal CAG repeats in the androgen receptor gene will yield the answer.

Manifesting Carrier The female children and mother of an affected male patient are all obligate carriers (except in rare instances of a de novo mutation). Male children of affected individuals cannot inherit the mutant gene on the X chromosome. Female siblings of an affected patient have a 50% chance of carrying the affected gene on the X chromosome. Through a process known as skewed X chromosome inactivation (lyonization), female carriers can present with neuromuscular symptoms such as exertional muscle pain, cramps, and late-onset bulbar dysfunction, and the EDX may detect mild chronic denervation in both upper and lower limb muscles.

Treatment Supportive and symptomatic therapy is the key to treatment, as outlined in the section on adult-onset SMA. Muscle cramps may be problematic but are often relieved by baclofen, clonazepam, or vitamin E. Patients with symptomatic diabetes require appropriate medical management. In Kennedy disease, dysarthria and dysphagia may cause marked disability. Although severe loss of bulbar function is rare, offer speech therapy and appropriate communicative devices when appropriate. Careful nutritional management is also important. Enteral feeding provided via gastrostomy is the most effective and practical means to meet nutritional and fluid requirements. Genetic counseling is important for patients, potential carriers, and male siblings. A natural history-controlled study recently showed that long-term use of leuprorelin, a gonadotrophin analogue, improves elements of functional decline and also reduces respiratory complications and death in Kennedy disease (Hashizume et al., 2017).

Progressive Muscular Atrophy

Fig. 97.3 A man with X-linked recessive bulbospinal muscular atrophy (Kennedy disease), showing gynecomastia. (From Perkin, G.D., Miller, D.C., Lane, R.J.M., Patel, M.C., Hochberg, F.H., 2011. Atlas of Clinical Neurology, third ed. pp. 28–56. © Saunders.)

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PMA, first described by Aran in 1850, is a clinical LMN disorder during its entire clinical course and comprises approximately 5%–8% of all adult-onset motor neuron diseases. It is an overwhelmingly sporadic disease, but rare genetic diseases, such as those due to mutations in dynactin, VAPB, and A4V SOD1, may present with a pure LMN disorder, so a careful family history is important. Although PMA occurs in both sexes, men are more often affected than women. In a recent study, the average age of onset of PMA was about 3 years older than that of ALS, but other studies report a younger age at onset (Kim et al., 2009; Murray, 2006). Several studies have demonstrated that PMA progresses more slowly than ALS, so the average survival is significantly

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CHAPTER 97 Disorders of Upper and Lower Motor Neurons longer. The mean duration of disease was 159 months in one series of cases, and in another study, the 5-year survival was 63.7% in PMA versus 36.8% in ALS. Most of the very longest-duration cases of “ALS” have the PMA variant. Interestingly, the recent paper by Kim et al. showed that the development of UMN signs was unrelated to survival time after diagnosis (Kim et al., 2009; Murray, 2006). However, Visser et al. (2007) showed that patients with a low vital capacity baseline with an early decline in pulmonary function in the first 6 months had an especially poor prognosis. It has been questioned whether PMA is an independent disease or represents one end of the spectrum of ALS. However, if followed over time, many patients with PMA go on to develop clinical features of upper motor neuron disease, which allows reclassification to ALS (and thus eligibility for entry into clinical trials). In a recent retrospective study of 916 cases diagnosed with ALS at a major neurological center, in 91, the original diagnosis was PMA; 20 of these developed UMN signs within 61 months of the original diagnosis. Autopsy studies have also demonstrated UMN involvement in some cases classified as PMA in life. Studies using magnetic resonance spectroscopy and/or TMS reveal evidence for upper motor neuron involvement in PMA patients. Furthermore, cognitive/behavioral changes similar to those seen in ALS are also detected in PMA (Kim et al., 2009; Maragakis et al., 2010; Rowland, 2006).

Etiology All hypotheses about the cause of ALS are also applicable to PMA (see Etiology, under Amyotrophic Lateral Sclerosis, later in this chapter).

Clinical Features By definition, the signs and symptoms of PMA are LMN in type throughout the entire clinical course. A common presentation is that of focal asymmetrical muscle weakness in the distal extremities, with gradual spread to other contiguous muscles. The weakness and muscle atrophy are purely LMN in type and eventually involve both the upper and lower extremities. A less common presentation is that of proximal rather than distal muscle weakness. Bulbar and respiratory involvement eventually develops but is not as common in the early stages as in classic “spinal” ALS.

Laboratory Studies The serum CK concentration may be moderately elevated, especially when patients are physically active, but never attains levels more than 10 times normal. Patients with PMA do not have high titers of anti-GM1 antibodies. The EMG examination reveals findings consistent with a widespread disorder of anterior horn cells and is useful to exclude other diagnostic possibilities such as CIDP, MMNCB, or myopathy. Muscle biopsy will show denervation atrophy, but it is usually unnecessary to perform this test unless the clinical features are unusual enough to suggest an alternative diagnosis.

Differential Diagnosis PMA is usually a fatal disease and has no cure. Therefore, the diagnosis of PMA requires the exclusion of all other potentially treatable or definable diseases. Indeed, PMA-like disease is the most common type of presentation in the “mimic” disorders spectrum (Cortes-Vicente et al., 2017). In a previous review, 17 of 89 patients originally diagnosed with PMA were later diagnosed with MMNCB, CIDP, inflammatory myopathy, and myasthenia gravis (Visser et al., 2002). MMNCB is the most important of the alternative conditions that may present with focal and asymmetrical weakness in the absence of UMN signs (for more detailed description, see Chapter 106). The classic form is associated with EDX

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evidence of multifocal demyelination conduction blocks and elevated titers of antibodies against GM1 gangliosides. Clinically, patients develop slowly progressive multifocal muscle weakness but less prominent muscle atrophy. The treatment of choice is human IVIG (Van den Berg-Vos et al., 2000). The clinical and electrodiagnostic findings of sensory involvement, high CSF protein levels, and response to immunotherapy readily separate CIDP and PMA. Important clues that should lead one to suspect inclusion body myositis (IBM) are elevated serum CK to levels more than expected in typical PMA and a selective weakness in wrist flexors, finger flexors, and quadriceps muscles, without fasciculations. EMG in IBM should show evidence of a primary myopathy with increased insertional activity but without fasciculations. In IBM, additional neurogenic changes are common, and quantitative EMG may be required to clearly identify the myopathic nature of this disorder. Muscle biopsy characteristically reveals rimmed vacuoles and nuclear inclusions. Adult-onset SMA is a far more indolent disorder than PMA, and the very chronic process of denervation and reinnervation in SMA leads to fiber-type grouping on muscle biopsy, which is not a prominent feature of the less-protracted PMA. It is important to carry out regular follow-up examinations on patients with PMA to search for signs of UMN involvement that indicate the diagnosis of ALS. The pure motor neuropathy forms of CMT (especially hereditary motor neuropathy type V) present with a slowly progressive distal pattern of weakness and wasting, with no sensory changes. A familial pattern is usual, and genetic testing may reveal mutations in different genes such as GARS or seipin. A paraneoplastic motor neuronopathy has been described with clinical features that are similar to PMA, albeit with more rapid progression and with later development of nonmotor features. Many such cases have anti-Hu antineuronal antibodies in the setting of solid cancers (especially small-cell lung cancer). A similar subacute presentation may also occur in patients with lymphoma or other lymphoproliferative disorders, although signs of corticospinal tract dysfunction may become apparent in over 50% of cases. The onset of lymphoma may or may not coincide with onset of motor features.

Treatment The treatment of PMA is identical to that of ALS, as summarized later in this chapter.

Subacute Motor Neuronopathy in Lymphoproliferative Disorders A subacute, progressive, and painless motor neuron syndrome may rarely develop in patients who have Hodgkin and non-Hodgkin lymphoma with or without a paraproteinemia (Rowland, 2006; Rudnicki and Dalmau, 2000). The lymphoma may or may not temporally coincide with the motor neuron disorder, and one or other disorder may present first. Although UMN signs may develop later in more than half of all cases, a LMN-onset syndrome is typical, with patchy, asymmetrical, lower extremity–predominant muscle weakness and wasting. Neuropathology shows a loss of anterior horn cells and ventral root nerve fibers; some have evidence of inflammation in the anterior horns of the spinal cord, and half have corticospinal tract degeneration. In some patients, the disease may be relatively benign. The rate of progression of muscle weakness and atrophy tends to slow down with time, and, in rare instances, the motor syndrome may respond to treatment of the underlying lymphoproliferative disorder. However, the prognosis appears to be less favorable in those who develop a combined UMN and LMN disorder. Twenty percent of all cases so far reported with motor neuron presentations in the setting of lymphoproliferative disease had myeloma or macroglobulinemia. The pathogenesis of this ALS-like disorder is undetermined, but an immune mechanism

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may be at play; small patient series and case reports reveal that some patients who develop this LMN syndrome may have various autoantibodies (such as antisulfatide antibody), paraproteinemia, increased CSF protein, and/or oligoclonal bands.

Postirradiation Lower Motor Neuron Syndrome Radiation directed to the retroperitoneal paraaortic area for the treatment of testicular or lymphoid cancers can cause a pure LMN syndrome in the lower extremities that first appears many years after the irradiation. Sensory abnormalities and sphincter dysfunction are rare, and the EDX findings are consistent with a disorder of the lumbosacral motor neurons or the cauda equina (the SNAPs are spared). Myokymic discharges and nonresolving conduction blocks are characteristic electrodiagnostic features. The disease usually progresses over the first few years after symptom onset but subsequently becomes stable. There is debate as to the exact mechanism. There is only anecdotal evidence that antiinflammatory therapies may be of benefit (Chamberlain et al., 2011).

DISORDERS OF BOTH UPPER AND LOWER MOTOR NEURONS Amyotrophic Lateral Sclerosis ALS is a neurodegenerative disorder of undetermined etiology that primarily affects the motor neuron cell populations in the motor cortex, brainstem, and spinal cord. It is progressive, and most patients eventually succumb to respiratory failure. The first detailed description was by Jean Martin Charcot in 1869, in which he discussed the clinical and pathological characteristics of “la sclérose latérale amyotrophique,” a disorder of muscle wasting (amyotrophy) and gliotic hardening (sclerosis) of the anterior and lateral corticospinal tracts (Gordon, 2006) involving both upper and lower motor neurons. ALS is known by several other names including Charcot disease, motor neuron disease, and, in the United States, “Lou Gehrig disease” in remembrance of the famous “Iron Horse” of baseball who was diagnosed with ALS in 1939. The World Federation of Neurology Research Group on Neuromuscular Disorders has classified ALS as a disorder of motor neurons of undetermined cause, and several variants are recognized. Included in this group are PLS and PBP. As previously mentioned, PMA is also thought to be a variant of ALS, despite its exclusion from current clinical research trial criteria. It is important to recognize that ALS is a progressive dynamic disorder. Some cases present with the classic combination of UMN and LMN signs, but others may have UMN onset, LMN onset, bulbar onset, or dyspnea at onset and only later develop signs of involvement of the other parts of the motor system (Box 97.6). Between 5% and 10% of ALS is familial rather than sporadic, the most common inheritance pattern being autosomal dominant. Thus one comes across the terms sporadic ALS (SALS) and familial ALS (FALS). A few other conditions have a phenotypical expression similar to that of ALS, including Western Pacific ALS-parkinsonism-dementia complex (PDC) (or Guamanian ALS) and juvenile ALS. The incidence and prevalence rates for sporadic ALS are surprisingly uniform throughout the world. The estimated incidence in North America and Europe is about 2 per 100,000, and the prevalence is about 5–7 per 100,000 (Mehta et al., 2016). In sporadic spinal ALS, the male-to-female ratio is 1.2–1.4 : 1, but a slight female predominance exists in the bulbar-onset variety. ALS may occur as early as in the second decade of life, but the peak incidence is in the 65to 74-year-old age bracket (McGuire and Nelson, 2006). The mean disease duration from symptom onset to death is approximately

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Practical Classification of Amyotrophic Lateral Sclerosis

BOX 97.6

Sporadic or acquired ALS: Classic (spinal-onset) ALS Mills hemiplegic variant Pseudoneuritic presentation Flail-arm presentation Monomelic presentation UMN onset LMN onset Bulbar onset Dyspnea onset Progressive muscular atrophy Primary lateral sclerosis Progressive bulbar palsy Western Pacific ALS Familial ALS: ALS1: SOD1 missense mutations, chr 21q-22.1, adult, AD (rare AR) ALS2: ALSIN mutations, chr 2q330, juvenile onset, AR ALS3: gene unknown, chr 18q, adult, AD ALS4: senataxin gene, chr 9q34, juvenile onset, AD ALS5: linked to chr 15q15, juvenile onset, AR ALS6: FUS/TLS, chr 16p, adult, FTD overlap, AD (some AR) ALS7: gene unknown, chr 20p, adult, AD ALS8: VAPB, chr 20q, adult, AD ALS9: angiogenin, chr 14q, adult, AD ALS10: TDP-43, chr 1q, adult, FTD overlap, AD ALS11: FIG4, chr 6q, adult, AD ALS12: optineurin, chr 10p15, AD ALS13: ATXN2 12q24, association ALS14: VCP, Chr 9p13 ALS15: UBQLN2, chr X ALS16: SIGMAR1, chr 9p13 ALS17: CHMP2B, chr 2q, adult, AD ALS18: PFN1, chr 17p13 ALS19: ERBB4, chr 2q34 ALS20: HNRNPA1, chr 12q13 ALS21: MATR3, chr 5q31.2 ALS22: TUBA4A, chr 2q35 ALS23: ANXA11, chr 10q22.3 ALS24: NEK1, chr 4q33 ALS25: KIF5A, chr 12q13.3 ALS due to rare mutations (e.g., p150 dynactin subunit mutation, DAO mutation, SQSTM1 mutation, hnRNPA1 mutation, ERLIN2 mutation, UNC13A mutation, cytochrome oxidase gene mutation, NF heavy chain gene mutation, peripherin, APEX nuclease gene mutation) FTD-ALS overlap: ALS-FTD, C9orf72, chr 9p21, adult, AD (can present as pure ALS also or as pure FTD) FTD with some ALS features; tau gene on chr 17 and progranulin gene on chr 17. AD, Autosomal dominant; ALS, amyotrophic lateral sclerosis; AR, autosomal recessive; chr, chromosome; FTD, frontotemporal dementia; LMN, lower motor neuron; UMN, upper motor neuron.

3 years, but roughly 1 in 5 patients survive to 5 years, and 1 in 10 patients survive to 10 years (Murray, 2006). The disease process may be more aggressive in patients with bulbar onset, older age at onset, and certain genotypes (Al-Chalabi and Hardiman, 2013). No specific environmental, occupational, or physical factors link with absolute

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Pathology The pathological hallmarks of ALS are the degeneration and loss of motor neurons, with astrocytic gliosis and microglial proliferation in the presence of intraneuronal inclusions in degenerating neurons and glial cells. UMN cell loss occurs in the motor cortex, with loss of Betz cells from Brodmann area 4 and astrocytic gliosis and axonal loss in corticospinal tracts. There is loss of LMNs in the brainstem and spinal cord, with both TAR DNA binding protein 43-positive and FUS-positive ubiquitinated inclusions in remaining neurons. Small eosinophilic cytoplasmic inclusions called Bunina bodies are common. Extramotor pathology may also be found in the frontotemporal cortex, hippocampus, thalamus, spinocerebellar tracts, dorsal columns, and substantia nigra.

Etiology The cause for sporadic ALS is unknown. A significant body of basic and clinical research lends strong support to a theory of ALS pathogenesis which proposes selective motor neuron damage from a complex chain of injurious events involving excitotoxins, oxidative stress, neurofilament dysfunction, altered calcium homeostasis, mitochondrial dysfunction, enhanced motor neuron apoptosis, and proinflammatory cytokines. Genetic factors may play a role in “sporadic” disease: several proposed ALS susceptibility genes include APOE, SMN, peripherin, apex nuclease gene, and vascular endothelial growth factor (VEGF) gene. Indeed, it has been proposed that onset of ALS is a multi-step process in which a genetic mutation represents one of several steps in the development of the disease (Al-Chalabi and Hardiman, 2013). Protein aggregation. One of the pathological hallmarks of sporadic ALS is the presence of TDP43- and FUS-positive ubiquitinated intraneuronal inclusion bodies in neurons and glial cells. TDP43 and FUS, both implicated in the pathogenesis of FALS and SALS, are normally nuclear proteins, but in ALS they are mislocalized to the cytoplasm in the form of distinct aggregates (inclusion bodies); how the mislocalization contributes to neuronal loss is still unclear. Several other pathological intracellular aggregates described in ALS can contain neurofilament proteins, chaperone proteins (14-3-3), and copper-zinc superoxide dismutase (SOD1). Furthermore, mutations in other ALSassociated genes, such as UBQLN2, C9orf72, SIGMAR1, PFN1, DAO, and ATXN2, are also associated with aggregate formation (Finsterer and Burgunder, 2014). It is still unclear whether protein aggregation is directly toxic to cells or is a defense mechanism to reduce intracellular aggregation of toxic proteins. Glutamate excitotoxicity and free radical injury. Glutamate, which is the most abundant free amino acid in the CNS, is one of the major excitatory amino acid (EAA) neurotransmitters. Glutamate produces neuronal excitation and participates in many neuronal functions, including neuronal plasticity. In excess, however, it causes neurotoxicity. The role of glutamate excitotoxicity in neurodegeneration is

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strengthened by the observation that exogenous glutamate receptor agonists result in clinically observable neurotoxicity, as seen in lathyrism, Guamanian ALS, and Konzo (see previous section on UMN disease). Domoic acid is another potent non-N-methyl-d-aspartic acid (NMDA) receptor agonist that can cause motor weakness. An outbreak of food poisoning caused by ingestion of mussels contaminated with domoic acid–producing phytoplankton diatoms led to an amnestic syndrome and, in some cases, significant muscle weakness (sometimes manifesting as an alternating hemiplegia) (Costa et al., 2010). Impaired glutamate transport reduces clearance of glutamate from the synaptic cleft, which may leave excessive amounts of free excitatory neurotransmitter to repeatedly stimulate the glutamate receptor and thus allow calcium ions to enter the neuron. Regional differences in the levels of activity of calcium buffering systems and in glutamate receptor subtype expression may explain the selective vulnerability of certain motor neuron pools within the CNS. Immunological and inflammatory abnormalities. Several pieces of evidence implicate an inflammatory process in the pathogenesis, if not the initiation, of ALS. It is now understood that there is a complex interplay between astrocytes, microglial cells, proinflammatory cytokines, and cell adhesion molecules as part of the pathogenesis of both sporadic and familial ALS. However, immunotherapies have been ineffective to date. Whether these inflammatory responses are part of the pathogenesis or are indeed part of a protective response remains to be elucidated (Haukedal and Freude, 2019). Unfortunately, various strategies aimed at modulation of the immune system have failed to alter the course of ALS in treatment trials to date. Mitochondrial dysfunction. Disturbances in mitochondrial function and structure occur in both human ALS and in transgenic animal models of the SOD1-associated disease, which suggests a role for aberrant redox chemistry in the earlier stages of disease. In effect, mitochondrial damage may impair the cellular energy production system. Mutant SOD1 aggregates appear to clump together on mitochondrial membranes and may also interfere with chaperoneassisted mitochondrial protein folding. Furthermore, axonal transport of mitochondria along axons may be disrupted (Shi et al., 2010). Recent evidence reports that Betz cells that display TDP-43 inclusions show dysfunction at the level of the mitochondria, endoplasmic reticulum, and the nuclear membrane. Furthermore, these changes emerge early in the disease (Gautam et al., 2019). Experimental ALS models also display a role for mitochondrial dysfunction in FUS-associated disease (Cozzolino et al., 2013). Neurofilament and microtubule dysfunction. Abnormalities of axonal transport likely play a significant part in the pathogenesis of ALS. Mutations in the genes for neurofilament subunits (neurofilament heavy chain and peripherin), although rare, appear to confer increased risk for the later development of SALS (Robberecht and Philips, 2013). It has been shown that mutations in profilin 1 (PFN1), which is an important protein involved in the polymerization of actin, can cause ALS, as can mutations in VAPB and dynactin (see Familial Amyotrophic Lateral Sclerosis section). Antibodies to phosphorylated neurofilament heavy subunit or neurofilament light subunit have emerged as new diagnostic biomarkers for ALS, although their use in detecting disease progression over time appears to be limited (Mitsumoto and Saito, 2018). Aberrant RNA processing. RNA metabolism refers to the various steps in the life of RNA molecules from pre–mRNA splicing through RNA editing and processing, and then on to transport, reassembly into polyribosomes, and degradation. An evolving theory, and perhaps the most important one in ALS pathogenesis is that mutations in such proteins as C9orf72, TDP43, FUS/TLS, senataxin, peripherin, SMN1, SOD1, and angiogenin may result

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in aberrant interactions in RNA metabolism (Chew et al., 2019, Finsterer and Burgunder, 2014; Haeusler et al., 2014; Robberecht and Philips, 2013).

Clinical Features The typical clinical picture in ALS is that of a patient with a progressive motor deterioration manifesting with both UMN and LMN symptoms and signs. Thus, one should consider this diagnosis when a patient presents with a combination of marked weakness and wasting but with brisk reflexes, spasticity, and pathological reflexes. Of course, not all patients present with this classic pattern: muscle weakness in ALS usually begins in a focal area, first spreading to contiguous muscles in the same region before involvement of another region. The first presentation may appear very similar to a focal mononeuropathy, sometimes called the pseudoneuritic or flail leg presentation (Wijesekera et al., 2009). More commonly, however, single-limb weakness appears to occur in muscles derived from more than one peripheral nerve and/or nerve root distribution; this is a monomelic presentation. Onset of muscle weakness is more common in the upper than the lower extremities (classic, spinal ALS), but in approximately 25% of patients, weakness begins in bulbar-innervated muscles (bulbar-onset ALS). On rare occasions (1% or 2% of patients, more often male), the weakness starts in the respiratory muscles (dyspnea or respiratory onset). Some patients present with weakness that is restricted to one side of the body (Mills hemiplegic variant), and up to 10% of patients appear with bilateral upper-extremity wasting, which is known as the flail arm or flail person in the barrel variant. The latter is more commonly seen in males and typically presents in proximal muscles of the upper limb before spreading distally into the hands, and then much later (one study used a 12-month interval) into other regions. Reflexes may be retained or even brisk in the markedly weakened limbs (Video 97.4).

Symptoms of muscle weakness vary, depending on which motor function is impaired. For example, when weakness begins in the hand and fingers, patients report difficulty in turning a key, buttoning, opening a bottle cap, or turning a doorknob (Fig. 97.4). When weakness begins in the lower leg, foot drop may be the first symptom, or the patient may complain of instability of gait, falling, or fatigue when walking (see Video 97.3). When bulbar muscles are affected, the first symptoms may be slurred speech, hoarseness, or an inability to sing or shout, soon followed by progressive dysphagia (Fig. 97.4; see Video 97.4). Patients with bulbar-onset ALS often initially consult ear, nose, and throat (ENT) specialists and not only experience progressive impairment in bulbar function but also excessive drooling (sialorrhea) and weight loss. Pseudobulbar palsy may present with inappropriate or forced crying or laughter (see Signs and Symptoms of Upper Motor Neuron Involvement, earlier in this chapter), which is often a source of great emotional distress for patients. Excessive forced yawning may also be a manifestation of pseudobulbar palsy. In the rare patient who presents with progressive respiratory muscle weakness, the first consultation may be with a pulmonologist or even admission to the intensive care unit; the diagnosis of ALS may be established when the patient fails weaning from the ventilator. Head drop (or droop) may be a feature in ALS, caused by weakness of cervical and thoracic paraspinal muscles (Fig. 97.6). Fasciculations are not commonly the presenting

Fig. 97.5 Atrophy of the Tongue in Amyotrophic Lateral Sclerosis.

A

B Fig. 97.4 A, B, Severe intrinsic hand muscle atrophy in a patient with amyotrophic lateral sclerosis. Note the “claw hand” and atrophy of muscles innervated by both ulnar and medial nerves.

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Fig. 97.6 Patient with amyotrophic lateral sclerosis, showing head droop caused by weakness of the thoracic and cervical paraspinal muscles.

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CHAPTER 97 Disorders of Upper and Lower Motor Neurons feature of ALS, but they develop in almost all patients soon after onset, and their absence should prompt one to reconsider the diagnosis. In some patients, waves of fasciculations spread across the chest or back. Muscle cramps are one of most common symptoms in patients with ALS and often precede other symptoms by many months. In ALS they can occur in unusual muscles such as in the thigh, abdomen, back, or tongue. Spasticity develops in wasted muscles, and patients may suffer painful flexor spasms in limbs. As dysphagia worsens, reduced caloric intake worsens fatigue and accelerates muscle weakness. Aspiration of liquids, secretions, and food becomes a risk. Patients may complain that they produce copious amounts of abnormally thick oral secretions, which may drool excessively from the mouth. This sialorrhea is made worse as perioral muscles weaken and/or head drop develops. Weight loss is often rapidly progressive; this does not simply reflect poor caloric intake but represents a form of ALS cachexia. Marked loss of muscle bulk exposes joints and associated connective tissues to abnormal mechanical stresses that can lead to joint contractures, joint deformities, painful shoulder pericapsulitis, and bursitis. Sleep disturbances in the form of increased awakenings from hypopnea and hypoxia are common in ALS and contribute to daytime sleepiness, morning headaches, and fatigue. As respiratory difficulty worsens, patients may be unable to lie supine because of worsening diaphragmatic weakness and thus compensate by using multiple pillows. In more advanced stages, patients are unable to lie in bed at all. Other manifestations of ventilatory failure include dyspnea on exertion and eventually dyspnea at rest. As the disease advances, motor function is progressively impaired, and activities of daily living (e.g., self-hygiene, bathing, dressing, toileting, walking, feeding, and verbal communication) become difficult. Accordingly, a patient’s quality of life progressively deteriorates. It may be difficult to distinguish daytime fatigue, broken sleep, affect lability, and sighing from depression, but it is vitally important to be aware of the latter, as both fatigue and depression may occur in ALS (McElhiney et al., 2009). FTD and/or cognitive impairment is present in many patients with ALS, albeit on a spectrum from apparently normal to a florid FTD. These observations lend support to the notion that ALS is not a pure disorder of motor neurons, but rather a disorder that primarily affects motor neurons, with the potential to involve nonmotor systems. One needs to be cautious when assessing apparently cognitively normal patients with ALS because the deficits may be so subtle as to require specific assessments of personality, behavior, praxis, verbal fluency, visual attention, and verbal reasoning. Dysarthria may mask language disturbances (especially anomia). With appropriate testing, cognitive deficits may be found in about 50% of patients with ALS, but the full clinical (Neary) criteria for a diagnosis of FTD are met in only about 15%–20% of cases (LomenHoerth, 2011). Many of the genetic causes of ALS can also present with frontotemporal dementia (e.g., C9orf72) (see section on familial ALS below, Box 97.6).

Atypical Features Extrapyramidal dysfunction, eye movement abnormalities, autonomic disturbances, and abnormal sphincter control are extremely rare in ALS, and their presence should always prompt one to reconsider the diagnosis. Eye movement abnormalities, however, occur in rare cases maintained on ventilators, and sphincter disturbances have appeared in a few reports. Although sparing of the sensory system is characteristic, some patients do report vague sensory symptoms such as numbness or aching, and there is electrophysiological evidence that ascending afferent pathways may be involved, despite the absence of objective sensory loss on physical examination. The motor neurons of

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Onufrowicz in the sacral cord are essentially not involved in ALS, and thus patients generally do not complain of significant problems with sphincter control (although some may report mild urgency of micturition). Similarly, eye movements are typically normal in ALS; it takes detailed quantitative testing to be able to identify abnormal vertical ocular saccades. Approximately 5% of patients with ALS exhibit signs of extrapyramidal tract dysfunction, usually in the form of retropulsions during attempted ambulation.

Natural History of the Disease Evidence exists for a preclinical phase in ALS. Patients lose motor neurons before they become aware of weakness. Wohlfart (1958) estimated that collateral reinnervation could offset the development of clinical weakness until at least 30% of anterior horn cell motor neurons had been lost. Swash and Ingram described a case of sporadic ALS who complained of muscle fatigue for 6 years before onset of weakness, wasting, and fasciculations. However, once the clinical phase is evident, a generally linear decline in motor function occurs over time. The pattern of disease spread is predictable. When onset is in one arm, spread is often first to the contralateral side, then the ipsilateral leg, the contralateral leg, and finally the bulbar region. Onset in the leg often follows a similar pattern, yet again with final involvement of the bulbar region. Bulbar-onset ALS tends to spread to the hands first, with spread to thoracic myotomes, and then the legs. Overall, the pattern suggests that rostral-caudal involvement is faster than caudal-rostral spread. During the course of the disease, transitory improvement, plateaus, or sudden worsening can occur, but spontaneous improvement, although reported, is exceedingly rare.

Prognosis The median duration of ALS from clinical onset ranges from 22 to 52 months and the mean duration from 23 to 43 months, with an average 5-year survival rate of 22% (roughly 1 in 5) and a 10-year survival rate of 9.4% (roughly 1 in 10) (Murray, 2006). The most robust poor prognostic factors in ALS are older age at onset and bulbar-onset pattern (Chio et al., 2009). Other important poor prognostic factors include short interval between onset and clinical diagnosis (correlating with a more aggressive presentation), rapid progression rate as assessed on return visits, low body mass index, FTD-ALS presentation, dyspnea at onset, and rapid rate of decline in pulmonary function. PLS and PMA (clinically UMN- or LMN-only presentations) usually portend a better prognosis, whereas several other clinical subtypes, including Mills hemiplegic variant, the pseudoneuritic presentation (flail leg), and the flail-arm variant, harbor a better prognosis. Those who have younger age at onset and those who are psychologically well adjusted have a better prognosis. Those who have low-amplitude CMAPs in the setting of normal sensory potentials (the generalized low motor-normal sensory pattern) as revealed by nerve conduction studies appear to have a poor prognosis. Low serum chloride levels are associated with a short-term survival without ventilatory support because they reflect accumulation of bicarbonate due to respiratory failure. There may be differences in natural history and prognoses in different parts of the world; a natural history study in China revealed that Chinese ALS is somewhat younger in onset (mean age, 49.8 years) and with less bulbar presentations and a median survival time of 71 months (Chen et al., 2015)

Laboratory Studies The diagnosis of clinically definite ALS can sometimes be established on the history and clinical examination alone, but owing to the seriousness of the diagnosis, ancillary investigations are necessary to exclude other possibilities. All such testing is an extension of a thorough history

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and physical examination and includes blood tests, the EDX, and neuroimaging. Several blood tests are commonly performed as part of the evaluation of patients with suspected ALS. The list includes serum CK concentration, blood count, chemistry panel (including calcium, phosphate, and magnesium), Venereal Disease Research Laboratories (VDRL) test results, HIV, GM1 autoantibody titers, sedimentation rate, serum protein immunofixation or immunoelectrophoresis, angiotensin converting enzyme (ACE) and glycosylated hemoglobin (HbA1c), thyroid function studies including thyroid-stimulating hormone, serum parathormone (if calcium is raised), and vitamin B12 levels. The serum CK concentration may be modestly elevated, particularly early in the disease and in active males. Patients older than 50 years and smokers of any age should have a chest radiograph taken. If any chest lesion is identifiable, or if the presentation is subacute with atypical features such as sensory loss, an anti-Hu antibody level should be determined. Certain patients may have clinical features that suggest a disorder of the neuromuscular junction and should have testing for antibodies against the acetylcholine receptor or voltage-gated calcium channel. If there is biochemical evidence of adrenal insufficiency, it is prudent to obtain a VLCFA assay to investigate for possible adrenomyeloneuropathy. Young-onset ALS with atypical clinical features such as early dementia, cramps, and tremor should prompt the physician to obtain a leukocyte Hex-A assay. Young age at onset, with perioral fasciculations and gynecomastia, should prompt genetic assessment for the trinucleotide repeat expansion on the androgen receptor gene that is present in Kennedy disease. If there is a positive family history in otherwise typical ALS, it is important to counsel the patient in preparation for appropriate mutation analysis. Reserve CSF examination for cases with features suggestive of an infectious or infiltrative process such as lymphoma or basal meningitis or suspected CIDP. No specific features on muscle biopsy distinguish ALS from other neurogenic disorders; reserve biopsy for cases that are more suggestive of a myopathy. The EDX is an invaluable tool in the investigation of ALS and its variants (see Chapter 36). It serves as an adjunct to the clinical examination and is particularly useful in determining the presence or extent of LMN disease. Again, none of the EDX findings are ALS specific, but they can strongly support the diagnosis. Furthermore, repeated investigations at intervals monitor disease progression. Sensory nerve conduction studies are characteristically normal unless the patient happens to have a coincidental mononeuropathy or polyneuropathy. Motor nerve conduction study results may be normal, although the conduction velocity and CMAP amplitude may diminish in keeping with the extent of motor axon loss. There should be no evidence of conduction slowing or block, which would suggest a primarily demyelinating disorder. Severe motor axon loss may give rise to the “generalized low motor-normal sensory” EDX pattern, which may portend a poorer prognosis. The EMG examination characteristically reveals a combination of acute (positive sharp waves and fibrillation potentials) and chronic (reduced neurogenic firing pattern with evidence of increased amplitude and duration, polyphasic MUPS) changes in a widespread distribution that is not in keeping with any single root or peripheral nerve distribution. Fasciculation potentials are common and typically of complex morphology; their absence should prompt an investigation for another disorder. The Awaji-shima algorithm for the neurophysiological diagnosis of suspected ALS stresses the importance of fasciculation potentials: the presence of fasciculations potentials is evidence of acute denervation in the same way that one regards fibrillation potentials and positive sharp waves. Moment-to-moment amplitude variation, indicating impaired motor unit stability, is also an important sign of denervation (Carvalho and Swash, 2009). Mention should be

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made of a special EDX finding, the split-hand phenomenon; in some patients with ALS, EDX reveals severe changes in muscles of the lateral hand (thenar eminence) but relative sparing of the medial hand (hypothenar eminence). EDX changes should be observed in a certain topographical distribution and ideally should be carried out in at least three of the four regions of the neuraxis (bulbar, cervical, thoracic, and lumbosacral). The most important role for neuroimaging studies in ALS is to exclude structural, inflammatory, or infiltrative disorders that may mimic this disease, and therefore all patients should undergo appropriate imaging of brain and spinal cord. On occasion, one may discern abnormal signal in the motor tracts when viewed with proton density–weighted MRI scans of brain; this signal change is due to Wallerian degeneration and if seen occurs in patients with more severe disease. FLAIR and T2-weighted fast-spin echo sequences are less specific in their ability to detect such corticospinal tract signal changes. Nonspecific atrophy of the frontal and parietal cortex may also occur. Ultrasound may have a role in detection of tongue fasciculations that may not be otherwise found by EMG (Misawa et al., 2011; O’Gorman et al., 2017). The search for ALS biomarkers has led to the investigation of other imaging techniques such as magnetization transfer ratio (MTR) imaging, magnetic resonance voxel-based morphometry, magnetic resonance spectroscopy, and DTI (Mazon et al., 2018). Functional imaging studies with blood oxygenation level–dependent (BOLD) functional MRI and magnetoencephalography may reveal abnormal activity in motor and nonmotor areas in ALS, but further studies are needed to determine their role in UMN assessment (Agosta et al., 2010; Turner et al., 2009). Similarly, additional research is necessary to clarify the role of TMS, whether used alone or in combination with DTI in the evaluation of the UMN system (Foerster et al., 2013; Mitsumoto et al., 2007; Vucic and Rutkove, 2018). While erect forced vital capacity is the most commonly measured index of pulmonary function in ALS, supine FVC provides a more accurate assessment of diaphragmatic weakness. The maximal inspiratory pressure (MIP) and nocturnal oximetry are possibly more effective for the detection of nocturnal hypoventilation. Transdiaphragmatic sniff pressure (sniff Pdi) and the sniff nasal pressure (SNP) are also useful indicators of hypercapnia and nocturnal hypoxemia (Carratù et al., 2011; Miller et al., 2009; Niedermeyer et al., 2019).

Diagnosis In May 1990, at El Escorial, Spain, the World Federation of Neurology established diagnostic criteria for ALS, which were later modified at Airlie House, Virginia (1998) (http://www.wfnals.org). These criteria (Table 97.4) include clinical, electrodiagnostic, and pathological components. The clinical criteria divide candidates into those with definite, probable, laboratory-supported probable, possible, and FALS-based on a careful history and examination of four regions of the neuraxis: bulbar, cervical, thoracic, and lumbosacral. The purpose of establishing these criteria was to facilitate entry of appropriate candidates into clinical research trials, but they prove invaluable in the assessment of all patients with ALS. A patient is referred to as having “definite ALS” if there is clinical evidence of both UMN and LMN signs in three or more regions. “Probable ALS” is UMN and LMN signs in two regions. “Possible ALS” implies that a patient either has UMN and LMN signs in one region only or has UMN signs alone in two regions. In addition, “possible ALS” may be applied to those with LMN signs in two regions as long as these are detected rostrally to the UMN signs. “Probable ALSlaboratory supported” refers to those patients who have clinical evidence of possible ALS but also have EDX evidence of more widespread

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Definite ALS Probable ALS Probable ALS, lab-supported Possible ALS Familial ALS, lab-supported

UMN and LMN signs in at least 3 regions (bulbar and 2 spinal regions or 3 spinal regions without bulbar) UMN and LMN signs in 2 regions, with some UMN signs rostral to LMN signs UMN and LMN signs in 1 region, with UMN signs alone in another region and EMG evidence of LMN involvement in at least 2 limbs UMN and LMN signs in 1 region; or UMN signs alone in 2 or more regions; or LMN signs are rostral to UMN signs Otherwise unexplained UMN or LMN signs in at least 1 region, with gene mutation in the proband or a positive family history of family member with a disease-causing gene mutation

ALS, Amyotrophic lateral sclerosis; EMG, electromyographic; LMN, lower motor neuron; UMN, upper motor neuron. Adapted from revised World Federation of Neurology Criteria for the Diagnosis of ALS. Available at http://www.wfnals.org.

LMN involvement. The proposal is that one should apply the Awaji neurophysiological algorithm to the revised El Escorial criteria to clarify the El Escorial electrodiagnostic criteria and improve diagnostic sensitivity. The Awaji algorithm has increased the importance of fasciculation potentials as being representative of acute denervation as long as there is evidence of chronic denervation in the same muscles. Using both sets of criteria together, Carvalho and Swash demonstrated an increased sensitivity in the diagnosis of bulbar-onset ALS from 38% with revised El Escorial alone to 87% when both sets of criteria were used. Another group achieved a specificity of over 95% when using both sets of criteria together (Carvalho and Swash, 2009; Douglass et al., 2010, Gawel et al., 2014). More recently, a combination of clinical, electrophysiological, and TMS measures can generate an entity known as the ALS diagnostic index (ALSDI), which may help distinguish suspected ALS from mimics (Geevasinga et al., 2019). Follow-up examinations may be helpful in assessing patients with ALS, as disease progression may move a patient up a category, which not only may clarify the diagnosis but also may allow entry of that patient into research trials.

Differential Diagnosis The differential diagnosis of ALS is rather extensive; motor symptoms and signs may be present in many other neurological and systemic disorders. Because there are no specific diagnostic markers for ALS, differentiating all other motor neuron diseases that may produce signs and symptoms of UMN, LMN, or both UMN and LMN involvement is essential for establishing the correct diagnosis. One may approach this task in an anatomical fashion and consider how ALS may appear similar to other disorders of the brain, brainstem, spinal cord, anterior horn cell, nerve root, peripheral nerve, neuromuscular junction, and muscle. Alternatively, one may approach this task in terms of the presentation: Is it UMN only, LMN only, combined UMN-LMN, bulbar only, and so on? Are there any atypical features such as prominent bladder or sensory involvement that suggest another diagnosis? For example, when UMN involvement is prominent, PLS, spastic paraparesis, or HAM should be considered, whereas pure LMN involvement suggests that one should also consider PMA, IBM, MMNCB, adultonset SMA, Lambert-Eaton myasthenic syndrome, or Kennedy disease. Severe cervical spondylosis may impinge upon both the cervical cord and the nerve roots and thus present with both UMN and LMN signs. Because pain, spastic bladder, and posterior column signs are not always present, EMG and neuroimaging may be required to distinguish it from ALS. Neuroimaging is also invaluable in assessing other disorders of the brainstem and spinal cord that may superficially mimic certain features of ALS such as intrinsic or extrinsic tumors, foramen magnum meningiomas, syringobulbia, and syringomyelia. MS usually presents with UMN signs, but on rare occasions, LMN signs develop when demyelinating plaques affect the ventral root exit zones. Neuroimaging and lumbar puncture studies should distinguish the two conditions. CIDP may manifest as a predominantly LMN

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disorder, but some patients also have demyelinating lesions in the CNS that cause additional UMN signs. It may be difficult to differentiate PBP from bulbar myasthenia gravis, as even repetitive stimulation studies and testing for serum antibodies against acetylcholine receptor may be negative in the latter. Follow-up examinations, however, usually reveal the insidiously progressive nature of the motor neuron disorder. Bulbar symptoms in ALS may be mistaken for brainstem stroke, but the progressive nature of bulbar symptoms and negative brainstem MRI will usually clarify the picture. On rare occasions, the increased tone, dysarthria, and sialorrhea of Parkinson disease may be confused with ALS. However, the former is characteristically responsive to l-dopa, and tremor is often prominent. Multiple-system atrophy may present with a combination of UMN and LMN signs together with dysarthria and dysphagia, but cerebellar ataxia, eye-movement abnormalities, sphincter disturbance, and dysautonomia are usually prominent features. SCA types 2 and 3 (Machado-Joseph disease) are also part of the differential diagnosis. Other diseases that mimic ALS include adult Hex-A deficiency, adrenomyeloneuropathy, and certain motor paraneoplastic syndromes. Hyperthyroidism may present with hyperreflexia, weight loss, and fasciculations but also tremor, heat intolerance, and tachycardia. Hyperparathyroidism may present with a LMN or even myopathic disorder that mimics PMA. Both the benign fasciculation syndrome and cramp-fasciculation syndrome may lead to referrals for the evaluation of ALS, but these patients have no other symptoms or signs that suggest a widespread progressive disorder of motor neurons.

Treatment Treatment of ALS is outlined in Box 97.7 and Table 97.5.

Presentation of the diagnosis of amyotrophic lateral sclerosis.

The first step in the management of ALS is to present the diagnosis in a compassionate yet informative manner. Allow adequate time to present the diagnosis. Whenever possible, the patient should not be

Comprehensive Care and Management for Patients With Amyotrophic Lateral Sclerosis

BOX 97.7

Presentation of the diagnosis of ALS Specific pharmacotherapy Symptomatic treatment Team approach at ALS clinic Ethical and legal issues Physical rehabilitation Speech and communication management Nutritional care Respiratory care Home care and hospice care ALS, Amyotrophic lateral sclerosis.

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Symptomatic Treatment in Amyotrophic Lateral Sclerosis

Symptoms

Pharmacotherapy

Other therapy

Fatigue

Pyridostigmine bromide Antidepressants Methylphenidate Amantadine Modafinil Baclofen Tizanidine Dantrolene sodium Diazepam Benzodiazepines Quinine sulfate Baclofen Vitamin E Clonazepam Carbamazepine Hyoscyamine sulphate Diphenhydramine Scopolamine patch Glycopyrrolate Atropine TCAs TCAs SSRIs, L-dopa/carbidopa Lithium Mirtazapine Venlafaxine Quinidine/dextromethorphan Guaifenesin Nebulized N-acetylcysteine Nebulized saline Propranolol

Energy conservation Work modification Sleep study: BiPAP if abnormal

Spasticity

Jaw clenching Cramps

Fasciculations Sialorrhea

Pseudobulbar laughing or crying

Thick phlegm

Physical therapy Range-of-motion exercises Botulinum toxin injections Botulinum toxin injections into masseters Massage Physical therapy

Assurance Suction machine Botulinum toxin injection into salivary glands Parotid gland radiation therapy Steam inhalation Nebulization Dark grape juice

Aspiration

Cisapride

Joint pains

Antiinflammatory drugs Analgesics TCAs SSRIs, venlafaxine, mirtazapine, bupropion Zolpidem tartrate Lorazepam Opioids TCAs Sublingual lorazepam Bronchodilators Morphine sulfate Increase oral liquid Metamucil Dulcolax suppositories Lactulose and other laxative

Depression Insomnia

Laryngospasm Respiratory failure Constipation

Insufflation-exsufflation High-flow chest wall oscillation therapy Cool mist humidifier Rehydration Pineapple or papaya juice Reduced intake of dairy products, caffeine, alcohol Modified food consistency Tracheostomy Modified laryngectomy and tracheal diversion Range-of-motion exercises Heat Counseling Support group meetings, psychiatry Pressure air pad/gel mattress Noninvasive positive pressure ventilation where appropriate

Hospital bed Nocturnal noninvasive ventilator IPPB Exercise “Power pudding”: prune juice, prunes, applesauce, bran

BiPAP, Bilevel positive airway pressure; IPPB, intermittent positive-pressure breathing; SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants.

alone. A second appointment, a short time later, is often required because many patients and their families find it difficult to absorb the information at first. At the appropriate time, it is important to bring up issues such as advance directives and issues regarding terminal care (Mitsumoto and Rabkin, 2007; Mitsumoto and Saito, F ECF

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2018) (see also Chapter 114). Providing information on progress in research, available pharmacotherapies, and the possibility of active participation in clinical trials may increase hope for patients. It is also important to convey the concept of the multidisciplinary care team. Owing to the serious nature of the diagnosis, it is important to 02 .4.(1( 4 (

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CHAPTER 97 Disorders of Upper and Lower Motor Neurons facilitate a second opinion if so requested. ALS is almost invariably a relentlessly progressive and terminal disorder, and physicians must raise the issues of the living will and durable power of attorney for health care relatively early after diagnosis to allow the patient and family to prepare ahead. Such decisions are not final and are reversible at any time. Furthermore, some patients either do not wish to or cannot make such decisions (Miller et al., 2013). Specific pharmacotherapy. In 1996, the US Food and Drug Administration (FDA) approved riluzole (Rilutek) as the first specific drug for the treatment of ALS. It principally functions as an antiglutamate agent, but its mechanism of action is uncertain. The two studies that led to riluzole approval showed that survival was significantly longer in patients with ALS who took 50 mg of riluzole twice a day compared with those who took placebo, although this survival benefit was only modest and was disproportionately beneficial in bulbar-onset disease. A Cochrane meta-analysis of the controlled riluzole trials has shown that 100 mg daily results in a 9% increase in the probability of survival for 1 year and prolongs median survival by 2–3 months when taken for 18 months (Miller et al., 2012). Side effects are relatively uncommon and include fatigue, gastrointestinal upset, dizziness, and an increase in liver function tests. To minimize side effects, we recommend 50 mg per day in the evening, and after a week or two, the patient can increase to the regular dose of 50 mg twice a day. Not all patients with ALS receive riluzole therapy; the cost of the drug is one of the main factors in this regard, although generic versions have mitigated this cost somewhat. Intravenous edaravone, a free radical scavenger, has been recently approved in Japan and then the results were presented to the FDA, which approved the medication without any additional trials. This agent was originally developed for acute stroke treatment in Japan and subsequently found to be useful in treatment of ALS (Abe et al., 2014). A further study was undertaken in responders only (ALS 19 Study Group, 2017). Over a 6-month trial period, it has been shown to improve the ALS Functional Rating Scale-revised (ALSFRS-R) to a modest degree. However, most patients were also taking concomitant riluzole and strict inclusion criteria suggest that it may only prove effective in a small cohort of patients. Assessment of several agents with antiglutamate activity revealed no clinical benefit, although dextromethorphan-quinidine has benefit in the treatment of pseudobulbar emotional lability. Many other agents have been trialed in ALS, including neurotrophic factors, antiinflammatory agents, creatine, coenzyme Q10, lithium and minocycline and other antibiotics, but none have been found to be effective (Mitsumoto et al., 2014). The rating scale used in most ALS trials is the ALSFRS-R. It has been argued that this measure may fail to show positive outcomes in trials, in part explaining the plethora of negative ALS trials. Other functional scales such as the King’s College and MiToS staging systems have been proposed to more accurately monitor progression of disease in clinical trials (Corcia et al., 2018). Perhaps one of the reasons for so many disappointing results over the years is that much promising preclinical work was based upon the mutant SOD1 mouse model, which is not representative of the pathogenesis of most ALS. It remains to be seen whether novel agents with relevance to TDP43 or FUS mislocalization might show more promise, and the search continues for new agents and techniques for the specific treatment of ALS. Research is ongoing into the potential role for stem cell therapy and gene therapy in patients with ALS (Chia et al., 2018; Gordon et al., 2013; Madigan et al., 2017; Staff et al., 2016). It is critical to improve the selection of candidate therapies, clinical trial methodology, and clinical trial practice. To this end, the Airlie House ALS clinical trial guidelines have been updated and renewed using the modified Delphi consensus method.

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Aggressive symptomatic treatment. Although specific pharmacotherapy is still markedly limited for the treatment of ALS, symptomatic treatment can substantially improve a patient’s symptoms and discomfort. Table 97.5 summarizes specific pharmacological and nonpharmacological symptomatic treatments (Miller et al., 2009, 2012).

Multidisciplinary team approach at amyotrophic lateral sclerosis clinic. The care of patients with ALS has become increasingly complex. As

a consequence, many patients receive care by a multidisciplinary team in a specialized ALS center rather than by a single treating physician. The team often consists of neurologists, a nurse coordinator, physical therapists, occupational therapists, dietitians, speech pathologists, and social workers. Pulmonary specialists and other health professionals should also be available. Using this holistic approach, the aim is to maintain physical independence for as long as possible and to provide psychosocial support to patients and families. As such, specialized multidisciplinary clinic referrals should be offered to patients to optimize and improve quality of life and possibly prolong survival (Miller et al., 2009, 2012). Physical rehabilitation. The main goal of rehabilitation for patients with ALS is to improve their ability to carry out activities of daily living for as long as possible without causing undue physical or emotional strain. Physical therapy also prevents complications secondary to disuse of muscles and immobilization, such as a frozen shoulder. Employ various types of exercise that maintain or enhance strength, endurance, and range of motion. There have been concerns that exercising ALSaffected muscles to the point of fatigue may actually be harmful, but this has not been borne out in the literature. The occupational therapist is another valuable member of the ALS care team. A range of assistive and adaptive devices are available to improve mobility and comfort and help carry out activities of daily living. For example, walkers, wheelchairs, splints, and collars are useful to manage wrist drop, foot drop, head drop, and gait instability. Successful rehabilitation also includes an evaluation of the home environment; customized home equipment can easily help preserve a patient’s independence and safety. Speech and communication management. Speech and communication dysfunction is one of the most serious factors reducing quality of life in the patient with ALS. Ideally, speech pathologists should assess speech and communication soon after establishing the diagnosis so the patient can maintain independent communication for as long as possible. Follow-up is thus required at regular intervals. Assessment and care should incorporate intelligibility strategies, energy-conserving techniques, nonverbal techniques (gestures and other body language), and assistive/augmentative communication devices. Numerous communication devices are available that vary in sophistication and complexity, ranging from simple and relatively inexpensive mechanical devices such as alphabet or picture boards to specialized computer devices such as a voice synthesizer. Nutritional care. Dysphagia and aspiration are distressing and dangerous complications of ALS and are particularly prominent in the bulbar-onset variety. As oral intake progressively declines, there is acceleration in weight loss and malnutrition, which not only aggravates muscle weakness but also shortens survival. Therefore, in every patient with ALS, evaluate the nutritional status at each visit. Although physicians can take such a history, evaluation by an experienced dietitian is often most helpful. Initially, patients should change the form and texture of their food and use a high-calorie food supplement, but eventually such measures become insufficient to maintain the patient’s weight, and proactive enteral tube feeding becomes imperative. Percutaneous endoscopic gastroscopy (PEG) is a standard minor surgical procedure that may improve quality of life but with unproven effect on survival (Katzberg and Benatar, 2011). PEG is also probably effective in helping patients maintain weight/body mass index (Miller et al., 2009, ProGas Study Group, 2015).

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Although it is a relatively simple surgery for otherwise healthy patients who have dysphagia, patients with ALS pose particular difficulties and often have impending respiratory failure that may complicate the procedure. Guidelines advocate placement of a PEG tube in consenting patients with dysphagia whose seated predicted forced vital capacity is more than 50%, but PEG may be performed for patients with a forced vital capacity of less than 50% predicted if NIPPV is also used during the procedure (Gregory et al., 2002). Radiologically inserted gastrostomy and percutaneous radiological gastrostomy are alternative approaches that may be preferable in such cases but are not yet in widespread use. It is important to emphasize that those who receive a PEG tube can continue to eat by mouth, and that the purpose of enteral feeding is to provide calories and fluid. Indeed, aspiration is a continued risk to the patient even after PEG tube insertion, and if recurrent aspiration of PEG contents becomes a persistent problem, one can either recommend percutaneous enteral jejunostomy (PEJ), which further reduces (but still does not eliminate) the risk, or a tracheostomy. Respiratory care. Respiratory failure is the most common cause of death in ALS. Indeed, dyspnea-onset ALS presents with obvious ventilatory difficulties, and it is for this reason that it harbors a particularly poor prognosis. It is important to make patients and family members aware that almost all forms of ALS will eventually end by ventilatory failure, although symptoms may go largely unnoticed until relatively late in the disease course. The patient must be made aware that although ventilation via a tracheostomy may indefinitely prolong life, there is no effect on the disease itself. In fact, by prolonging the natural history of the disorder, there is a strong possibility that atypical symptoms may arise, such as visual changes or even sensory loss. Nonetheless, some patients choose to have a tracheostomy and invasive ventilation; this option should be a consideration to improve the quality of life of such individuals (Niedermeyer et al., 2019). Most patients and their physicians opt for the noninvasive ventilation (NIV) approach. Evidence exists that patients should be offered NIV at the onset of dyspnea when the forced vital capacity falls to less than 50% predicted or when a rapid, progressive weakness and wasting of perioral muscles may prevent adequate use of the NIV mask. Nasal pillows can be helpful in this circumstance and are often better tolerated than the mask at all stages. Several factors should be borne in mind when offering this form of treatment. Evidence exists that NIV improves quality of life and may prolong survival in ALS (Bourke et al., 2006; Miller et al., 2009), but NIV does not prolong life indefinitely, and these patients still face the difficult decision of whether to use an invasive ventilator. Diaphragmatic pacing has been approved for use in patients with ALS, but its clinical effectiveness and long-term safety require further study (Amirjani et al., 2012). When making the decision to withdraw ventilatory support or when noninvasive means of ventilatory assistance are insufficient, it is imperative that all attempts focus on effective and compassionate palliative end-oflife care. Hospice care and judicious amounts of opioids, oxygen, and anxiolytics should be prescribed to allow patients to live their final days with dignity and in as much comfort as possible. Home care and hospice care. When the patient’s condition deteriorates, home hospice care or admission to a residential hospice care facility is required (Mitsumoto et al., 2005). Close collaboration between patients, their caregivers, home-care nurses, and ideally the ALS clinic team will ensure effective and satisfying home care. When a patient has no caregiver, choose a site other than the home for extended care. Hospice care provides highly effective palliative services to patients and their families. Just as important, hospice philosophy strongly affirms life, so that patients who are in the terminal stages of their disease can maintain their independence and dignity to the greatest degree possible (Connolly et al., 2015; Mitsumoto, 2009). F ECF

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Familial Amyotrophic Lateral Sclerosis Between 5% and 10% of all ALS is an inherited trait, in which case it is termed familial ALS (FALS). It is quite possible that the true frequency of FALS is higher because anything less than a detailed family history may fail to identify an affected family member, and reduced penetrance may account for some apparently sporadic disease. There are autosomal dominant, autosomal recessive, and X-linked forms, some being juvenile onset and others being adult onset (see Box 97.6). Over 30 genes have been implicated as causative, increasing the risk of developing ALS, or accelerating the disease, but many of these account for only rare cases (Oskarsson et al., 2018). The clinical presentation varies considerably, not just in terms of age and site of onset but also in terms of disease duration. FALS is currently classified from ALS1 to ALS25. Mutations in C9orf72 (open reading frame 72 on chromosome 9) are the most common cause of familial ALS (circa 40%) and a significant percentage of apparently sporadic ALS (circa 7%) (Balendra and Isaacs, 2018). The mutation is one of a hexanucleotide expansion repeat. Presentation can be that of ALS, particularly with bulbar onset. However, it can also present as an ALS-FTD overlap or indeed a pure behavioral variant FTD (which can include psychosis). Some versions can include ataxia and parkinsonism and the repeat expansion has recently been found to cause Huntington disease phenocopies (Hensman Moss et al., 2014) (Video 97.5). Age of onset is apparently slightly younger and there is more rapid progression with shorter survival. Penetrance of the gene increases with age and in one study was shown to reach 100% above the age of 80 years (Majounie et al., 2012). The function of C9orf72 still remains to be clearly elucidated but its structure suggests that it might function as a GDP-GTP exchange factor for RAB GTPases, in turn implying a role in cell signaling and autophagy. The hexanucleotide repeats lead to the formation of pathogenic DNA-RNA “quadruplexes” which appear to generate abnormal transcripts that in turn lead to nucleolar stress (Haeusler et al., 2014). Whether the mutation leads to a loss of function, toxic gain of function, or indeed both, remains to be seen (Robberecht and Philips, 2013). Cerebral imaging may reveal symmetrical frontal and temporal atrophy (Yokoyama and Rosen, 2012). Up until recently, SOD1 (which encodes superoxide dismutase 1), located on chromosome 21q21, was considered the most important gene in ALS. ALS1 is a form of late-onset (usually > age 30) motor neuron disorder associated with mutations in SOD1 that accounts for 15%–20% of all cases of FALS (and thus 1%–2% of all ALS) (Rosen et al., 1993). Inheritance in most is in an autosomal dominant pattern, but a recessive variant occurs (Andersen et al., 1996). Mutations in SOD1 confer toxic gain of function, leading to disease through multiple possible mechanisms, including oxidative stress, protein aggregation, apoptosis, and impairment of axonal transport. There is a large degree of phenotypical variability in the expression of SOD1-associated FALS, not only between different families but also between individual members of the same family. Furthermore, penetrance is rather variable and age dependent. Generally, establishing the diagnosis of FALS is only by the fact that other family members in successive generations are, or were, affected by ALS. The clinical features of individual FALS patients overlap considerably with those of patients with SALS. ALS2 is a rare recessively inherited disorder mapped to a gene on chromosome 2q33 that encodes a novel protein called alsin. Analysis of the original families revealed that all were due to truncated protein product from frameshift or nonsense mutations, but missense mutations occur. This juvenile ALS, originally described in consanguineous families from Tunisia, was also discovered in families from Saudi Arabia and Kuwait. The phenotype of this disorder varies according to the family of origin; in the Tunisian family, it presents as a slowly progressive ALS-like disorder with mean age of onset at age 12 years; in the 02 .4.(1( 4 (

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CHAPTER 97 Disorders of Upper and Lower Motor Neurons Kuwaiti family, the phenotype is similar to early-onset PLS. Sequence homology analysis of this protein supports that it is a guanine-nucleotide exchange factor for Rab 5 and is thus important in intracellular cell signaling, endosomal dynamics, mitochondrial trafficking, and cytoskeleton organization. In contrast to the toxic gain-of-function theory of pathogenesis in ALS1, it appears that loss of function of the gene product is responsible for the selective injury to, and dysfunction of, the corticospinal tract in ALS2. Alternate splicing of the alsin gene results in both long and short transcripts. Frameshift and nonsense mutations cause an ALS phenotype when there is homozygous loss of both the short and long forms, whereas the PLS presentation occurs with homozygous loss of the long form alone. Missense mutations may cause an unstable protein product or lead to a protein product that is directly toxic to the cell via aberrant regulation of the apoptotic pathway. Certain mutations in the alsin gene also give rise to an infantile ascending hereditary spastic paraparesis, which demonstrates the link between ALS and related motor neuron diseases (Eymard-Pierre et al., 2006; Panzeri et al., 2006). ALS3 describes a large European family with adult-onset autosomal dominant ALS linked to chromosome 18q21 (Hand et al., 2002). The gene for this disorder has not yet been identified. ALS4 is a juvenile-onset, slowly progressive, dominantly inherited distal amyotrophy with UMN signs but sparing bulbar features. It is caused by mutations in the senataxin gene (SETX) on chromosome 9q34, which has a DNA/RNA helicase domain suggesting a role in DNA repair and RNA processing. SETX has homology to IGHMBP2, the gene responsible for SMARD1, a rare form of SMA. Mutations in SETX also cause a recessively inherited disorder called oculomotor apraxia and cerebellar ataxia. However, it has recently been shown that caution should be exercised as not all missense mutations are pathogenic and functional assays are required (Arning et al., 2013). A form of slowly progressive, usually mild, recessive juvenile ALS (ALS 5) described in North African and European families is due to mutations in the spatacsin (SPG11) gene (and thus is also a cause of hereditary spastic paraparesis; see Table 97.2). ALS6 is an autosomal dominant ALS that can also be associated with frontotemporal dementia and hallucinations. Mutations on the FUS/TLS (fused in sarcoma/translocated in liposarcoma) gene on chromosome 16q12 have the pathological characteristic of FUS-immunoreactive skein-like cytoplasmic inclusion bodies. FUS is normally a nuclear protein, so this is yet another example of protein mislocalization in neurodegenerative disease. FUS mutations have a worldwide distribution and account for about 5% of FALS; they are also detectable in about 1% of SALS (Lai et al., 2010). Furthermore, it has recently been shown that FUS-immunoreactive cytoplasmic inclusions are common in both SALS and non-SOD1 FALS and are also immunoreactive to TDP43 and ubiquitin (Deng et al., 2010). ALS7 is a rare, late-onset, autosomal dominant disorder linked to chromosome 20p13. The cause for ALS8 is a mutation in a vesicle trafficking protein gene called VAPB (vesicle-associated membrane protein/synaptobrevin-associated membrane protein B) on chromosome 20q13.3. The clinical presentation displays quite marked heterogeneity: some patients develop a slowly progressive ALS-like picture with prominent tremor and onset between the ages of 31 and 45 years, whereas others present with a late-onset SMA or a severe, rapidly progressive ALS (Nishimura et al., 2004). ALS9 results from mutations on the angiogenin gene on chromosome 14q. This is an autosomal dominant disorder of adults (from the fourth to the eighth decade). Angiogenin may help protect motor neurons from excitotoxic- and hypoxia-induced injury, but it may also play an important role in RNA transcription as well as interact with cellular cytoskeletal proteins. ALS10, which accounts for 2%–5% of FALS, is caused by mutations in the TDP43 gene on chromosome 1 and presents clinically as ALS with either limb or bulbar onset. Despite the association of TDP inclusions with some forms of FTD, cognitive deficits do not occur in F ECF

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TDP43 mutation–associated ALS. TDP43 immunoreactive ubiquitinated inclusions are present in degenerating neurons and glial cells just as they in sporadic ALS (Kuhnlein et al., 2008; Van Deerlin et al., 2008). The TDP43 gene product is a dual DNA/RNA binding protein mainly expressed in the nucleus and may play an important part in the regulation of RNA trafficking and translation. TDP43 can modulate human low-molecular-weight neurofilament mRNA stability, which in turn underlies neurofilament aggregates, sometimes seen in ALS (Strong et al., 2006). TDP43 inclusion bodies are in fact seen in several disorders apart from ALS, including FTD, frontotemporal lobar degeneration with motor neuron degeneration, corticobasal degeneration, Guamanian ALS–PD complex, and hippocampal sclerosis. While this might suggest that TDP43 inclusion bodies are a nonspecific marker of neuronal injury or indeed representative of a physiological cell response to injury, the frequency of TDP43 mutations (30 to date) in both SALS and FALS suggests a pathogenic role. ALS11 is due to mutations of the FIG4 gene on chromosome 6q21, which encodes a phosphoinositide 5-phosphatase, a regulator of a signaling lipid on the surface of endosomes. Mutations in this gene are known to cause a recessively inherited severe axonal sensorimotor form of Charcot– Marie–Tooth known as CMT4J, which is usually early onset (although one family presented with an adult disorder resembling ALS). FIG4 mutations can cause an ALS or PLS presentation, and additional personality changes were noted in two cases. Of the nine cases with FIG4 mutations, only three were FALS, the rest apparently being sporadic (Chow et al., 2009). Mutations in the OPTN gene for optineurin, a negative regulator of tumor necrosis factor alpha (TNF-α)–induced activation of nuclear factor kappa B (NF-κB) cause ALS12. OPTN may also play a role membrane trafficking, exocytosis, and maintenance of the Golgi apparatus. Mutations in this gene are known to cause primary open angle glaucoma. For patients presenting with ALS, the inheritance patterns were both autosomal recessive and autosomal dominant, with onset between the ages of 30 and 60 years and longdisease duration. One case which came to autopsy showed optineurin-positive cytoplasmic inclusion bodies in anterior horn cells; the investigators also showed that TDP43- and SOD1-positive inclusions in SALS and SOD1 FALS were co-labeled with optineurin, suggesting a broader role for this protein in the pathogenesis of ALS (Maruyama et al., 2010). It is proposed that certain individuals with ATX2 mutations in the intermediate range may suffer an increased risk of ALS (ALS 13) through an interaction between the polyglutamine repeat and TDP43 resulting in mislocalization of the latter to the cytoplasm (Elden et al., 2010). Another adult onset autosomal dominant ALS which can be associated with FTD is ALS14, caused by mutations in the VCP gene. Pathologically, ubiquitin positive inclusions can be seen in neurons. Interestingly, VCP mutations can also cause an inclusion body myopathy with Paget disease and FTLD. ALS15, due to UBQLN2 mutations, can in fact be sporadic as well as inherited and again can be a cause of both ALS and FTD. Mutations in this gene lead to disturbances in the proteasomal pathway. ALS16 is a juvenile-onset ALS which is only rarely associated with FTD. It is due to mutations in SIGMAR1, which normally encodes an endoplasmic reticulum chaperone protein, thus suggesting a role for altered ER (ER) and Golgi function in disease pathogenesis. Again, SIGMAR1 mutations can cause ubiquitinated inclusions in the proximal axon. Mutations in CHMP2B cause ALS17, an adult-onset, progressive disorder with predominantly lower motor neuron involvement, and can also cause FTD. Mutations of the gene appear to confer injury to the motor neurons through abnormalities in protein breakdown and clearance within cells. Mutations in PFN1 (ALS18), which encodes profilin, can cause an FTD overlap or ALS alone. Profilin is important in axonal transport. ALS19 is due to mutations in ERBB4, which normally encodes a receptor tyrosine kinase, and mutations of which disrupt neuregulin pathway. This

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presents with typical autosomal dominant ALS of late onset. ALS20 is caused by HNRNPA1 gene mutations on chromosome 12, which may lead to inclusion body formation due to dysregulated protein polymerization. Although not formally classified as a familial ALS (it has been described as a spinal and bulbar muscular atrophy), it is apparent that mutations in the p150Glued subunit of the dynactin gene may cause ALS-like presentations. Furthermore, a family history is not always evident (Munch et al., 2004). Dynactin 1 is a vital component of the dynein-dynactin motor complex and is important in retrograde axonal transport. Puls et al. have described a particular LMN disorder caused by a mutation in the p150Glued subunit of dynactin 1. The clinical phenotype is distinctive, with early bilateral vocal cord paralysis followed by prominent involvement of intrinsic hand muscles (especially those of the thenar eminence), the legs, and the face (Puls et al., 2005).

Amyotrophic Lateral Sclerosis–Parkinsonism-Dementia Complex (Western Pacific Amyotrophic Lateral Sclerosis) In 1954, Mulder and colleagues described an unusually high incidence of ALS in the adult native Chamorro population on the Western Pacific island of Guam. Soon afterwards, a related disorder of high incidence characterized by dementia and parkinsonism was also found in this population, with some patients displaying overlap features between ALS, parkinsonism, and dementia. A similar disorder was subsequently described in western New Guinea and the Kii peninsula of Japan, with an ALS incidence between 50 and 150 times higher than elsewhere (Kaji et al., 2012). Clinically, about 5% of patients develop a predominantly ALS type of disorder, whereas 38% manifest principally with a combination of parkinsonism and dementia. The pathology of this unusual disorder bears similarities to that of Alzheimer disease, with prominent loss of CNS neurons and the presence of abundant tau-immunoreactive neurofibrillary tangles. However, the characteristic pathology of Guamanian ALS and PDC is by TDP43-positive inclusions in neurons and glial cells. α-Synuclein pathology also is detectable in the amygdala of affected brain tissue (Mimuro et al., 2018). Multiple members of a single family may be affected, and it has recently been shown that first-degree relatives of patients with ALSPDC have a significantly higher risk of developing the disease than controls. Despite these observations and a genetic association study implicating the tau gene as a susceptibility gene for ALS-PDC, accumulated epidemiological evidence strongly suggests that an environmental factor rather than a genetic factor is more important in disease pathogenesis. Various environmental toxins have been implicated in the pathogenesis of ALS-PDC, chief among them being neurotoxins derived from the native cycad seed. This seed contains β-methylamino-l-alanine (BMAA), an amino acid that is toxic to cortical and spinal motor neurons and thought to be the product of cyanobacterial activity in the roots of the cycad palm. Cycad seed also contains a carcinogenic substance called cycasin that may act either alone or in concert with BMAA to damage motor neurons. Toxic sterol glucosides have also been isolated from washed cycad flour, and they can cause the release of glutamate (Khabazian et al., 2002). However, the role of cycad seeds in neurotoxicity is still subject to debate (Snyder et al., 2011). The cyanobacteria/BMAA hypothesis has wider implications for research in SALS worldwide. It has been recently shown that protein-bound BMAA is present in the brains of North American patients dying with ALS and Alzheimer disease and it has been hypothesized that such patients may be genetically susceptible to BMAA-induced neurodegeneration (Bradley and Mash, 2009). The cycad seed has many uses: in West Papua and Guam as a topical medicine for skin lesions and in Japan as an oral medicine (Spencer et al., 2016). Cox and Sacks (2002) proposed a process of biomagnification of cycad toxins in Guam through the Chamorro practice of eating flying foxes, which

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themselves feed on cycad seeds. The incidence of the Guamanian ALS variant has rapidly declined over the past several decades, a process thought to reflect the Westernization of the region. The decline in the incidence of ALS-PDC in Guam may reflect the dwindling flying fox population on Guam through a massive increase in commercial hunting using firearms introduced to the island in the decades following World War II. However, other social and dietary shifts have occurred in Guam that might be responsible for the decrease.

Spinocerebellar Ataxia Type 3 (Machado-Joseph Disease) Machado-Joseph disease is an autosomal dominant syndrome with onset varying from the third to seventh decade of life. Although cerebellar ataxia is the predominant clinical feature, patients often present with slowly progressive generalized spasticity, cramps, muscle wasting, and fasciculations of the face and tongue. Other characteristic findings include extrapyramidal signs such as dystonia and rigidity, protuberant eyes, and progressive external ophthalmoparesis. Affected patients have a twofold to threefold expansion of a CAG trinucleotide repeat on the ataxin-3 gene on chromosome 14q32.1. The expanded triplet repeat results in a mutant gene product containing an expanded polyglutamine tract. This appears to aggregate into intranuclear neuronal inclusion bodies and may interfere with the function of the cellular proteasome in degradation of proteins (Schmidt et al., 2002). The Machado-Joseph disease phenotype may also occur in SCA-2, with slowly progressive ataxia, eyelid retraction, and facial fasciculations. Patients often have slow saccades or ophthalmoparesis and may have reduced or absent deep tendon reflexes. The cause of SCA-2 is an expanded polyglutamine-encoding CAG triple repeat sequence on chromosome 12q.

Adult Hexosaminidase-A Deficiency Adult Hex-A deficiency is an autosomal recessively inherited lateonset GM2 gangliosidosis (the other subtypes being infantile and juvenile). All three subtypes are caused by an abnormal accumulation of GM2 ganglioside in neurons due to a deficiency in the activity of the lysosomal enzyme. Hex-A is encoded by a gene on chromosome 15q23–q24 and normally degrades GM2 ganglioside. Only about 10% of Hex-A activity is required for normal health, but in the severe infantile form of this disorder, also known as Tay-Sachs disease, mutations in the α subunit of Hex-A result in complete deficiency of enzyme activity. Juveniles and adults with Hex-A deficiency, however, are compound heterozygotes with varying degrees of residual enzymatic activity and thus have a later-onset disorder with considerable variability in the phenotype. It is more common in males and those of Ashkenazi Jewish ancestry, but females and non-Jewish persons can also develop this disorder. The adult form has a mean of onset of about 18 years and usually presents as slowly progressive weakness of predominantly proximal muscles of the upper and lower extremities (Barritt et al., 2017; Neudorfer et al., 2005). In some patients, severe cramps may present in association with muscle weakness, mimicking SMA. In others, however, a combination of dysarthria, spasticity, and LMN signs may resemble ALS. Additional sensory, cerebellar, cognitive, psychiatric, and extrapyramidal features may later develop. The EDX may reveal prominent complex repetitive discharges and abnormal SNAPs. Generally, this constellation of symptoms and signs is not easily mistaken for ALS, but in the relatively early stages, patients with Hex-A deficiency may not manifest many features other than motor system dysfunction. Genetic counseling is important before assaying a patient’s serum or leukocytes for deficiency of Hex-A activity.

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CHAPTER 97 Disorders of Upper and Lower Motor Neurons

Allgrove Syndrome (Four-A Syndrome)

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Four-A syndrome (Allgrove syndrome) is a very rare autosomal recessive disorder that derives its name from the combination of achalasia, alacrima, adrenocorticotropic insufficiency, and amyotrophy. The AAAS gene is located on chromosome 12q13 and encodes a ubiquitous protein called aladin which heavily expresses in the neuroendocrine system and may be important in regulation of the cell cycle, cell signaling, intracellular transport, and the cell cytoskeleton. The syndrome can manifest from the first decade of life with dysphagia and adrenocortical insufficiency, but a wide a range of neurological problems can arise later in life, including cognitive deterioration, optic atrophy, seizures, autonomic disturbance (dry mouth, postural hypotension, and syncope), and bulbospinal amyotrophy (amyotrophy of limbs and tongue, with tongue fasciculations and pyramidal signs) (Ikeda et al., 2013; Kimber et al., 2003).

signs, and some may improve either with treatment of the cancer or spontaneously. Elevated CSF protein levels or the presence of a paraprotein in the blood should prompt a detailed investigation for lymphoma. Although there is insufficient evidence to conclude that there is increased risk of cancer in ALS, a combination of UMN and LMN signs has been well described in patients with breast, uterine, ovarian, and non–small-cell cancer. This ALS-like disorder is quite rapidly progressive and does not appear to respond either to treatment of the underlying cancer or to immune therapies. UMN signs and symptoms that mimic PLS may rarely occur in patients with breast tumors and may in fact precede the cancer diagnosis by a few months. In general, one should investigate for a paraneoplastic disorder if there are atypical features such as ataxia, sensory loss, and dysautonomia, and it would seem to be prudent to carry out breast screening on women with a PLS presentation.

Adult Polyglucosan Body Disease

Human Immunodeficiency Virus Type 1-Associated Motor Neuron Disorder

Polyglucosan body disease is a very rare, late-onset, slowly progressive disorder characterized by a combination of UMN and LMN signs, cognitive decline, distal sensory loss, and disturbances of bladder and bowel function. MRI of the brain may reveal diffuse white-matter signal increase on T2-weighted images. The diagnosis is clinched by the finding of characteristic pathological changes in tissue from peripheral nerve, cerebral cortex, spinal cord, or skin. Axons and neural sheath cells contain non-membrane-bound cytoplasmic periodic acid–Schiffpositive polyglucosan bodies. Ultrastructural examination shows that the inclusions consist of 6- to 8-nm branched filaments and are most abundant in myelinated nerve fibers. In Ashkenazi Jewish patients (and one reported non-Ashkenazi Jewish patient), the disorder was caused by mutations of the glycogen-branching enzyme (GBE) gene, with subsequent deficiency of the protein product. However, adult polyglucosan body disease (APBD) occurs in many different populations, and considerable molecular heterogeneity has been noted, with otherwise typical cases lacking GBE mutations despite deficiency of enzyme activity (Klein et al., 2004). The recent (albeit inadvertent) generation of muscle polyglucosan bodies in a transgenic mouse engineered to overexpress glycogen synthase in the presence of normal levels of glycogen-branching enzyme suggests that an imbalance in the activities of these two enzymes is the possible molecular mechanism underlying this unusual disorder (Raben et al., 2001). It is interesting to note that two types of polyglucosan body may be seen in ALS—Lafora bodies and corpora amylacea—although neither is considered a characteristic pathological feature.

Paraneoplastic Motor Neuron Disease There is evidence that motor neuron disease may rarely be a paraneoplastic phenomenon, although there is a possibility that the ALS and the neoplasm are chance associations. (Corcia et al., 2014). Patients may present with features that are rather typical of pure “spinal” ALS or manifest in a manner akin either to PMA or to PLS. Other motor neuron manifestations may represent only one part of a larger paraneoplastic syndrome, such as anti-Hu antibody associated encephalomyelitis, with atypical features such as dysautonomia or ataxia. Unfortunately, most paraneoplastic motor disorders are unresponsive to treatment of the underlying tumor. Rare motor disorders have been described in association with other paraneoplastic antibodies, including anti-Yo antibody in a patient with ovarian carcinoma and a novel antineuronal antibody in a patient with breast cancer. A subacute painless and progressive LMN-predominant disorder has been well characterized in lymphoma (both Hodgkin and non-Hodgkin types: see earlier discussion). Patients may eventually develop UMN

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A retrospective review of 1700 cases of HIV-1-infected patients with neurological symptoms identified 6 cases presenting as a reversible ALS-like syndrome (Moulignier et al., 2001), representing a 27-fold increased risk of developing an ALS-like disorder in that particular HIV-1 patient population. Overall, patients were somewhat younger than the normal ALS population, all but one being younger than 40 years at the time of diagnosis. Onset was characteristically in a monomelic pattern followed by a very rapid spread to other regions over a period of weeks. There were clinical features of both UMN and LMN involvement, with fasciculations, cramps, and bulbar symptoms. Two patients also had rapidly progressive dementia, with other features suggesting an additional diagnosis of AIDS-dementia complex. Sensory and sphincter disturbances were not apparent. CSF protein levels were sometimes mildly increased, and a lymphocytic pleocytosis was evident in three patients, but all remaining laboratory results (HIV-1 seropositivity apart) were negative. EDX revealed a widespread disorder of anterior horn cells in the absence of demyelinating conduction block, and MRI in one patient showed diffuse white-matter signal increase suggestive of AIDS-dementia complex. At the pathological level, there are some features that are shared between ALS and HIV encephalitis; HIV cases also develop TDP-43 deposits (Douville and Nath, 2017). In each case, antiretroviral therapy was beneficial either in stabilizing or (in two instances) curing the disease. No similar cases have been identified in this particular study population since the introduction of highly active antiretroviral combination chemotherapy in the management of HIV infection. Another case report found similar clinical features in a 32-year-old HIV-positive patient who also enjoyed a complete response to antiretroviral therapy. MRI of brain showed increased T2-weighted signal in the brachium pontis with some minimal contrast enhancement. The resolution of motor symptoms coincided with a lack of detectable HIV in plasma and CSF. In addition, the abnormal MRI signal almost completely resolved (MacGowan et al., 2001). Flail-arm ALS-like variants have also been described, with MRI signal changes in the anterior cervical spinal cord (Henning and Hewlett, 2008; Nalini et al., 2009). Other forms of HIV may also relate to the pathogenesis of motor neuron disease; a pure LMN syndrome occurred in a woman who was seropositive for HIV-2. Overall, there seems to be sufficient evidence to implicate HIV as a potential cause of an ALS-like disorder, but one must also consider the possibility of coincidental HIV infection in patients who have true sporadic ALS. The complete reference list is available online at https://expertconsult. inkling.com/.

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98 Channelopathies: Episodic and Electrical Disorders of the Nervous System Min K. Kang, Geoffrey A. Kerchner, Louis J. Ptáček OUTLINE Ion Channels, 1568 Ion Channel Classification, 1571 Genetic Disorders of Muscular Ion Channels, 1573 Hypokalemic Periodic Paralysis (hypoKPP), 1574 Hyperkalemic Periodic Paralysis (hyperKPP), 1575 Paramyotonia Congenita, 1576 Myotonia Congenita, 1576 Potassium-Aggravated Myotonia, 1577 Andersen-Tawil Syndrome, 1578 Malignant Hyperthermia, 1578 Congenital Myasthenic Syndromes, 1579 Genetic Disorders of Neuronal Ion Channels, 1579 Familial Hemiplegic Migraine, 1579 Familial Episodic Ataxias, 1580 Hereditary Hyperekplexia, 1581

Hereditary Peripheral Nerve Disorders, 1582 Paroxysmal Dyskinesia, 1583 Other Inherited Neuronal Channelopathies, 1583 Epilepsy, 1583 Familial Focal Epilepsies, 1583 Idiopathic Generalized Epilepsies, 1584 Theoretical Considerations, 1586 Autoimmune Channelopathies, 1586 Myasthenia Gravis, 1586 Lambert-Eaton Myasthenic Syndrome, 1587 Acquired Neuromyotonia (Isaacs Syndrome), 1587 Paraneoplastic Cerebellar Degeneration, 1587 Limbic Encephalitis, 1587 Summary, 1588

Channelopathies are disorders caused by ion channel dysfunction. Because of the great diversity of ion channel proteins and their expression in different tissues, channelopathies comprise a wide variety of clinical diseases (Table 98.1), the discovery of which helps elucidate how ion channels function in both illness and health. The periodic paralyses—the first group of ion channel disorders characterized at a molecular level—defined the field of channelopathies, which now encompasses diseases not only in muscle but also in the kidney (Bartter syndrome), epithelium (cystic fibrosis), and heart (long QT syndrome), as well as neurons. Because muscles and neurons are electrical organs, it is not surprising that most channelopathies are associated with neurological disease. Despite significant heterogeneity, a pervasive feature of neurological channelopathies is a paroxysmal phenotype of various neurological presentations, encompassing myopathy, peripheral neuropathy, epilepsy, migraine headache, and episodic movement disorders. After a brief introduction to ion channels, this chapter describes disorders caused by congenital and acquired dysfunction of ion channels expressed in skeletal muscle, neurons and neuromuscular junction.

ion preferentially conducted (e.g., Na+, K+, Ca2+, Cl−). Ligand-gated ion channels respond instead to specific chemical neurotransmitters (e.g., acetylcholine, glutamate, γ-aminobutyric acid [GABA], glycine). Distributed ubiquitously in excitable tissues, voltage-gated ion channels are critical for establishing a resting membrane potential and generating action potentials, especially in tissues where rapid conduction of messages is required (e.g., nerves, cardiac cells, or skeletal muscles). Most channels have a similar basic structure, consisting of one or more pore-forming subunits (generally referred to as α-subunits) and a variable number of accessory subunits (often denoted β, γ, etc.). An α-subunit is composed of four homologous domains (I–IV) and typically has six transmembrane segments (S1–S6). The S4 segment has positively charged residues and serves as “a sensor.” The S5–S6 segments usually form the ion pore. These segments determine ion selectivity for the α-subunits, and voltage sensing is conferred by the S4 segment, while the remaining accessory subunits act as modulators. Voltage-gated channels are “gated” with high sensitivity to changes in transmembrane potential. The conductance is tightly regulated by changes in conformations of the channel, as channels exist in one of three states: open, closed, or inactivated. Voltage-gated channels open (or activate) with threshold changes in membrane potential, then transition after a characteristic interval to either a closed or an inactivated state. From the closed state, a channel can reopen with an appropriate change in membrane potential. In the inactivated state, a change in membrane potential normally sufficient to open the channel is ineffective and the channels will not conduct current. Inactivation is both time and voltage dependent, and many channels display both fast and slow components of inactivation. Inactivation is a means of negative regulation of the channel, influencing electrical stability in excitable cells.

ION CHANNELS One needs a basic understanding of channel structure and function before addressing channelopathies and their clinical manifestations. Ion channels are transmembrane glycoprotein pores that underlie cell excitability by regulating ion flow into and out of cells across the lipid bilayers of the cell membrane. They are composed of distinct protein subunits, each encoded by a separate gene. The categorization of most channels, depending on their means of activation, is as voltage-gated or ligandgated. Changes in membrane potentials activate and inactivate voltage-gated ion channels. They are named according to the physiological

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TABLE 98.1

Channelopathies: Episodic and Electrical Disorders of the Nervous System

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Genetic Channelopathies

Disease Muscular Channelopathies Andersen-Tawil syndrome Central core disease Congenital myasthenic syndromes

Hyperkalemic periodic paralysis Hypokalemic periodic paralysis Malignant hyperthermia Myotonia congenita Paramyotonia congenita Potassium-aggravated myotonia Neuronal Channelopathies ADNFLE

ADPEAF Alternating hemiplegia of childhood BFNS BFNIS, BFIS Childhood absence epilepsy

Congenital stationary night blindness Deafness (nonsyndromic type 2) Episodic ataxia 1 Episodic ataxia 2 Episodic ataxia 5 Episodic ataxia 6 Familial hemiplegic migraine 1 Familial hemiplegic migraine 2 Familial hemiplegic migraine 3 Familial temporal lobe epilepsy / febrile seizures GEFS+

Hereditary hyperekplexia

JME

Mental retardation, autosomal dominant PED PKD

Ion Channel

Gene

Chromosome

Kir2.1*; potassium (inward rectifier) Kir3.4; potassium (inward rectifier) Calcium (ryanodine receptor) nAChR α1-subunit nAChR β1-subunit nAChR δ-subunit nAChR ε-subunit (nAChR anchoring protein: rapsyn) Nav1.4; sodium α4-subunit Cav1.1; calcium (L-type) Nav1.4; sodium α4-subunit Calcium (ryanodine receptor) Cav1.1; calcium (L-type) Chloride Nav1.4; sodium α4-subunit Nav1.4; sodium α4-subunit

KCNJ2 KCNJ5 RYR1 CHRNA1 CHRNB1 CHRND CHRNE RAPSN SCN4A CACNA1S SCN4A RYR1 CACNA1S CLCN1 SCN4A SCN4A

17q23.1–q24.2 11q24 19p13.1 2q24–q32 17p12–p11 2q33–q34 17p13–p12 11p11.2–p11.1 17q23.1–q25.3 1q32 17q23.1–q25.3 19q13.1 1q32 7q35 17q23.1–q25.3 17q23.1–q25.3

nAChR α4-subunit nAChR β2-subunit KCa4.1; potassium (sodium-activated) (Potassium channel regulator) (Na+/K+-ATPase) Kv7.2; potassium (M channel) Kv7.3; potassium (M channel) Nav1.2; sodium α2-subunit (Na+/K+-ATPase†) GABAA receptor γ2-subunit GABAA receptor β3-subunit Cav3.2; calcium (T-type) Cav2.1; calcium (P/Q-type) Cav1.4; calcium (L-type) Kv7.4; potassium Kv1.1; potassium Cav1.4; calcium (P/Q-type) Calcium β4-subunit (EAAT1†) Cav1.4; calcium (P/Q-type) (Na+/K+-ATPase) Nav1.1; sodium α1-subunit (Carboxypeptidase†)

CHRNA4 CHRNB2 KCNT1 LGI1 ATP1A2 KCNQ2 KCNQ3 SCN2A ATP1A2 GABRG2 GABRB3 CACNA1H‡ CACNA1A‡ CACNA1F KCNQ4 KCNA1 CACNA1A CACNB4 SLC1A3 CACNA1A ATP1A2 SCN1A CPA6

20q13.2–q13.3 1q21 9q34.3 10q24 1q21–q23 20q13.3 8q24 2q23–q24.3 1q21–q23 5q31.1–q33.1 15q11.2–q12 16p13.3 19p13 Xp11.23 1p34 12p13 19p13 2q22–q23 5p13 19p13 1q21–q23 2q24 8q13.2

Nav1.1; sodium α1-subunit Sodium β1-subunit Nav1.2; sodium α2-subunit Nav1.7; sodium α9-subunit GABAA receptor γ2-subunit GABAA receptor δ-subunit Glycine receptor α1-subunit Glycine receptor β-subunit (Glycine transporter†) GABAA receptor α1-subunit Calcium β4-subunit (R-type calcium channel regulator†) Glutamate receptor NR2B subunit (GLUT1†) (Proline-rich transmembrane protein 2†)

SCN1A SCN1B SCN2A SCN9A GABRG2 GABRD GLRA1 GLRB GLYT2 (SLC6A5) GABRA1 CACNB4‡ EFHC1‡ GRIN2B SLC2A1 PRRT2

2q24 19q13.1 2q23–q24.3 2q24 5q31.1–q33.1 1p36.3 5q32 4q31.3 11p15.2–p15.1 5q34–q35 2q22–q23 6p12–p11 12p13.1 1p34.2 16p11.2 Continued

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TABLE 98.1

Neurological Diseases and Their Treatment

Genetic Channelopathies—cont’d

Disease

Ion Channel

Gene

Chromosome

PNKD with epilepsy PNKD without epilepsy Primary erythermalgia Scapuloperoneal spinal muscular atrophy/ congenital distal spinal muscular atrophy/ CMT2C/HMSN2 Spinocerebellar ataxia type 6

KCa1.1; potassium (BK) (PNKD protein†) Nav1.7; sodium α9-subunit TRPV4

KCNMA1 PNKD SCN9A TRPV4

10q22.3 2q35 2q24 12q24.1

Cav2.1; calcium (P/Q-type)

CACNA1A

19p13

Na-K-2Cl cotransporter Kir1.1; potassium (inward rectifier) Chloride Chloride Chloride Potassium (accessory subunit) Kir6.2; potassium (inward rectifier) Sodium (non-voltage-gated) Sodium (non-voltage-gated) Sodium (non-voltage-gated) Kv7.1; potassium Kv11.1; potassium Nav1.5; sodium α5-subunit (anchoring protein ankyrin-B†) Potassium (accessory subunit) Potassium (accessory subunit)

SLC12A1 KCNJ1 CLCNKB CFTR CLCN5 ABCC8 KCNJ11 SCNN1A SCNN1B SCNN1G KCNQ1 KCNH2 SCN5A ANK2 KCNE1 KCNE2

15q15–q21.1 11q24 1p36 7q31.2 Xp11.22 11p15.1 11p15.1 12p13 16p13–p12 16p13–p12 11p15.5 7q35–36 3p21–24 4q25–q27 21q22.1–q22.2 21q22.1

Nonneurological Channelopathies Bartter syndrome antenatal 1 Bartter syndrome antenatal 2 Bartter syndrome 3 Cystic fibrosis Dent disease FPHHI Liddle syndrome 1

LQT1 LQT2 LQT3 LQT4 LQT5 LQT6

ADNFLE, Autosomal dominant nocturnal frontal lobe epilepsy; ADPEAF, autosomal dominant partial epilepsy with auditory features; BFNS, benign familial neonatal seizures; BFNIS, benign familial neonatal–infantile seizures; BFIS, benign familial infantile seizures; CMT2C, Charcot–Marie–Tooth disease type 2C; EAAT1, excitatory amino acid transporter 1; FHM, familial hemiplegic migraine; FPHHI, familial hyperinsulinemic hypoglycemia of infancy; GEFS+, generalized epilepsy with febrile seizures plus; HMSN2, hereditary motor and sensory neuropathy type 2; JME, juvenile myoclonic epilepsy; LQT, long-QT syndrome; nAChR, nicotinic acetylcholine receptor; PED, paroxysmal exercise-induced dyskinesia; PKD, paroxysmal kinesigenic dyskinesia; PNKD, paroxysmal nonkinesigenic dyskinesia. *Where appropriate, ion channel names are provided according to the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR). †These associated genes/proteins may not be ion channels; they may instead contribute indirectly to ion channel function, regulate neurotransmitter kinetics, or possess other or unknown functions. ‡Unproven association.

A neuron typically has a resting potential of –75 mV, with the intracellular side being negative relative to the extracellular space. When the resting potential reaches a threshold or more positive membrane potential of –55 mV, depolarization occurs, which leads to the production of an action potential. This is achieved by opening a specific ion channel—a voltage-gated sodium channel—in which case sodium ions will rush into the cells down the concentration gradient. In order to reach the action potential, the sodium channel changes its confirmation from a closed or resting state to an open state. When the membrane potential reaches its peak, about 40 mV, the sodium channels close and become inactive. Then, repolarization occurs, due to the opening of another voltage-gated channel, such as a potassium channel. This leads to a rapid return to the resting potential via an outflux of potassium ions (down the potassium concentration gradient). Before achieving a stable resting potential, the membrane potential becomes “hyperpolarized” for a short time. Slowly, the sodium channels return to the closed state from the inactivated state. While in the inactivated state, sodium channels are not responsive to voltage changes. However, in the closed state, they become sensitive to voltage changes again. Different tissues and cells express different ion channels; thus, dysfunction of a specific ion channel can lead to a broad spectrum of phenotypes, depending on the tissue/cell type/ion channel involved. This

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is particularly important in the nervous system, where there is tremendous heterogeneity of the cells with regard to ion channel expression. Each subtype is encoded by a different gene, and its expression is highly cell specific. Depending on the location within the channel, mutations could alter voltage-dependent activation, ion selectivity, or time and voltage dependence of inactivation. Thus, two different mutations within the same gene can result in dramatically different physiological effects. For example, a mutation that prevents or slows inactivation could lead to a persistent ionic current. Conversely, a mutation elsewhere in the same gene that prevents activation will decrease ionic current. Phenotypic heterogeneity describes how different mutations in a single gene cause distinct phenotypes. For instance, mutations in the skeletal muscle voltage-dependent sodium channel can result in hyperkalemic periodic paralysis, hypokalemic periodic paralysis, potassium-aggravated myotonia (PAM), or paramyotonia congenita (PMC; see Table 98.1 and Fig. 98.1). In contrast, genetic heterogeneity occurs when a consistent clinical syndrome results from a variety of underlying mutations in distinct genes. For example, familial hypokalemic periodic paralysis can result from distinct mutations in the SCN4A or CACNA1S genes. Ion channel mutations may lead to either “loss of function” or “gain of function” in each case. Generally speaking, loss-of-function

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Channelopathies: Episodic and Electrical Disorders of the Nervous System

mutations cause reduced permeability, whereas gain of function implies the gain of an abnormal function (e.g., increased permeability or altered selectivity vs. normal permeability in the wrong part of the cell). Furthermore, genetic channelopathies are not restricted to mutation of the channels, but other mutations involving regulatory,

Genotype

Phenotype PMC

SCN4A

PAM HypoKPP2

SCN1A

HyperKPP

SCN1B SCN2A

GEFS+

GABRG2

modifiers, posttranscriptional, and posttranslation changes can also result in ion channel dysfunction (Fig. 98.2)

Ion Channel Classification Voltage-gated potassium channels (VGKCs) consist of four homologous α-subunits that combine to create a functional channel. Humans possess many distinct VGKC genes, and the resulting channels exhibit specialized properties and display rich tissue-type and cellular-compartment specificity. Each α-subunit of voltage-gated channels contains six transmembrane segments (S1–S6) linked by extracellular and intracellular loops (Fig. 98.3). The S5–S6 loop penetrates deep into the central part of the channel and lines the pore. The S4 segment contains positively charged amino acids and acts as the voltage sensor. These channels serve many functions, most notably to establish the resting membrane potential and to repolarize cells following an action potential. A unique class of potassium channel, the inwardly rectifying potassium channel, is homologous to the S5–S6 segments of the VGKC. Because the voltage-sensing S4 domain is absent, voltage dependence results from a voltage-dependent blockade by magnesium and polyamines rather than from the movement of the positively charged S4 domain in response to membrane depolarization. Voltage-gated sodium and calcium channels are highly homologous and share homology with VGKCs, from which they evolved. The α-subunits contain four highly homologous domains in tandem within a single transcript (DI–DIV; Fig. 98.4). Each domain resembles a VGKC α-subunit, with six transmembrane segments, as described earlier. Sodium and calcium channels differ in several regards, despite their many similarities. The amino acid sequence forming the selectivity

Trafficking and localization

Transcriptional regulation

Interacting proteins regulating function

Posttranslational regulation of function

Primary channelopathies

Secondary channelopathies

Fig. 98.1 Illustration of the principle that various mutations within a single gene (e.g., SCN4A) can lead to distinct clinical syndromes; conversely, mutations in different genes may result in a single recognized clinical entity. GEFS+, Generalized epilepsy with febrile seizures plus; hyperKPP, hyperkalemic periodic paralysis; hypoKPP2, hypokalemic periodic paralysis type 2; PAM, potassium-aggravated myotonia; PMC, paramyotonia congenita.

Autoantibodies (acquired channelopathies)

Ion channels

Developmental disorders

Synaptopathies

Cell membrane excitability

Synaptic regulation

Developmental circuit regulation

Excitability of brain circuits

Ptácek LJ. 2015. Annu. Rev. Physiol. 77:475-79 Fig. 98.2 Proposed Classification Scheme for Electrical and Episodic Disorders. Channelopathy is referred to as an abnormal function of ion channels themselves or secondary to disrupted orchestration of signaling from other proteins.

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filter and the modulatory auxiliary subunits are different. The sodium channel is composed of an α- and a β-subunit, and the calcium channel is composed of a pore-forming α1-subunit, an intracellular β-subunit, a membrane-spanning γ-subunit, and a membrane-anchoring α2δ-subunit. Sodium channels mediate fast depolarization and underlie the action potential, whereas voltage-gated calcium channels (VGCCs) mediate neurotransmitter release and allow the calcium influx that leads to second messenger effects. Ligand-gated ion channels activate on binding with their respective agonists. GABAA, glycine, and nicotinic acetylcholine receptors

(nAChRs) are examples of ligand-gated ion channels with known disease-causing mutations. Although distinguished by their ligand binding and ion permeability, channels gated by GABA, glycine, and acetylcholine share several structural similarities. Five intrinsic membrane subunits assemble to form hetero- or homopentamers. Each subunit contains four transmembrane domains (M1–M4), the second of which lines the pore and determines ionic selectivity (Fig. 98.5). Subunits contributing to nAChRs at the neuromuscular junction differ from those expressed in the central nervous system, explaining why the mutation of one gene may cause seizures without affecting

283 (2 bp) 214W

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–

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544 534 (5 bp) COOH

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Fig. 98.3 Proposed Structure of the Voltage-Gated Potassium Channel, Kv1.1 (KCNA1), Implicated in Episodic Ataxia Type 1. Voltage-dependent potassium channels comprise four subunits that form a channel pore. Each subunit contains six transmembrane domains, with the S4 segment containing positively charged amino acids that act as the voltage sensor. Mutations associated with episodic ataxia type 1 are illustrated. Disease-causing mutations are indicated by the one-letter amino acid representation. Amino acids with circles are wild-type, and the corresponding mutation is indicated by a connecting line with the corresponding position and amino acid.

I

1 2

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Fig. 98.4 Diagram of the Voltage-Gated Sodium Channel and the Four Most Common Mutations Causing Hyperkalemic Periodic Paralysis. The α-subunit consists of four highly homologous domains (I to IV), each containing six transmembrane segments (S1–S6). When inserted into the membrane, the four domains fold so as to encircle a central ion-selective pore lined by the S5–S6 loops. Analogous to the potassium channel (see Fig. 98.3), the S4 segments contain positively charged residues conferring voltage dependence on the channel. Auxiliary β-subunits are not shown.

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NH2 a g a b g

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a

B Fig. 98.5 Molecular Structure of the Nicotinic Acetylcholine Receptor. A, Three-dimensional model showing a pentameric protein forming a pore. Two molecules of acetylcholine (ACh) bind to the α-subunits to open the channel. B, Each subunit contains four α-helical domains, labeled M1 to M4. The M2 domain forms the channel pore. C, An enlarged diagram of the α-subunit showing the extracellular N and C termini and the four transmembrane domains. The amino acids at boundaries of the M2 domain are negatively charged, forming a selectivity filter for cations.

neuromuscular transmission, or vice versa. Binding of acetylcholine opens the channel, which conducts monovalent cations (Na+ and K+) with little or no selectivity, and some are additionally permeable to calcium. Channel activation results in membrane depolarization and excitation of the postsynaptic neuron or muscle fiber. The GABAA and glycine receptors belong to the nAChR superfamily and similarly consist of five subunits. GABAA receptors include α-, β-, and either γ- or δ-subunits. The predominant glycine receptor is a heteropentamer of three α-subunits and two β-subunits. In either case, agonist binding opens the channel and allows the flux of chloride (Cl−) into the cell, generally causing hyperpolarization and decreased excitability. Therefore, both GABA and glycine mediate inhibitory synaptic transmission. Channelopathies encompass a variety of diseases in multiple systems, including neurological, cardiac, endocrine, and kidney disorders, as summarized in Table 98.1. In the nervous system, most channelopathies are characterized by episodic attacks. Phenotypically, it ranges from muscle disease and peripheral neuropathy to episodic movement disorders, epilepsy, and migraine headache. Patients experience recurrent “attacks” throughout life, usually with complete resolution between attacks. Although there are strikingly diverse presentations, depending on the expression pattern of the gene, this group of disorders shares many similarities. First, as mentioned earlier, they are episodic with various frequencies of attacks. Second, these disorders have triggers or precipitating factors such as stress, sleep deprivation, and certain dietary factors that often precede the onset of an attack. Third, these disorders typically have a similar natural history, with an onset in childhood to young adulthood, worsening through adolescence and young-adult life, and improvement in middle- and late-adult life.

GENETIC DISORDERS OF MUSCULAR ION CHANNELS Skeletal muscle channelopathies are characterized by periodic paralyses and nondystrophic myotonia. These disorders include

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familial hypokalemic periodic paralysis (hypoKPP), hyperkalemic periodic paralysis (hyperKPP), PMC, myotonia congenita, PAM, and Andersen-Tawil syndrome (ATS). The patients with these disorders present with episodic muscle weakness, lasting minutes to hours, typically with full recovery between episodes. With recurrent episodes, one can develop permanent and fixed weakness later in life. Inheritance is autosomal dominant, with high penetrance, though for some mutations, there can be sex-dependent penetrance. Usually, there are triggers, as mentioned earlier, including stress, alcohol, recent illness, exercise followed by rest, fasting, or glucose-rich meals. Weakness can be regional or generalized, while bulbar and respiratory involvement is rare. Carbonic anhydrase inhibitors such as acetazolamide can be used to reduce the frequency of attacks of weakness. Sodium channel blockers like mexiletine are sometimes effective in reducing myotonic symptoms and signs (see Table 98.2). The patients may describe myotonia as muscle “stiffness” or “cramping.” Myotonia can be found clinically, and subclinical myotonia can be detected using electromyography (EMG). Myotonia is enhanced muscle excitability that leads to sustained bursts of discharges. Due to hyperexcitability of the muscle, one experiences involuntary contraction in said muscle, resulting from the inability to relax after forceful voluntary contraction. This can be demonstrated in the exam room, asking the patient to make a tight fist or forceful eye closure, and it is called “action myotonia.” Percussion myotonia is another supporting exam finding of muscle channelopathies. When a muscle, such as the gastrocnemius muscle, is tapped with a reflex hammer, a persistent dimpling of the muscle can be seen. Myotonia is a nonspecific sign found in several other diseases, including myotonic dystrophy 1, myotonic dystrophy 2 (proximal myotonic myopathy), myotonia congenita, PMC, and hyperKPP. The “paramyotonia” in paramyotonia congenital describes the ability to demonstrate worsening of myotonic stiffness with repeated muscle contractions and is best seen in the orbicularis oculi. This can be also be precipitated by muscle cooling (i.e., a temperature-sensitive phenotype). PMC is one disorder in this group with a distinct clinical finding of paramyotonia, commonly demonstrated with repeated forceful eye closure, leading to increasing myotonia of the orbicularis oculi. Clinical and subclinical myotonia can be demonstrated using EMG, which shows sustained bursts of muscle after-discharges that persist following voluntary contraction or occur in response to insertion of an EMG needle. It produces a characteristic “dive-bomber” discharge, with waxing and waning discharges (20–80 Hz). In addition to distinct myotonic discharges using EMG, nerve conduction studies (NCS), in particular the short and long exercise tests (SET and LET), can be further utilized to narrow down the differential diagnosis (Fournier et al., 2004). The compound motor action potentials (CMAPs) are recorded at a basline and every 10 seconds after 10 seconds of short isometric exercise up to 60 seconds. This 60 second set of CMAP recording is repeated twice, with a resting period of 1 minute between each set. It is noteworthy that maintaining a warm temperature is important, as cooling may change the pattern with decreased CMAP amplitude yet increased CMAP duration. The LET is performed by isometric exercise for 5 minutes. CMAPs are recorded every minute during the exercise, after exercise, and every 5 minutes after exercise, for 40–45 minutes. The pattern of decrement and increment of CMAP amplitude over time are helpful to identify distinct subgroups of mutations causing periodic paralysis. Fournier et al. (2004) analyzed the patterns after short and long exercises and categorized muscle channelopathies into 5 groups, as summarized in Table 98.4.

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Clinical Features of the Periodic Paralyses and Nondystrophic Myotonias HypoKPP

HyperKPP

PMC

MC

PAM

Age at onset Duration of attack Severity of attack Triggers

2nd decade Hours–days Moderate–severe Postexercise, CHO load

Infancy Hours Mild–moderate Cold, postexercise

1st decade Minutes–hours Mild–moderate Rest

1st–2nd decade N/A

Myotonia Serum K+ Progressive weakness Treatment for weakness Treatment for myotonia

Absent Usually low Some patients CAI N/A

1st decade Minutes–hours Mild–moderate Postexercise, fasting, K load Present Normal or high Some patients CAI Mexiletine

Present Variable Absent CAI Mexiletine

Present Normal Present in Becker myotonia N/A Mexiletine, phenytoin

Present Normal Absent N/A CAI

K

CAI, Carbonic anhydrase inhibitor; CHO, carbohydrate; hyperKPP, hyperkalemic periodic paralysis; hypoKPP, hypokalemic periodic paralysis; MC, myotonia congenita; PAM, potassium-aggravated myotonia; PMC, paramyotonia congenita; K, potassium.

Hypokalemic Periodic Paralysis (hypoKPP) Clinical

The prevalence of hypoKPP is approximately 1 per 100,000. Episodes of limb weakness accompanied by hypokalemia usually begin during adolescence. Attacks usually occur in the morning and are often triggered either by the ingestion of a carbohydrate load and high salt intake the previous night or by rest following strenuous exercise. Generalized muscle weakness and reduced or absent tendon reflexes are characteristic. Heralding the weakness may be sensory changes, fatigue, or a feeling of heaviness or aching in the legs or back. During paralysis, level of consciousness and sensation are preserved. Paralysis either spares the facial and respiratory muscles or causes only mild weakness, making medical intervention rarely necessary. The frequency, length, and severity of attacks vary. Although attacks may occur several times a week, they more often occur at intervals of weeks or months. Attack duration varies from minutes to days, typically lasting several hours. Occasionally the attacks are sufficiently brief to cause difficulty in documenting the accompanying hypokalemia. Patients usually recover full strength, although mild weakness may persist for several days or (more rarely) be permanent. A progressive permanent myopathy with mild proximal weakness may develop later in life, although it is rare.

Pathophysiology There are largely two genes that are responsible for hypoKPP. HypoKPP1 is up to 70% of cases, and it is caused by mutations in the CACNA1S gene encoding the α1-subunit of the dihydropyridine-sensitive L-type voltage-gated skeletal muscle calcium channel, Cav1.1, on chromosome 1q32.1 (Venance et al., 2006). Cav1.1 is the slow-inactivating, L-type calcium channel and can be blocked by 1,4-dihydropyridine (e.g., amlodipine and nifedipine), phenylalkamines (e.g., verapamil), and benzothiazepines (e.g., diltiazem; Fialho et al., 2018). This channel functions as the voltage sensor of the ryanodine receptor and plays an important role in excitation–contraction coupling in skeletal muscle. Four mutations in the S4 segments alter voltage sensitivity. Two mutations, involving arginine-to-histidine substitutions within the highly conserved S4 segments of DII and DIV (Arg-528-His and Arg-1239-His), account for most cases. The others involve arginine-to-glycine substitutions at the same locations. HypoKPP2 is caused by a mutation in SCN4A gene on chromosome 17q23.3 encoding the pore-forming α-subunit of the skeletal muscle voltage-gated sodium channel, Nav1.4. Approximately 10%– 20% of families with hypoKPP have this mutation. This is the same

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channel implicated in hyperKPP and other disorders described later (see Fig. 98.1). Evidence suggests that this sodium channel–associated syndrome is phenotypically different from the more common CACNA1S form. A proposed separate clinical entity, hypoKPP2, may be distinguishable from hypoKPP1 associated with CACNA1S by the presence of myalgias following paralytic attacks, and the presence of tubular aggregates instead of vacuoles in the muscle biopsy. In some patients, acetazolamide worsens symptoms (Bendahhou et al., 2001; Sternberg et al., 2001). In a large retrospective series, hypoKPP2 was associated with an older age of onset and shorter duration of attacks than classical hypoKPP1 (Miller et al., 2004). Whether involving SCN4A or CACNA1S, virtually all mutations causing hypoKPP involve an S4 voltage-sensor domain. In the case of the sodium channel, these mutations allow a leak current to pass through the “gating pore” at resting membrane potentials, bypassing the central channel pore and leading to inappropriate muscle fiber depolarization and consequent channel inactivation and action potential failure (Sokolov et al., 2007). Speculation exists that this phenomenon may also occur in mutated VGCCs.

Diagnosis An accurate medical history is essential for the diagnosis because observation of attacks is unusual, and patients are often normal between attacks. Characteristic features of hypoKPP that distinguish it from hyperKPP are that paralytic attacks are less frequent, longer lasting, precipitated by a carbohydrate load, and often begin during sleep (see Table 98.2). Potassium concentrations are usually low during an attack, less than 3.0 mM, although concentrations less than 2 mM should suggest a secondary form of periodic paralysis. Electrocardiogram (ECG) changes such as increased PR and QT intervals, T-wave flattening, and prominent U waves suggest an underlying hypokalemia. Provocative testing can be dangerous and is not routine. Test performance requires a hospitalized setting with continuous cardiac monitoring and should be performed only in patients without cardiac or renal disease. After giving an oral glucose load (2–5 g/kg up to a maximum of 100 g) with or without subcutaneous insulin (0.1 U/kg), one performs serial examinations of strength while monitoring serum glucose and potassium concentrations. Myotonia is not found in hypoKPP, either clinically or with EMG. EMG may reveal membrane irritability with myopathic changes but often is normal. Short and long exercise tests reveal Fournier pattern V, with decrement CMAPs following the long exercise test without significant change in the SET. Creatine kinase (CK) can be normal but may be elevated. Potassium between attacks is normal. Muscle

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Side effects

Monitoring Metabolism

Channelopathies: Episodic and Electrical Disorders of the Nervous System

be of prophylactic benefit in patients with normal renal function in whom other more conservative measures are insufficient. Many believe that reducing the frequency or severity of paralytic attacks provides protection against the development of myopathy based on anecdotal experience, although this has never been formally tested in a controlled trial. Inhibition of Na, K, Cl cotransporter (NKCLC), particularly with bumetanide (which is a NCLC blocker) is currently in clinical trial. During an acute attack, the preferred method of treatment is oral potassium chloride given at 0.5–1.0 mEq/kg, not exceeding 200 mEq in a 24-hour period. If a patient is unable to take oral potassium (e.g., arrhythmia due to hypokalemia or airway compromise due to altered mental status), then intravenous potassium (KCl bolus 0.05–0.1 mEq/ kg or 20–40 mEq/L of KCl in 5% mannitol) is indicated. Cardiac monitoring is important during the administration of potassium.

Acetazolamide

Prophylactic agent for some channelopathies (see text). Inhibits carbonic anhydrase. Adults: start 125 mg daily, titrating as needed up to a maximum daily dose of 1000–1500 mg, divided bid– qid. An extended release formulation is available. Children: consult a pharmacist. Taste changes (especially for carbonated drinks), fatigue, paresthesias, metabolic acidosis, blurred vision, myelosuppression, nephrolithiasis, etc. (Increased dietary citrate might be recommended to compensate for decreased urinary citrate observed during acetazolamide therapy.) Check electrolytes, BUN, creatinine, and CBC at baseline and periodically throughout therapy. None; excreted unchanged by kidneys.

Hyperkalemic Periodic Paralysis (hyperKPP)

bid, Twice daily; BUN, blood urea nitrogen; CBC, complete blood cell count; qid, four times daily. Please note that this table is for brief informational purposes only. Prescribing physicians should consult a pharmacist or an appropriate reference for complete and updated information.

histology reveals nonrimmed vacuoles within muscle fibers in biopsies in hypoKPP1 or tubular aggregates in hypoKPP2. Genetic testing should render muscle biopsy and provocative testing obsolete for diagnosis. Thyrotoxic periodic paralysis (TPP) may be clinically indistinguishable from hypoKPP, except that it is not familial and serum potassium levels are often lower than in familial hypoKPP (4.5 mEq/L) also has the additional advantage of narrowing the QT interval, thus reducing the likelihood of developing ventricular arrhythmias. Treatment of the prolonged QT interval depends on the severity of the underlying arrhythmias. The use of beta-blockers is a mainstay of treatment in long QT. Clinical experience shows that patients with ATS tolerate these agents well. In the presence of syncope due to sustained ventricular tachycardia, the placement of an implantable defibrillator is useful. Some evidence suggests that flecainide may be effective in the treatment of severe ATS-associated ventricular arrhythmias (Bökenkamp et al., 2007; Pellizzón et al., 2008).

Pathophysiology Mutations in the KCNJ2 gene on chromosome 17q account for approximately two-thirds of ATS probands. KCNJ2 encodes a widely expressed inwardly rectifying potassium channel (Plaster et al., 2001). Interestingly, among all identified probands, about 50% have an autosomal dominant disorder, and identification of sporadic cases with de novo mutations is common. The mechanisms of channel dysfunction are heterogeneous, including impaired phospholipid binding, pore function, or protein trafficking. Because VGKCs are tetrameric complexes, many (if not all) of the mutations are dominant negative. KCNJ5, encoding another inwardly rectifying potassium channel, may represent a second ATSassociated gene, as a mutation there was identified in one patient with ATS who did not harbor any KCNJ2 mutation (Kokunai et al., 2014).

Diagnosis Previous studies that took into account the variable penetrance of ATS classified individuals as affected if two of three criteria were met: paroxysmal weakness, prolonged QT interval with or without ventricular dysrhythmias, or characteristic dysmorphic features (Yoon et al., 2006a). ATS should be included in the differential diagnosis of any individual with documented long-QT syndrome, even in the absence of periodic paralysis or dysmorphism. Some family members of patients with the full clinical triad show only prolonged QT intervals. Similarly, perform ECG on all patients with suspected periodic paralysis for careful measurement of the QT interval. Often the diagnosis of ATS is established when an individual with paroxysmal weakness presents during an acute phase with ECG abnormalities. However, one often overlooks the diagnosis because the cardiac abnormalities, as with periodic muscle weakness, can be transitory and missed on routine ECG. A Holter monitor can capture episodic dysrhythmias or longer tracings for QT-interval analysis when ATS is

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Malignant Hyperthermia Malignant hyperthermia is an uncommon syndrome that manifests as a hypermetabolic reaction to volatile anesthetics and depolarizing neuromuscular blocking agents. Inheritance is usually autosomal dominant, but multifactorial inheritance also occurs. Further complicating efforts to define the inheritance and the incidence is that many people with malignant hyperthermia do not develop symptoms on all exposures, and some never experience exposure to inciting agents. Malignant hyperthermia displays genetic heterogeneity. Diseasecausing mutations have been identified in RYR1, the gene encoding the skeletal muscle ryanodine receptor, and CACNA1S, the L-type VGCC implicated in hypoKPP. The ryanodine receptor is a calcium channel expressed on the endoplasmic reticulum mediating calcium release in excitation–contraction coupling. To date, more than 20 disease-causing point mutations in RYR1 have been identified in humans, accounting for half of affected families. Clinical manifestations of malignant hyperthermia include tachypnea, tachycardia, rigidity, acidosis, rhabdomyolysis, and hyperthermia. Unfortunately, an intraoperative diagnosis often becomes apparent when symptoms develop. In patients in whom there is a family history suggestive of the diagnosis or in those who have had an event during previous anesthesia, the caffeine-contracture test remains the bestavailable test for diagnosis. A thin strip of explanted muscle is stimulated electrically to achieve maximal contraction and then exposed to caffeine; increased contracture signifies the disease. Although this test is useful, results are highly operator dependent. Therefore, if any possibility of this condition exists, the standard of practice is the pretreatment of every patient undergoing anesthesia with dantrolene. Although malignant

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hyperthermia is always a consideration in patients who become weak with anesthesia, a periodic paralysis—distinguished by flaccidity rather than rigidity—may be uncovered during periods of stress. Immediate termination of exposure to anesthesia, immediate effective core cooling, and the administration of dantrolene sodium, an inhibitor of calcium release from the sarcoplasmic reticulum, are the mainstays of treatment for this condition and have significantly reduced mortality since their introduction into clinical use.

FHM2 FHM3 AHC

Seizure

SMEI Paroxysmal dyskinesias?

The congenital myasthenic syndromes are a rare, heterogeneous, nonimmune group of disorders of neuromuscular transmission. Chapter 108 covers these disorders in detail.

GENETIC DISORDERS OF NEURONAL ION CHANNELS

Familial Hemiplegic Migraine Clinical

Familial hemiplegic migraine (FHM) is a rare autosomal dominant subtype of migraine with motor aura, characterized by lateralized motor weakness of variable intensity—hemiparesis to hemiplegia. Other aura symptoms such as visual aura, paresthesia, ataxia, fever, or lethargy may present during the attack. Motor symptoms often start in the hand and gradually spread to other areas, over 20–30 minutes, although it may occur suddenly mimicking a stroke. The duration of the symptoms can be variable, from a few hours to weeks. The diagnostic hallmark is episodic, reversible, unilateral motor weakness, along with at least one other kind of aura. Cortical spreading depression (CSD) is a widely accepted physiology underlying the migraine aura. CSD is a slow self-propagating wave of neuronal and glial depolarization, followed by hyperpolarization. Four subtypes, genetically defined (see later discussion), are distinguishable by clinical characteristics. FHM type 1 (FHM1) accounts for about 50%–75% of families. FHM1 is commonly associated with cerebellar degeneration. In addition to weakness, auras always involve additional symptoms, including sensory, visual, and language disturbances (Ducros et al., 2001). Severe aura attacks may last days or weeks and may involve fever, meningismus, and impaired consciousness, ranging from confusion to coma. Recovery between attacks is typically complete, although 30%–50% of patients with FHM1 exhibit permanent progressive cerebellar signs that include nystagmus, gait or limb ataxia, or dysarthria. These manifestations of FHM1 overlap with episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (Fig. 98.6), which are allelic with CACNA1A mutations (see the following discussion). By contrast, the characteristic features of FHM2 are an absence of cerebellar signs and a tendency for lower penetrance than in FHM1. FHM2 accounts for less than 25% of cases. Ataxia does not occur in FHM3, a rarer and more recently defined entity. FHM4 is diagnosed if there is no known genetic mutation of FHM. Importantly, patients with FHM exhibit a spectrum of disease expression, and subtype classification is likely to evolve with our knowledge of underlying genetics.

Pathophysiology FHM is a genetically heterogeneous condition that links to three loci on chromosomes 1q, 2q, and 19p; other loci are possible (Ducros et al., 1997). FHM1 includes the 50%–75% of families that show genetic

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The disorders considered here involve inherited ion channel defects in neurons. Like muscle channelopathies, these defects also result in episodic phenotypes. Many such mutations cause epilepsy, considered separately in a later section.

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Fig. 98.6 Venn Diagram Showing Phenotypic Overlap Among Various Channelopathies. AHC, Alternating hemiplegia of childhood; EA, episodic ataxia; FHM, familial hemiplegic migraine; SMEI, severe myoclonic epilepsy of infancy.

linkage to chromosome 19p13, with causative missense mutations in the CACNA1A gene (Ophoff et al., 1996). This gene encodes the pore-forming α1A-subunit of the neuronal P/Q-type VGCC, which is distributed widely throughout the brain. It is present at motor nerve terminals and the neuromuscular junction and is the principal calcium channel expressed by cerebellar Purkinje and granular neurons. These channels play an integral role in the action potential–triggered presynaptic calcium influx at nerve terminals that triggers vesicular fusion, playing an important role in neurotransmitter release. At least 17 different missense mutations and one nonsense mutation (Jen et al., 1999) are reported in CACNA1A (Fig. 98.7). These cause a variety of altered but not lost functions: changes in channel conductance, kinetics of inactivation, and current density (Hans et al., 1999; Kraus et al., 2000). Indeed, these mutations may confer gain of function, because many appear to cause a hyperpolarizing shift in the activation voltage, meaning that channels open and permit calcium influx at abnormally low membrane potentials. In one extreme case, the S218L mutation confers both the tendency to open near the resting potential of many neurons (−60 to −50 mV) and overall slowing and reduction in channel inactivation, thus causing marked increases in overall calcium influx. In keeping with this extreme biophysical profile, S218L produces a severe clinical phenotype of aura attacks triggered by minor head trauma and leading to deep coma and prolonged cerebral edema (Tottene et al., 2005). On the other hand, some loss-of-function mutations associated with episodic ataxia type 2 (EA2) may also cause migraine symptoms (Jen et al., 2004), suggesting that a direct correlation between presynaptic VGCC-mediated calcium entry and disease severity is too simplistic. Importantly, the mechanism linking altered channel biophysics to disease expression is controversial and defies a simple model. As mentioned earlier, other mutations in CACNA1A cause different dominantly inherited neurological disorders, including EA2 and spinocerebellar ataxia type 6 (SCA6). Although most patients with FHM1 also suffer persistent cerebellar deficits, a few mutations in CACNA1A cause only hemiplegic migraine (Ducros et al., 2001), and one mutation appears to cause classical migraine with aura but

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Fig. 98.7 P/Q-Type Calcium Channel and the Mutations Causing Familial Hemiplegic Migraine Type 2. Voltage-gated calcium channels are classified into transient (T-type), long-lasting (L-type), N (neuronal), P/Q (Purkinje cell), and R (toxin-resistant) channels. Shown is the CACNA1A-encoded α1A-subunit, which forms the voltage sensor and pore of the channel. Disease-causing missense mutations are illustrated.

no weakness (Serra et al., 2010). These observations suggest that a spectrum of disease exists from pure ataxia at one extreme to classical migraine at the other. Patients with FHM2, representing 10%–20% of all FHM sufferers, exhibit mutations in the ATP1A2 gene encoding the α2-subunit of the Na+/K+-ATPase, a protein responsible for maintaining the membrane potential in neurons and other cells (De Fusco et al., 2003). This pump plays a critical role in establishing transmembrane ionic gradients and is in this way directly integral to the function of innumerable ion channels and other proteins. Many missense mutations have been identified, probably resulting in a loss of function but not loss of surface expression (De Fusco et al., 2003), possibly by a reduced affinity for potassium (Segall et al., 2004). Although an ionic mechanism is likely, the precise pathophysiological connection to hemiplegic aura or head pain remains obscure. Additional mutations in ATP1A2 may also cause a form of benign familial infantile seizures (see the later section on Epilepsy; Vanmolkot et al., 2003) and alternating hemiplegia of childhood (Swoboda et al., 2004). A single mutation was found to cause hemiplegic migraine with cerebellar findings (Spadaro et al., 2004), challenging the conception that this association is specific for CACNA1A mutations. FHM3 involves mutations in the SCN1A gene on chromosome 2q24 that encodes a neuronal voltage-gated sodium channel α1-subunit. To date, three missense mutations have been identified, and the two that have been characterized electrophysiologically each confer upon the channel more rapid recovery from fast inactivation and thus the potential for faster firing frequency and neuronal hyperexcitability (Castro et al., 2009; Dichgans et al., 2005). Other mutations in SCN1A cause some cases of severe myoclonic epilepsy of infancy and generalized epilepsy with febrile seizures plus (see the later section on Epilepsy). Interestingly, mutations causing epilepsy occur near those causing FHM3, and one mutation—L263V—causes both clinical phenotypes (Castro et al., 2009). Epilepsy has also been reported in cases of FHM1 and FHM2, pointing to the intriguing possibility of a pathogenic link between seizure and migraine.

Diagnosis Genetic testing is now commercially available, but the diagnosis is mostly made clinically. Family history is clearly helpful in demonstrating autosomal dominance, but it is important to note that typical migraine syndromes may also show a strong (if less regular) familial pattern. Certain clinical elements of FHM help distinguish it from classical migraine with aura. Although the aura symptoms may be similar to those in classical migraine, FHM patients are more likely

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to experience motor, speech, and sensory symptoms. Furthermore, the duration of the headache, as well as the duration of the visual and sensory components of the aura, are typically greater in FHM patients (Thomsen et al., 2002). Although patients with classical migraine often experience the aura in isolation from the headache, FHM patients experience an associated headache virtually all the time. Infrequently, FHM patients may experience bilateral weakness, whereas this is generally not the case in patients with classical migraine. Finally, although defined genetically, one might clinically suspect FHM based on an association with cerebellar abnormalities or seizures (see Fig. 98.6).

Treatment Anecdotal evidence suggests that acetazolamide reduces the frequency of migraine attacks (Battistini et al., 1999; Jen et al., 2004). As suggested by functionally enhanced calcium currents in many cases of FHM, the calcium channel blocker verapamil aborted an attack when administered intravenously (Yu and Horowitz, 2001). To date, no controlled study has tested the efficacy of these or other agents in FHM. The guidelines for treating common migraine may be applied, except that triptans and ergotamine are not used, out of concern— possibly unwarranted—for stroke (Artto et al., 2007). Nimodipine is contraindicated because of the risk of worsening symptoms (Mjåset and Russell, 2008).

Familial Episodic Ataxias The familial episodic ataxias (EAs) are rare, dominantly inherited diseases characterized by episodes of ataxia of early onset, often with completely normal cerebellar function between attacks (Jen et al., 2007). Of the seven syndromes now recognized (EA1–EA7), the two most common forms, EA1 and EA2, are best described.

Clinical Characteristic of EA1 are attacks of cerebellar incoordination with jerking limb movements, often accompanied by slurred speech, that last for seconds to minutes. The episodes can occur spontaneously, but common triggers include exertion, infection, stress, or startle. Between attacks, patients may show myokymia, muscle rippling resulting from motor nerve hyperexcitability, especially in the hands and around the eyes. Symptom onset is in infancy, with spontaneous resolution in the second to third decade. Frequency, duration, and intensity of attacks vary greatly. EA1 is associated with epilepsy and hearing impairment (Spillane et al., 2016). Patients with EA2 experience episodes of truncal ataxia lasting hours to days, precipitated by exertion and stress. Age of onset varies

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between childhood and young adulthood but is most frequently in the second decade. Vertigo, nausea, and vomiting are present in more than half of patients, and many exhibit spontaneous nystagmus that is not seen interictally. Between episodes, the patient returns to normal but frequently displays gaze-evoked nystagmus with features typical of rebound nystagmus (Jen et al., 2007). Less commonly, positional and, later in the disease course, spontaneous downbeat nystagmus occurs. Approximately half of EA2 patients report headaches that meet criteria for migraine. Since mutations causing EA2 are in the same gene as in FHM1, this is not surprising.

Pathophysiology The mutation underlying EA1 is on chromosome 12. At least 15 missense mutations have been described in the responsible gene, KCNA1, which encodes a delayed rectifier VGKC (Kv1.1) that opens with a delay after membrane depolarization, allowing K+ efflux and membrane repolarization (see Fig. 98.3). Co-expression of mutant and wild-type channels results in delayed outward potassium current and impaired membrane repolarization following an action potential (Zerr et al., 1998), a dominant-negative effect that could lead to increased neuronal excitability and neurotransmitter release. The delayed rectifier potassium channel is widely expressed in the nervous system, with highest levels in the cerebellum and myelinated axons of peripheral nerves. In the cerebellum, an imbalance between inhibition and excitation could result in brief episodic incoordination. Similarly, in the peripheral motor nerves, impaired repolarization could lead to repetitive neuronal activity and resultant myokymia. Suggesting that these two effects may be mechanistically distinct is a KCNA1 missense mutation that causes an episodic ataxia more akin to EA2 without myokymia (Lee et al., 2004a) and another missense mutation resulting in myokymia without ataxia (Rea et al., 2002). EA2 is caused by mutations in CACNA1A, which encodes Cav2.1, a pore-forming α1A subunit of the calcium channel (Ophoff et al., 1996). In addition to FHM1, CACNA1A mutations also causes SCA6, resulting in cerebellar dysfunction. While FHM and EA are paroxysmal, SCA is not paroxysmal but characterized by progressive cerebellar degeneration. Various mutations have been found; however, the common pathophysiology appears to be cortical depression from neural hyperexcitability (Vincent et al., 2007). Whereas FHM1 is associated with missense mutations in the same gene, the genetic alterations associated with EA2 seem more dramatic. Of the approximately 30 mutations described so far, most are truncating, a few are missense, one is insertional, and one is due to expansion of a triplet CAG domain. Functional expression studies of some of these mutations reveal loss of voltage sensitivity or complete loss of channel function (Guida et al., 2001), suggesting that haploinsufficiency may underlie the phenotype. Some mutations may additionally interfere with protein folding and trafficking (Wan et al., 2005). EA5 results from mutation of the VGCC β4-subunit gene CACNB4, also implicated in idiopathic generalized epilepsy (see the later section on Epilepsy); it is clinically similar to EA2, except that seizures are an additional feature (Escayg et al., 2000a). Mutations in SLC1A3, the gene encoding the excitatory amino acid transporter EAAT1, cause EA6, an episodic ataxia associated with hemiplegia and seizures (Jen et al., 2005). The genes for EA3 (1q42), EA4, or EA7 (19q13) have not been identified.

Diagnosis Diagnosis is mostly clinical. Family history is helpful in making the diagnosis, despite rare cases of de novo mutations. The probability of examining a patient during an attack is low, so careful examination for interictal signs is important. Although almost half of EA1 patients

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Fig. 98.8 Sagittal Magnetic Resonance Image From a Patient with Episodic Ataxia Type 2. Note the significant cerebellar atrophy from this relatively advanced case. Type 1 patients do not display cerebellar atrophy (not shown).

complain of diplopia, they do not have nystagmus, which helps distinguish them from EA2 patients. The brevity of attacks and the persistent interictal myokymia seen in EA1 also help distinguish this from EA2. EA2 patients may demonstrate interictal end-point tremor or impaired suppression of the vestibulo-ocular reflex. They tend to have subtle and slowly progressive interictal cerebellar signs, particularly gazeevoked nystagmus. Although progressive ataxia often develops, it is rarely severe enough to prevent walking without assistance. Magnetic resonance imaging (MRI) may detect cerebellar atrophy, especially of the anterior vermis (Fig. 98.8), whereas EA1 patients have no cerebellar atrophy. Interestingly, there appears to be an increased incidence of epilepsy in both EA1 and EA2 patients, emphasizing the overlapping symptoms, possibly due to shared mechanisms (see Fig. 98.6). Genetic testing is available clinically and on a research basis.

Treatment Acetazolamide reduces the severity of attacks. Response to treatment varies among families, but generally, patients with EA2 have a greater response than those with EA1. Carbamazepine or 4-aminopyridine (Strupp et al., 2004) are beneficial in some patients. Because stress and strenuous exercise often exacerbate attacks, lifestyle modification can be quite effective.

Hereditary Hyperekplexia Clinical

Human startle disease, or hereditary hyperekplexia, is a rare hereditary disease characterized by an exaggerated startle response to sensory stimuli, plus neonatal hypertonia, hyperreflexia, and myoclonic jerks. It was first described in a Swedish family with startle reflexes and violent falls due to generalized stiffness (Kirstein et al., 1958). The usual inheritance is autosomal dominant, but several recessive mutations exist. Patients have generalized stiffness immediately after birth, which resolve over time (Koning-Tijsssen et al. 2000). The normal startle response is a primitive reflex that manifests as a stereotyped sequence of blinking, grimacing, neck flexion, and arm abduction and flexion. Both pathological and normal startle responses originate from the caudal brainstem, spreading rostro-caudally, as demonstrated using EMG in different muscles (Bakker et al., 2009). Patients exhibit

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heterozygous patient with spontaneous hyperekplexia possessing a missense mutation on one allele and a splice-site mutation on the other (Rees et al., 2002). Electrophysiological studies showed reduced sensitivity of the mutant channel to agonist, suggesting impaired binding of glycine to the channel. Finally, loss-of-function mutations in GLYT2 (also named SLC6A5), the gene encoding the presynaptic glycine transporter 2 protein, have been identified in three families with hereditary hyperekplexia. Glycine transporters mediate synaptic reuptake of the neurotransmitter, and its genetic deletion reproduces hyperekplexia in mice (Eulenburg et al., 2006). Reduction of glycine transporter function is expected to prolong glycine neurotransmission; how this leads to hyperekplexia is unknown.

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an overreaction to unexpected visual, tactile, or particularly auditory stimuli, with sudden generalized myoclonic jerks followed by stiffness, often resulting in uncontrolled falling during standing and walking. Following a startle reflex, there is generalized stiffness for a few seconds (Suhren et al., 1966). Consequently, patients often develop a characteristic slow, wide-based, cautious gait. Consciousness is preserved during the attacks, which helps distinguish this from startle epilepsy. Attack frequency may increase during times of stress, fear, lack of sleep, or the expectation of being frightened. The onset of symptoms may be as early as the neonatal period, with rigidity or generalized hypertonia, nocturnal limb jerking, and an exaggerated startle response. Attacks vary in severity and frequency and may be so severe as to cause apneic episodes and even death. Affected children may show a slight delay in motor development. A minor form of hyperekplexia, less common than the major form, manifests as an exaggerated startle response without associated symptoms, such as neonatal stiffness.

Pathophysiology Since being first reported in 1958, there are many reported mutations responsible for hereditary hyperekplexia, including GLRA1, GLRB, GPHN, GLYT2 (also named SLC6A5), and ARHGEF9 (Harvey et al., 2004, Rees et al., 2002, 2003). Eighty percent of hereditary hyperekplexia is caused by a mutation in the GLRA1 gene on chromosome 5q encoding the glycine receptor α1-subunit. The glycine receptor is a heteropentameric ligand-gated chloride channel composed of three ligand-binding α1-subunits and two β-subunits, located in postsynaptic membrane, mediating fast inhibitory neurotransmission in the brainstem and spinal cord. Several dominant, recessive, and de novo GLRA1 missense point mutations are seen in familial hyperekplexia patients. Most mutations flank the M2 pore-forming domain (Fig. 98.9). The physiological consequence of mutations in the α1-subunit is decreased glycine sensitivity, impaired channel opening, and uncoupling of agonist binding from channel activation. These changes reduce glycinergic inhibition and increase neuronal excitability. Mutations in the gene encoding the glycine receptor β-subunit (GLRB) also cause hyperekplexia. An example is a compound

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Physical examination may reveal diffuse hyperreflexia. The diffuse hypertonicity in infancy generally resolves with time, and adults have normal tone between attacks. An exaggerated head-retraction reflex is common in these patients. Tapping the forehead or root of the nose downward with a reflex hammer causes a brisk involuntary backward jerk of the head. This reflex is generally absent in unaffected individuals. Distinguish this condition from startle epilepsy, a rare seizure disorder characterized by startle-induced tonic spasm of a limb followed by a complex partial seizure; asymmetrical tonic posturing occurs during spells, and patients often have developmental delay and focal neurological signs. Neuroimaging in startle epilepsy reveals cortical dysplasia, although an interictal electroencephalogram (EEG) rarely shows a clear seizure focus. By contrast, familial hyperekplexia patients typically have normal development, display no ictal EEG findings to suggest a seizure disorder, have normal brain imaging, and maintain full consciousness during attacks. Brainstem pathology, including pontine hemorrhage or infarction, multiple sclerosis, vascular brainstem compression, and brainstem encephalitis, may cause a syndrome similar to hyperekplexia. Rarely, sporadic cases of hyperekplexia occur; therefore, do not exclude the diagnosis in patients lacking a family history.

Treatment Treatment with benzodiazepines helps reduce neonatal hypertonia and significantly reduces the severity and frequency of startle-induced attacks in some patients. Although clonazepam is the standard treatment, low-dose clobazam is effective in the treatment of hyperekplexia and well tolerated in infants. Benzodiazepines act by increasing GABAmediated inhibition and have no effect on glycinergic transmission. This suggests that enhancing the GABA-mediated inhibition may compensate for glycinergic dysfunction.

Hereditary Peripheral Nerve Disorders SCN9A Mutation

Primary erythromelalgia (PE), also known as familial erythromelalgia or Weir Mitchell disease, is an autosomal dominant disorder characterized by burning pain and redness in the limbs in response to warmth or moderate exercise (Dib-Hajj et al., 2008; Yang et al., 2004). Paroxysmal extreme pain disorder (PEPD), previously known as familial rectal pain syndrome, is characterized by burning pain in the rectal, ocular, and mandibular areas accompanied by autonomic dysfunction, such as skin flushing (Hayden, 1959). Both PE and PEPD are caused by mutations in SCN9A, encoding a voltage-gated sodium channel selectively expressed in small-diameter dorsal root ganglion neurons (mostly nociceptors) and sympathetic ganglion neurons. The mutations responsible for PE are gain-of-function mutations that enhance current through the channels by decreasing the voltage threshold for

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activation, among other effects, while mutations causing PEPD impair the fast inactivation of the sodium channel. The discovery that expression of this sodium channel is narrowly restricted to a population of pain-mediating neurons, and that its enhanced function can result in pain, raises the exciting hypothesis that selective channel blockade may result in relief of chronic pain. Mexiletine and topical lidocaine are used for PE, and carbamazepine has shown benefit in PEPD. Supporting a more general role for this gene, some polymorphisms correlate with a lowered pain threshold in patients without primary erythermalgia (Reimann et al., 2010). Loss-of-function mutations in the same gene lead to an inherited insensitivity to pain (hereditary sensory and autonomic neuropathy type IID). A selective antagonist of this channel does not yet exist.

TRPV4 Mutation Scapuloperoneal spinal muscular atrophy, congenital distal spinal muscular atrophy, and Charcot-Marie-Tooth disease type 2C (or hereditary motor sensory neuropathy type 2) are related disorders. Characteristic of all are autosomal dominant inheritance, muscle weakness and wasting, and other features that can include arthrogryposis, scoliosis, or vocal cord paralysis. These disorders result from mutations in TRPV4, the gene on chromosome 12q encoding the vanilloid transient receptor potential (TRP) protein, a peripheral nerve nonselective cation channel activated by many noxious stimuli such as heat, mechanical stress, osmotic pressure, and inflammatory cytokines (Auer-Grumbach et al., 2010; Deng et al., 2010; Landoure et al., 2010). Although the pathogenic mechanism remains unclear, all known mutations affect the ankyrin repeat region of the protein, where regulatory proteins, second messengers, and other TRPV4 channels normally bind. Unlike most disorders in this chapter, the phenotypes resulting from TRPV4 mutations are not episodic.

Paroxysmal Dyskinesia The paroxysmal dyskinesias are rare syndromes characterized by recurrent, episodic attacks of involuntary movements, such as dystonia, chorea, athetosis, ballism, or a combination. While some cases may be sporadic, most exhibit autosomal dominant inheritance. Paroxysmal non-kinesigenic dyskinesia (PNKD) involves attacks of dystonia, chorea, or athetosis, occurring spontaneously or triggered by alcohol, coffee, stress, or fatigue. An aura of paresthesia, tension, or dizziness may precede abnormal movements that typically involve the limbs. The attacks last for minutes to hours, which is longer in duration and less frequent than paroxysmal kinesigenic dyskinesia (PKD). In a family with an autosomal dominant pattern of PKND and generalized epilepsy (mostly absence attacks, as discussed later), a mutation of KCNMA1 on chromosome 10q was identified (Du et al., 2005). This gene encodes the α-subunit of the BK channel, a potassium channel that normally activates with both membrane depolarization and a rise in intracellular calcium; the mutation heightens calcium sensitivity, enhancing channel activity. Ethanol may also activate the BK channel (Davies et al., 2003), suggesting a mechanism whereby alcohol consumption in synergy with the mutation may precipitate a dyskinetic attack (Du et al., 2005). PNKD without epilepsy is linked to mutation of the PNKD gene (previously called the myofibrillogenesis regulator gene, MR1) on chromosome 2 (Lee et al., 2004b); subsequently, the protein encoded by this gene has been shown to encode a novel synaptic protein regulating exocytosis (Shen et al., 2015). Studies in a mouse model of the human mutations recapitulated caffeine- and ethanol-sensitive attacks and abnormal dopamine signaling. Neuropharmacological experiments showed that the abnormal signaling is being mediated through the indirect pathway of the striatum (Lee et al. 2012). Treatment of PNKD involves avoidance of triggers; benzodiazepines, including clonazepam, often help.

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Another related disorder is PKD. It involves attacks triggered by sudden movement, change in direction or startle, often with auras as in PNKD. Attacks commonly manifest with choreoathetosis and dystonia, typically lasting for 5–10 seconds. It may occur as frequently as daily or only a few times per year. Mutations in the proline-rich transmembrane protein 2 (PRRT2) gene on chromosome 16q cause PKD and benign familial infantile seizures (as discussed later; Chen et al., 2011; Lee et al., 2012). PRRT2 function is not known but thought to be involved in neurotransmitter release and synaptic vesicle fusion (Valtorta et al., 2016). Distinguishing PKD from PNKD is beneficial, as PKD usually responds dramatically to antiepileptic therapy, like carbamazepine and phenytoin (Bruno et al, 2004). Paroxysmal exercise-induced dyskinesia (PED) is less common than PKD and PNKD and involves lower limb dystonia lasting up to 30 minutes, triggered by exercise. Unlike PKD, where sudden movement may precipitate attacks immediately, PED attacks occur after 15–20 minutes of vigorous exercise. The episode lasts from 5 to 30 minutes, and patients with PED usually do not experience aura. SLC2A1 on chromosome 1p is the gene encoding the GLUT1 glucose transporter protein, and mutations cause PED (Weber et al., 2008) or idiopathic generalized absence seizures (Suls et al., 2008); some mutations in SLC2A1 may cause more severe clinical phenotypes that include cognitive dysfunction and microcephaly. PED is usually autosomal dominantly inherited. Treatments include trigger avoidance and a ketogenic diet. A theme emerges from these disorders, such that mutations in certain genes may give rise to phenotypic heterogeneity, involving a spectrum of paroxysmal dyskinesia and epilepsy.

Other Inherited Neuronal Channelopathies The rapid proliferation and lowering cost of whole-exome sequencing have led to frequent discoveries of new, rare genetic disorders. As one example, de novo mutations in GRIN2B, the gene encoding the N-methyl-d-aspartate receptor (NMDA) subunit 2B protein, associate with mental retardation (Endele et al., 2010; O’Roak et al., 2012). NMDA receptors are well known to neuroscientists as the subtype of glutamate receptor that mediates long-term potentiation, a form of synaptic plasticity thought to underlie learning and memory, and the 2B subunit in particular has special importance in the developing brain; it is not surprising that disruption of this receptor would result in impaired learning.

EPILEPSY Epilepsy is a disorder with recurrent seizures that affects 1%–2% of the general population. Ion channels are crucial in regulating the excitability of the neurons. Thus the dysfunction of ion channels is believed to cause excessive electrical excitability and resultant seizure activity. In some cases, channel mutations leading to lower excitability in inhibitory neurons could have led to a common final pathway of seizures. Among 977 identified epilepsy-associated genes, 60 genes are ion channel genes (Wang et al., 2016). Although most epilepsies have a complex mode of inheritance, some rare idiopathic epilepsies are monogenic, most of which are autosomal dominant. Discussed here are syndromes associated with an identified gene. As might be expected from diseases characterized by abnormal electrical activity in the brain, familial epilepsy syndromes often result from aberrant ion channel function.

Familial Focal Epilepsies Unlike generalized epilepsy syndromes, which exhibit a strong genetic pattern, few focal epilepsy syndromes are genetic. Of these syndromes, only two have known causative mutations.

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Autosomal Dominant Nocturnal Frontal Lobe Epilepsy A syndrome characterized by clusters of brief partial seizures that occur during light sleep, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a monogenic disorder with a penetrance of 70%–80%. The motor seizures, which manifest as hyperkinetic tonic stiffening and clonic jerking movements, may occur several times per night, usually shortly after falling asleep or just before awakening. Aura may precede seizures, manifesting as various somatosensory, sensory, and psychic phenomena. Episodes often start with a gasp, grunt, or vocalization, followed by eye opening or staring. Secondary generalization is unusual, and patients remain conscious during the seizures. Patients become symptomatic within the first or second decade of life, although later onset occurs. Seizures generally persist throughout adult life, becoming less severe beyond the fifth decade. Suggesting an important contribution of genetic background, intrafamilial variability in seizure frequency and severity is significant, with some patients experiencing several seizures nightly and others remaining seizure-free for months. Interictal EEG is normal, and ictal EEG may show bifrontal epileptiform discharges. Because of the clinical similarities, ADNFLE is often mistaken for benign nocturnal parasomnia or night terror. Therefore, nocturnal video polysomnography is very useful in distinguishing ADNFLE from these other conditions. ADNFLE was initially shown to be caused by a point mutation in the nAChR α4-subunit gene CHRNA4 on chromosome 20q (Steinlein et al., 1995). The nAChRs are acetylcholine-activated cation channels that play an important role in postsynaptic excitation and neurotransmitter release. Four mutations in CHRNA4 were identified in several ethnic groups. Mutations have also been identified in CHRNB2 (Phillips et al., 2001) and CHRNA2 (Aridon et al., 2006), encoding the nAChR β2- and α2-subunits. The β2-subunit associates closely with the α4-subunit, and the α4–β2 combination is the dominant subtype of nAChR in the brain. Mutations in CHRNA4 and CHRNB2 involve M2, the second transmembrane domain and the part of the protein thought to line the channel pore. Some cases of ADNFLE link to chromosome 15q24, close to a cluster of three other nAChR subunits, although the responsible mutations have not been elucidated (Philips et al., 1998). Mutations result in increased sensitivity both to activation by acetylcholine and to block by carbamazepine. This latter in vitro observation bears clinical relevance because ADNFLE patients have a good therapeutic response to carbamazepine. Given the wide distribution of nAChRs within the brain, it remains unclear why the epilepsy is focal and why the seizures arise selectively in the frontal lobes. Missense mutations in the sodium-gated potassium channel gene KCNT1 on chromosome 9q were found to cause a severe form of ADNFLE. As KCNT1 is highly expressed in frontal lobes, this may explain cognitive dysfunction and psychiatric symptoms (Heron et al., 2012). The same gene is implicated in malignant migrating partial seizures of infancy (Barcia et al., 2012), in which mutations disrupt a protein kinase C phosphorylation site and lead to constitutive channel hyperactivation, the postulated pathophysiological mechanism (Barcia et al., 2012). Furthermore, a missense mutation in the corticotropin-releasing hormone (CRH) gene has been detected in one Italian family with ADNFLE. It is an interesting finding, as this seems not directly related to channelopathy (Sansoni et al. 2013). Further physiological connection is to be elucidated.

Familial Temporal Lobe Epilepsies Temporal lobe epilepsies exist in both sporadic and inherited forms, and the genetics of familial syndromes remain largely unknown (Andermann et al., 2005). The onset of familial lateral temporal lobe epilepsy (FLTLE), or autosomal dominant partial epilepsy with auditory features (ADPEAF), a benign syndrome distinguished from the

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more common mesial form by characteristic auditory auras, is in the second or third decade, and transmission is autosomal dominant with incomplete penetrance. Approximately 50% of cases involve mutations in the leucine-rich, glioma-inactivated gene 1 (LGI1) on chromosome 10q (Kalachikov et al., 2002; Morante-Redolat et al., 2002), whose product was shown to complex with presynaptic A-type VGKCs (Schulte et al., 2006). Normally, LGI1 appears to reduce channel inactivation, and its dysfunction results in faster inactivation kinetics and, likely, neuronal hyperexcitability. A different gene, CPA6 on chromosome 8q, encodes a carboxypeptidase enzyme (not an ion channel), in which partial loss of function associates with familial temporal lobe epilepsy (heterozygous mutations) or febrile seizures (homozygous; Salzmann et al., 2012).

Idiopathic Generalized Epilepsies The idiopathic generalized epilepsies (IGEs) are among the most common seizure disorders, occurring at an overall frequency of 15%–20% among cohorts of adults and children (Jallon and Latour, 2005). A strong genetic component to IGE transmission exists, but the pattern of inheritance varies between individual disorders. Some rare syndromes, including benign familial neonatal seizures (BFNS) and generalized epilepsy with febrile seizures plus, are monogenic autosomal dominant traits, now known to be due to mutations in ion channel genes. Other more common syndromes—juvenile myoclonic epilepsy (JME), childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), and epilepsy with grand mal seizures on awakening (EGMA)— exhibit a more complex pattern of inheritance. These disorders, which relate to each other by a continuum of clinical phenotypes and similar EEG findings (see Chapter 100), probably encompass a broad range of individual diseases. We now know that aberrant ion channels underlie at least some of these diseases.

Benign Familial Neonatal Seizures BFNS is a rare autosomal dominant disorder. Multifocal or generalized tonic-clonic convulsions appear after the third day of life. Myoclonic seizures are rare. Seizures are generally brief and well controlled by antiepileptic medications, although status epilepticus occurs. Age of onset may extend up to the fourth month of life, and in most cases, seizures disappear spontaneously after a few weeks or months. Although these children usually have normal neurological examination and development, the risk of recurring seizures later in life is about 15%. These later seizures, often provoked by auditory stimuli or emotional stress, are easily controllable with antiepileptic medications. Interictal EEG activity is usually normal, whereas the ictal EEG attenuates at the onset, followed by slow waves, spikes, and a burst–suppression pattern. Two BFNS-causing genes have been identified—one on chromosome 20q and the other on chromosome 8q. The mutated genes both encode VGKCs: KCNQ2 and KCNQ3, respectively (Biervert et al., 1998; Charlier et al., 1998; Singh et al., 1998). These channels activate by membrane depolarization and contribute to the repolarization of the action potential. Reports appear of missense amino acid deletion, splice-site frameshift mutations, and gene deletions; most involve the KCNQ2 gene (Fig. 98.10). Functional expression of mutant channels results in reduced potassium current, likely leading to impaired membrane repolarization and thus increased neuronal excitation. KCNQ2- and KCNQ3-encoded products combine to form a heteromeric channel underlying the M-current (Wang et al., 1998), a potassium conductance found widely in the central nervous system that plays a crucial role in the regulation of neuronal excitability. Co-expressing the mutant gene (KCNQ2 or KCNQ3) together with its wild-type allele and its wild-type partner results in mild (25%) reduction in M-current amplitude. Although it is unclear how the mutated

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channels either independently or in the form of the M-current lead to seizures, KCNQ2 channels are concentrated in the septum and hippocampus, areas key for control of rhythmic brain activity and neuronal synchronization, and both associated with the generation of epileptic seizures. Thus, even slight alterations in neuronal excitability through impaired KCNQ2/KCNQ3 channel-mediated repolarization could presumably lead to aberrant neuronal synchronization and seizures. In light of reports that lamotrigine and carbamazepine enhance neocortical potassium currents in vitro, they may be of particular use in BFNS patients.

Generalized Epilepsy with Febrile Seizures Plus Febrile seizures are the most common seizure disorder in children, affecting 2%–5% of all children younger than 6 years. Although most febrile seizures show complex inheritance, a small proportion transmits in an autosomal dominant pattern. The disorder termed generalized epilepsy with febrile seizures plus (GEFS+) refers to the phenotype of individuals who have febrile seizures extending beyond 6 years of age, with or without afebrile generalized tonic-clonic seizures. Although most patients experience only febrile or febrile seizures

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plus, approximately 30% of patients may experience other generalized epilepsy phenotypes, such as absence, myoclonic, and atonic spells, and even partial seizures with secondary generalization. More severe phenotypes include myoclonic-astatic epilepsy and severe myoclonic epilepsy of infancy. EEG may show irregular 2.5- to 4-Hz generalized spike-and-wave or polyspike-wave discharges. A high level of genetic heterogeneity exists in GEFS+ (see Fig. 98.1). Mutations in four voltage-gated sodium channel genes (SCN1B on chromosome 19q and SCN1A, SCN2A, and SCN9A on chromosome 2q; Escayg et al., 2000b; Singh et al., 2009; Sugawara et al., 2001; Wallace et al., 1998) and two GABAA receptor genes (GABRG2 and GABRD) encoding the γ2- and δ-subunits (Baulac et al., 2001; Dibbens et al., 2004) cause GEFS+ (Fig. 98.11). Evidence exists for other mutated genes not yet identified. Functional analysis of several mutated sodium channels reveals slow inactivation, enhanced inward sodium current, and thus neuronal hyperexcitability (Lossin et al., 2002). Functional studies of the two GABRG2 mutations showed reduced channel conductance in one case and abolished benzodiazepine sensitivity in the other. The GABRD mutations reduce current amplitude, each leading in different ways to a decrease in synaptic inhibition and thus an increase in neuronal excitability. These functional observations evoke compelling molecular explanations for clinical disease and, like ADNFLE and BFNS, illustrate how heterogeneous genetic defects may converge on a single clinical phenotype.

SCN2A Mutation and Other Early Childhood Seizures

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Fig. 98.10 The neuronal potassium channel α-subunit encoded by the KCNQ2 gene, and the proposed pathogenic mutations causing benign familial neonatal seizures. The majority of mutations have been identified in this channel, which is believed to coassemble with the KCNQ3 gene product and underlie the M-current.

Other rare convulsive disorders of early childhood include benign familial infantile seizures and benign familial neonatal-infantile seizures, differentiated from BFNS by the age of onset. At least some cases involve mutations in the sodium channel α2-subunit gene, SCN2A, the same gene affected in some cases of GEFS+ (see the preceding section). Two mutations are present in families with seizures beginning at 1–3 months of age and ending at around 4 months (“neonatal-infantile”; Heron et al., 2002). Both mutations occur in cytoplasmic loops, inhibiting channel inactivation. A third mutation, also affecting a cytoplasmic loop, was identified in a family with similar seizures beginning at 4–12 months of age (“infantile”; Striano et al., 2006). Of note, ATP1A2 mutations account for some cases of benign familial infantile seizures (see the earlier section, Familial Hemiplegic Migraine).

Juvenile Myoclonic Epilepsy JME accounts for 4%–10% of all epilepsy (Jallon and Latour, 2005). Featuring myoclonic jerks, generalized tonic-clonic seizures, and

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Fig. 98.11 Mutations in the voltage-gated Na+ channel causing generalized epilepsy with febrile seizures plus (GEFS+). The α-subunit is encoded by SCN1A (A), and the β1-subunit (B) is encoded by the SCN1B gene. Disease-causing mutations are shown. Mutations in other genes, including SCN2A and GABRG2, also cause GEFS+ (see Fig. 98.1).

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absence spells, JME typically begins during adolescence (see Chapter 100). A genetic pattern is clear, but the mixed inheritance pattern suggests multiple heritable causes. One French-Canadian family suffers an autosomal dominant form of JME associated with a mutation in the GABAA receptor α1-subunit gene, GABRA1 (Cossette et al., 2002), that results in loss of function and possible neuronal hyperexcitability (Krampfl et al., 2005). Less well described is the possible role of the VGCC β4-subunit gene, CACNB4, in JME and episodic ataxia (see the previous discussion; Escayg et al., 2000a). GABRD variations may influence susceptibility to JME (Dibbens et al., 2004). EFHC1 is a gene on chromosome 6p, and five missense mutations have been identified in 6 of 44 JME families in whom it was sequenced (Suzuki et al., 2004). Although the precise function of the EFHC1 protein is unknown, it binds specifically to R-type VGCCs, alters their function, and perhaps thereby influences cell death pathways when transfected into cells in vitro. Whether or not this model turns out to be correct, it illustrates that an inherited channelopathy may result not only from mutation of a channel gene itself but also of genes whose products regulate the function of otherwise normal channels (Fig. 98.12). Chromosome 15q has genetic loci implicated by linkage studies as possible contributors to some cases of JME. This area is known to contain, among other genes, the α7-subunit of the nicotinic acetylcholine receptor, CHRNA7 (Elmslie et al., 1997). Similar to JME is familial adult myoclonic epilepsy (FAME) and autosomal dominant cortical myoclonus and epilepsy (ADCME), characterized by autosomal dominant inheritance, adult onset, varying degrees of myoclonus in the limbs, rare tonic-clonic seizures, and a benign course. These syndromes bear some similarity to JME, except for the adult onset and the highly penetrant autosomal dominant transmission. Whereas the genes are not yet known, the FAME gene has been mapped to chromosome 8q24 (Plaster et al., 1999) and the ADCME gene to chromosome 2q11.1–q12.2 (Guerrini et al., 2001).

Childhood Absence Epilepsy CAE, a syndrome less common than JME and typified by brief, frequent absence spells (see Chapter 100), exhibits a multigenic pattern of inheritance. Mutations in GABRB3, encoding the GABAA receptor β3-subunit, appear to cause CAE in some families (Tanaka et al., 2008; Urak et al., 2006). A mutation in the GABAA receptor γ2-subunit gene, GABRG2, on chromosome 5q, conferring loss of benzodiazepine-induced enhancement of GABA-induced currents in vitro, is present in a family with CAE and an increased incidence of febrile seizures (Wallace et al., 2001). The GABAA receptor mediates phasic or tonic inhibitory transmission leading to hyperpolarization by allowing chloride anion influx through its pore (Hirose et al, 2014). Mutations in the T-type VGCC gene, CACNA1H, may contribute to some cases of CAE (Chen et al., 2003) and influence susceptibility to other IGEs (Heron et al., 2007). Mutations in other genes—CACNA1A, GABRA1, and a locus on chromosome 8q24—may also play a role.

Theoretical Considerations The phenotypic and EEG characteristics of various IGEs overlap to a considerable extent, implying that the boundaries separating some of these disorders may be blurred. Moreover, the relationships between molecular defects and clinical expression are irregular. Mutations in some genes (e.g., SCN2A, GABRG2) lead to heterogeneous clinical syndromes or genotype–phenotype divergence. Genotype-phenotype convergence is typified by ADNFLE, BFNS, and GEFS+, each of which may result from myriad underlying genetic roots (see Fig. 98.1). These considerations challenge existing definitions of disease, which will likely shift as knowledge advances. Cheaper and more widely available genetic tests will eventually free clinicians from the ambiguities of syndromic classification, and the elucidation of the molecular basis of familial epilepsy syndromes will eventually lead to tailored pharmacological treatments.

AUTOIMMUNE CHANNELOPATHIES Most channelopathies result from genetic mutation and are present from conception, usually with a family history of similar disorders. However, some ion channel disorders may develop in a previously normal individual. Beyond the obvious roles of drugs, toxins, and electrolyte disturbances in disrupting the function of structurally normal channels, circulating autoantibodies are the next most common known cause of acquired channelopathies. In some cases, these are autoimmune disorders, and, in some cases, they are paraneoplastic phenomena. A paraneoplastic syndrome is a remote nonmalignant effect of a primary tumor, thought to be caused by a cross-reactive autoimmune response against a tumor antigen. The syndrome is often apparent before the tumor itself is recognized. Therefore, paraneoplastic channelopathies are important to recognize, not only for their own sake but also because they may herald a more morbid underlying process.

Channel

Regulator Anchoring protein

Targeting

Myasthenia Gravis

Protein expression, posttranslational modification, etc. Fig. 98.12 Normal Ion Channel Function Relies Not Only on a Normal Channel Protein. Illustrated are examples of other processes that when defective may theoretically result in aberrant ion channel function and disease.

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The best characterized autoimmune disease, myasthenia gravis, is characterized by “fatigable weakness.” This results in most cases from circulating antibodies directed against nAChRs. Polyclonal immunoglobulin G (IgG) reacts against variable extracellular nAChR epitopes at the neuromuscular junction, with the main immunogenic region located on each of two α-subunits of the heteropentameric receptor complex (Tzartos et al., 1998). Antibodies produce disease by activating complement, causing lysis of the muscle membrane, and by cross-linking AChRs, leading to accelerated protein degradation. In addition to AChR antibodies (blocking,

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modulating, and binding), antibodies against muscle-specific tyrosine kinase (MuSK) or LDL receptor-related protein 4 (LRP) 4 also have been found in myasthenic patients lacking the AChR antibodies. Understanding of the cause of autoantibody production is poor, but it probably results from multiple disease processes, sometimes involving thymoma or thymic hyperplasia (see Chapter 108).

Lambert-Eaton Myasthenic Syndrome Like myasthenia gravis, Lambert-Eaton myasthenic syndrome (LEMS) produces weakness by obstructing neuromuscular transmission. LEMS is caused by defected postsynaptic neurotransmitter transmission, typically presenting with proximal leg weakness and fatigue in middle-aged adults. Autoantibodies directed against P/Q-type VGCCs impair presynaptic calcium influx, thereby reducing action potential-triggered vesicle release. These autoantibodies are not specific to the neuromuscular junction, and patients also exhibit autonomic dysfunction. However, the antibodies probably do not cross the blood–brain barrier to a sufficient extent to cause diseases mimicking CACNA1A mutants—FHM1, EA2, SCA6, or seizures—although some patients may exhibit ataxia (see the later section Paraneoplastic Cerebellar Degeneration). Conversely, weakness is not a typical feature in patients with loss-of-function CACNA1A mutations, although EMG studies reveal expected neuromuscular abnormalities (Jen et al., 2001). Small-cell lung cancer cells express VGCCs, likely triggering immunogenesis in the large proportion of patients in whom LEMS turns out to be a paraneoplastic phenomenon. As in myasthenia gravis, polyclonal antibodies may be detectable in LEMS. The extracellular S5–S6 linker regions of the α-subunit are the proposed pathogenic epitopes (Takamori, 2004).

Acquired Neuromyotonia (Isaacs Syndrome) Isaacs syndrome presents with painful muscle cramps and stiffness, slow muscle relaxation after contraction, commonly affecting adolescents and young adults. Characteristic features of acquired neuromyotonia are fasciculations and myokymic and neuromyotonic discharges on EMG, reflecting motor nerve hyperactivity driven by abnormal peripheral nerve firing. Due to excessive muscle fiber activities, the patients with Issacs syndrome often present with weight loss, muscle hypertrophy, and hyperhidrosis. The syndrome may occur in association with thymoma. The autoimmune target is the VGKC found along peripheral motor axons and responsible for repolarization after action potential firing (Shillito et al., 1995). This is the same channel affected in EA1, and the mechanism of interictal myokymia is identical: reduced potassium efflux from axons and nerve terminals leads to higher membrane potentials, inappropriate action potential firing, and acetylcholine release. This same phenomenon probably also affects autonomic fibers, explaining why excessive sweating, salivation, and lacrimation are often observed. The action of these antibodies is complement-independent and appears to involve cross-linking of channels (Tomimitsu et al., 2004). VGKC antibodies probably also cause Morvan syndrome, which encompasses all the clinical features of acquired neuromyotonia plus a fluctuating delirium (Barber et al., 2000; Lee et al., 1998). Supporting a role for circulating autoantibodies is the effectiveness of plasma exchange in the treatment of these patients (Liguori et al., 2001). VGKC antibodies were present in a series of patients suffering from an encephalopathy indistinguishable from limbic encephalitis, with temporal lobe-onset seizures and behavioral and cognitive disturbances, but no neuromuscular abnormality (Thieben et al., 2004). Thus, a peripheral-to-central spectrum of disease may exist, with acquired neuromyotonia on the one extreme and VGKC antibody-associated limbic encephalitis on the other.

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Other antibodies have been also identified in patients with Issacs and Morvan syndrome. Patients with CASPR2 antibodies may present with neuromyotonia alone, limbic encephalitis, or Morvan syndrome. CASPR2 is not an ion channel, but this protein is important in clustering of Kv1.1 and Kv1.2, located in the juxtaparanodal regions of both peripheral and CNS axon (Amato and James, 2016). Other associated antibodies are often paraneoplastic and include nAChR, CRMP-5, amphiphysin, and antinuclear neuronal type 4.

Paraneoplastic Cerebellar Degeneration Paraneoplastic cerebellar degeneration (PCD), presenting as a rapidly progressive ataxic syndrome, most commonly occurs in cases of breast, ovarian, and lung malignancies. PCD probably represents a spectrum of diseases associated with distinct autoimmune targets. Among these may be the anti-P/Q-type VGCC antibodies found in small-cell cancer. Although these antibodies more typically cause peripheral disease (LEMS), they are found less commonly in the CSF of patients with PCD (Graus et al., 2002). Purkinje cell loss is the pathological hallmark of PCD; these cells express high levels of P/Qtype VGCCs, and it seems likely that antibodies directed against these channels are pathogenic. PCD associated with small-cell lung cancer may occur with or without neuromuscular dysfunction, and the factors predisposing to central versus peripheral action of the paraneoplastic antibodies are unknown. Finally, despite the fact that the same molecule may be the target of pathology in PCD and CACNA1Aassociated diseases (FHM1, EA2, SCA6), PCD is not an episodic disorder but rather characterized by rapid deterioration, perhaps due to target cell destruction.

Limbic Encephalitis The term limbic encephalitis encompasses an array of autoimmune disorders associated with psychiatric symptoms, cognitive dysfunction, and seizures, often in the context of an underlying malignancy. Some of these disorders result from an autoantibody directed against a brain ion channel. VGKC antibody-associated limbic encephalitis, mentioned earlier, is one example. Anti–N-methyl-d-aspartate (NMDA) receptor limbic encephalitis is the most common antibody-mediated encephalitis (Dalmau et al., 2008). This syndrome, which occurs mainly in women, causes psychiatric symptoms, seizures, delirium, and other neurological symptoms. Like PCD, anti-NMDA receptor encephalitis strongly suggests an underlying malignancy—typically ovarian teratoma. NMDA receptors represent one of three classes of glutamate-gated ion channels in the brain; α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors represent another class, and antibodies against those receptors may also cause limbic encephalitis (Lai et al., 2009). Antibodies against GABAB receptors were isolated in a series of patients with limbic encephalitis and prominent seizures (Lancaster et al., 2010). While not an ion channel, this G protein-coupled GABA receptor regulates ion channels and synaptic transmission. Leucine-rich glioma inactivated-1 (LGI-1) and CASPR2 are the proteins that complex with a voltage-gated potassium channel. LGI-1 is rich in the hippocampus and neocortex. Dysfunction of LGI-1 causes secondary channel dysfunction, causing reduction of the synaptic AMPA receptor. Patients with LGI-1 antibodies often present with focal seizure, and approximately 50% of them have pathognomonic faciobrachial dystonic seizures. Seizures progress over time to an established limbic encephalitis. As for PCD, acquired neuromyotonia, and LEMS, limbic encephalitis should be treated with intravenous immune globulin (IVIG), plasma exchange, steroids, or other immunosuppressant therapies in parallel with an aggressive search for an underlying neoplasm.

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SUMMARY Advances in molecular biology and electrophysiology have allowed discovery and the characterization of a new group of disorders termed the channelopathies. Understanding the underlying pathophysiology of these diseases has not only expanded our knowledge of basic ion channel physiology but, more importantly, has also provided insight into mechanisms of common neurological disorders such as epilepsy and migraine. The channelopathies, a seemingly heterogeneous group of diseases, share striking similarities. Most have intermittent symptoms, despite the invariant presence of the mutation, with interictal return to a normal state. Exacerbating factors such as stress, exertion, and fatigue are common to many of the channelopathies. Response to treatment with carbonic anhydrase inhibitors (acetazolamide) is a common feature among these genetic disorders (see Table 98.3), leading some clinicians to use acetazolamide responsiveness as a diagnostic litmus test for the channelopathies. The mechanism by which acetazolamide prevents and ameliorates attacks is not completely understood, although recent evidence suggests the activation of potassium channels may play a role. These similarities suggest a common underlying pathophysiological basis shared among the channelopathies. In fact, many of the channelopathies, such as EA2 and FHM, share several characteristics. This chapter has attempted to provide a clinical approach to the recognition, diagnosis, and treatment of the channelopathies. Furthermore, knowing where the genetic mutation is located does not necessarily predict the clinical phenotype. Diagnostic confusion arises from phenotypic variability within a given syndrome and phenotypic similarities among different syndromes, as well as the realization that mutations in the same gene can produce seemingly unrelated phenotypes (see Fig. 98.1). This underscores the importance of careful clinical assessment. The clinician’s most useful diagnostic tool remains a detailed history and physical examination. Genetic contributions to common seizure and headache syndromes are well known but more difficult to dissect at a molecular level. This is due to the large number of genes/proteins that almost certainly contribute to headache and epilepsy susceptibility. Further complicating this genetic heterogeneity is the complex interaction of genes and the environment. Normal variations in proteins, like those discussed earlier, occur in the general population. One exciting hypothesis is that some of these “normal” variations have functional consequences for channels (and other proteins, too). Innumerable factors contribute to net neuronal excitability, circuit dynamics, and brain function. These factors subtly increase or decrease by polymorphisms in the many ion channel proteins and in other proteins expressed by a neuron. In most families, these many polymorphisms average each other out, resulting in “normal” excitability. However, in occasional families segregating multiple hyperexcitability alleles, offspring may be more susceptible to seizure or headache than the general population and experience attacks unmasked by appropriate precipitating conditions. This model is consistent with familial clustering of such disorders, but it is inconsistent

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with simple Mendelian traits segregating from generation to generation. Whether clues from Mendelian episodic neurological disease ultimately bear on the complex genetics of epilepsy and migraine remains to be seen. The example of thyrotoxic hypoKPP is quite exciting. Worldwide, thyrotoxic hypoKPP is about 10 times more common than all the familial periodic paralyses put together. However, since it is a sporadic disorder, mapping of causative genes is impossible. Clues from the familial periodic paralyses motivated the hypothesis that led to the identification of inwardly rectifying potassium channel mutations in some of these patients (Ryan et al., 2010). In this case, the mutations are segregating in families but are only “uncovered” in those (sporadic) individuals who develop thyrotoxicosis. Additional insights into many common and sporadic diseases will continue to be gained through the study of rare familial cases and better understanding of the genetics and pathophysiology. Despite considerable progress in the understanding of channelopathies, several unanswered questions remain, such as why these syndromes are episodic, why acetazolamide is effective in such a diverse group of disorders, and how identical mutations within a gene can cause dominant or recessive behavior. Although disease-targeted pharmacological therapy is ideal, this has largely remained theoretical, and such work is still in early stages. Understanding where a certain mutation lies within a gene does not fully reveal the intricacies of the clinical phenotype, and mutational effects in vivo are likely to be considerably more complicated than those demonstrated in vitro. Thus future advances in defining the various channelopathy phenotypes and understanding the underlying molecular mechanism will greatly contribute to the understanding of these and other related disorders. Finally, disruption of ion channel function may occur in more complex ways than simply by mutation in an ion channel gene or by an autoantibody to the channel protein itself. Our appreciation of the complex association of ion channels with other proteins that target, anchor, regulate, or otherwise influence their behavior is growing (see Fig. 98.12). Examples include EFHC1 and LGI1, discussed earlier in the chapter, which encode ion channel-regulating proteins and cause ion channel dysfunction when mutated. Mutation in ankyrin-B, an anchoring protein that co-localizes a diverse range of ion channels and other membrane proteins, causes long-QT syndrome type 4 (Mohler et al., 2003). Mutations in similar anchoring proteins are likely to be discovered in neurological disease; perhaps Schwartz-Jampel syndrome is an example. This rare autosomal recessive syndrome characterized by myotonia and chondrodysplasia results from mutations in HSPG2, the gene encoding perlecan, the heparan sulfate proteoglycan enriched in basement membranes and cartilage (Stum et al., 2006); the pathophysiological link between perlecan and myotonia has yet to be established. The spectrum of episodic and electrical disorders of the nervous system will continue to grow. The complete reference list is available online at https://expertconsult. inkling.com/.

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99 Neurocutaneous Syndromes Monica P. Islam, E. Steve Roach

OUTLINE Tuberous Sclerosis, 1590 Cutaneous Features, 1590 Neurological Features, 1591 Retinal Features, 1593 Cardiac Features, 1593 Renal Features, 1593 Pulmonary Features, 1593 Neurofibromatosis Type 1, 1593 Cutaneous Features, 1594 Neurological Features, 1595 Systemic Features, 1595 Neurofibromatosis Type 2, 1597 Clinical Features, 1597 Sturge-Weber Syndrome, 1597 Cutaneous Features, 1597 Ocular Features, 1598 Neurological Features, 1598 Diagnostic Studies, 1599 Treatment, 1599 Von Hippel-Lindau Syndrome, 1600 Neurological Features, 1600 Ocular Features, 1600 Systemic Features, 1600 Molecular Genetics, 1601 Treatment, 1601 Hereditary Hemorrhagic Telangiectasia, 1601 Neurological Features, 1601 Treatment, 1602 Hypomelanosis of Ito, 1602 Cutaneous Features, 1602 Neurological Features, 1602 Systemic Features, 1602 Incontinentia Pigmenti, 1602 Cutaneous Features, 1602 Neurological Features, 1603 Genetics, 1603 Ataxia-Telangiectasia, 1603 Cutaneous Features, 1604

Neurological Features, 1604 Immunodeficiency and Cancer Risk, 1604 Laboratory Diagnosis, 1604 Epidermal Nevus Syndrome, 1604 Cutaneous Features, 1605 Neurological Features, 1605 Other Features, 1605 Neuroimaging, 1605 Neurocutaneous Melanosis, 1605 Cutaneous Features, 1605 Neurological Features, 1606 Laboratory Findings, 1606 Neuroimaging, 1606 Ehlers-Danlos Syndrome, 1607 Neurovascular Features, 1608 Cerebrotendinous Xanthomatosis, 1608 Neurological Features, 1608 Xanthomas, 1608 Other Clinical Features, 1608 Treatment, 1609 Progressive Facial Hemiatrophy, 1609 Clinical Features, 1609 Kinky Hair Syndrome (Menkes Disease), 1609 Cutaneous Features, 1610 Other Clinical Features, 1610 Neurological Features, 1610 Neuroimaging, 1610 Genetic Studies, 1611 Diagnosis and Treatment, 1611 Xeroderma Pigmentosum, 1611 Complementation Groups, 1611 Related Syndromes, 1611 Cutaneous and Ocular Features, 1611 Treatment, 1612 Other Neurological Conditions With Cutaneous Manifestations, 1613 Conclusions, 1613

Neurocutaneous disorders are congenital or hereditary conditions that feature lesions of both the skin and nervous system. Although each condition, or phakomatosis, is distinct and characterized by a unique pathophysiology, the concept of neurocutaneous disorders unifies those neurological disorders, whose identification depends primarily on simple visual diagnosis. These disorders may be inherited or sporadic;

some of the sporadic disorders result from somatic mosaicism. Advances in clinical genetics have established the molecular basis for some of the disorders, although recognition and treatment still require an appreciation of the cutaneous and systemic symptoms. This chapter reviews the clinical features of the more common neurocutaneous syndromes.

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TUBEROUS SCLEROSIS Tuberous sclerosis complex (TSC) is a disorder of cellular differentiation and proliferation that can affect the brain, skin, kidneys, heart, and other organs. Many clinical features of TSC result from hamartomas, but true neoplasms also occur, particularly in the kidney and brain. Abnormal neuronal migration plays a major additional role in neurological dysfunction (Roach, 2016; Roach & Sparagana, 2004). Population-based studies suggest a prevalence of one per 6000 individuals. However, because of the striking variability of clinical expression, establishing the diagnosis of TSC can be difficult in individuals with subtle findings, and the true prevalence may be considerably higher. Cutaneous findings are usually the first clue that a patient has TSC, but other features may lead to the diagnosis. In infants, cardiac involvement and seizures frequently are presenting signs, whereas dermatological, pulmonary, or renal involvement may lead to diagnosis in older individuals. Updated guidelines have introduced genetic testing as the potential sole diagnostic criterion in addition to clinical findings (Box 99.1). The inheritance of TSC is autosomal dominant with variable penetrance. The estimated spontaneous mutation rate for TSC varies from 66% to 86%, depending in part on the completeness of investigation of the extended family. Two genes are responsible for TSC: TSC1, coding for hamartin at chromosome 9q34.3; and TSC2, coding for tuberin adjacent to the gene for adult polycystic kidney disease at chromosome 16p13.3. The clinical features of TSC1 and TSC2 overlap, since the two gene products form a single functional unit that is an upstream modulator in the mammalian target of rapamycin (mTOR) signaling pathway. Both gene products downregulate small G-protein Ras-homolog enriched in brain (RHEB) activity in this pathway. However, genotype-phenotype studies indicate that individuals with a TSC2 mutation tend to have more severe disease, and the frequency of TSC2 mutations is greater among individuals with spontaneous mutations (Sancak et al., 2005). Multiple mutation types exist in different regions of each gene, and even individuals with identical genetic mutations can have different phenotypes. Molecular diagnostic testing—including prenatal testing— has been available since the early 2000s, and a disease-causing mutation is identified in about 85% of the individuals who meet the clinical diagnostic criteria. Some of the individuals with no mutation identified via routine gene analysis prove to have mosaicism (Roach, 2016). Large genomic deletions and rearrangements are more common in the TSC2 gene than in TSC1, and more mutations have been identified for TSC2 than for TSC1. TSC2 mutations appear more commonly than TSC1 in patients with subependymal nodules (SENs), intellectual disability, renal angiomyolipomas, and retinal phakomas. Intellectual disability and other neuropsychiatric involvement are more likely in individuals with TSC2 than in those with TSC1 mutation (Au et al., 2007).

Cutaneous Features The cutaneous lesions of TSC include hypomelanotic macules, the shagreen patch, ungual fibromas, and facial angiofibromas (Fig. 99.1). Hypomelanotic macules (ash leaf spots) occur in over 90% of affected individuals (Fig. 99.2). The lesions usually are present at birth but may be evident in the newborn only with an ultraviolet light (Wood’s lamp). Other pigmentary abnormalities include confetti lesions (areas with stippled hypopigmentation, typically on the extremities) and poliosis (a white patch or forelock) of the scalp, hair, or eyelids. Hypomelanotic macules are common in normal individuals (Table 99.1), but three or more hypomelanotic macules greater than 5 mm is a major diagnostic criterion for TSC. Facial angiofibromas (previously termed adenoma sebaceum) consist of vascular and connective tissue elements. Although multiple facial

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Updated Diagnostic Criteria for Tuberous Sclerosis Complex 2012

BOX 99.1

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A. Genetic Diagnostic Criteria The identification of a pathogenic mutation in either TSC1 or TSC2 is sufficient to make a definite diagnosis of TSC. A pathogenic mutation is defined as a mutation that clearly inactivates the function of the TSC1 or TSC2 proteins (e.g., out-offrame indel or nonsense mutation), prevents protein synthesis (e.g., large genomic deletion), or is a missense mutation whose effect on protein function has been established. Other TSC1 or TSC2 variants whose effect on function is less certain do not meet these criteria and are insufficient to support a definite diagnosis of TSC. Note that 10%–25% of TSC patients have no mutation identified by conventional genetic testing, so a normal result does not exclude TSC or affect the use of clinical diagnostic criteria to diagnose TSC. B. Clinical Diagnostic Criteria Major Features 1. Hypomelanotic macules (≥3, at least 5-mm diameter) 2. Angiofibromas (≥3) or fibrous cephalic plaque 3. Ungual fibromas (≥2) 4. Shagreen patch 5. Multiple retinal hamartomas 6. Cortical dysplasias* 7. Subependymal nodules 8. Subependymal giant-cell astrocytoma 9. Cardiac rhabdomyoma 10. Lymphangioleiomyomatosis (LAM)† 11. Angiomyolipomas (≥2)† Minor Features 1. “Confetti” skin lesions 2. Dental enamel pits (≥3) 3. Intraoral fibromas (≥2) 4. Retinal achromic patch 5. Multiple renal cysts 6. Nonrenal hamartomas Definite diagnosis: Two major features or one major feature with ≥2 minor features Possible diagnosis: Either one major feature or ≥2 minor features *Includes tubers and cerebral white-matter radial migration lines. †A combination of the two major clinical features (LAM and angiomyolipomas) without other features does not meet criteria for a definite diagnosis. TSC, Tuberous sclerosis complex. Adapted from: Northrup, H., Krueger, D.A., 2013. Tuberous sclerosis complex diagnostic criteria update: Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus conference. Pediatr Neurol 49, 243–254.

angiofibromas are relatively specific for TSC, they are found in only three-fourths of affected individuals and often appear several years after the diagnosis has been established by other means. The lesions typically become apparent during the preschool years as a few small red macules on the malar region; they gradually become papular, larger, and more numerous, sometimes extending down the nasolabial folds or onto the chin. Angiofibromas often become less prominent after starting an mTOR inhibitor, and topical application has been studied (Koenig et al., 2018). Forehead plaques or fibrous facial plaques resemble angiofibromas histologically, though they are not papular. The shagreen patch most often is found on the back or flank area; it is an irregularly shaped, slightly raised, or textured skin lesion. About 20%–30% of patients with TSC have a shagreen patch, which may not be seen in young children.

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A

Fig. 99.2 A Hypomelanotic Macule (Ash Leaf Spot) (Arrow) From the Leg of a Patient With Tuberous Sclerosis. (Reprinted with permission from Weiner, D.M., Ewalt, D.H., Roach, E.S., et al., 1998. The tuberous sclerosis complex: a comprehensive review. J Am Coll Surg 187, 548–561.)

B

C Fig. 99.1 Classic cutaneous manifestations of tuberous sclerosis include (A) ungual fibromas, (B) shagreen patch on the lower back, and (C) facial angiofibromas. (A, Reprinted with permission from Roach, E.S., Delgado, M.R., 1995. Tuberous sclerosis. Dermatol Clin 13, 151–161.)

Ungual fibromas are nodular or fleshy lesions that arise adjacent to (periungual) or underneath (subungual) the nails. The presence of two or more is considered a major criterion as a single lesion can develop after trauma in individuals without TSC. Ungual fibromas are among the latest cutaneous manifestation of TSC, present in up to 80% of older adults but only 20% overall (Northrup et al., 2013).

Neurological Features The predominant neurological manifestations of TSC are intellectual disability, epilepsy, and behavioral abnormalities, although milder forms of the disease with little or no neurological impairment are common. Impaired cellular interaction results in disrupted neuronal migration along radial glial fibers and abnormal proliferation of glial elements. Neuropathological lesions of TSC include SENs, cortical and subcortical hamartomas (tubers), areas of focal cortical dysplasia, and heterotopic gray matter. SENs commonly arise from germinal matrix

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progenitors in the caudothalamic groove near the foramen of Monro. These lesions can grow over time, but usually only into adolescence, after which time they calcify. These remain asymptomatic unless they transform into subependymal giant-cell astrocytomas (SEGAs). Tubers frequently extend from the ventricle wall to the cortical surface, with a linear or wedge-shaped distribution. Similar to normal brain, tubers develop between 14 and 16 weeks, gestation, such that the tuber load is established before birth, though they may not be visible on imaging until later childhood, given myelination status. These focal malformations of cortical development most frequently involve one gyrus at a time, but more diffuse involvement such as hemimegalencephaly can occur as well. Histology of these areas demonstrates disorganized cortical lamination and underlying abnormal myelination with indistinct gray-white-matter junction architecture. Calcification frequently is present. Dysmorphic neurons are often present, and other abnormal astrocytes similar to those seen in sporadic focal cortical dysplasias are termed balloon cells or giant cells for their abundant cytoplasm (Wong, 2008). Seizures of various types occur in 80%–90% of patients. Most develop during the first year of life, which is a poor prognosticator for autism and poor cognitive development. TSC is the most common cause of infantile spasms, and one-third of children with TSC develop them. Children with infantile spasms are more likely to have a high burden of cortical lesions demonstrated by magnetic resonance imaging (MRI) and are more likely to exhibit long-term cognitive impairment. For many, vigabatrin has been a more effective treatment option than adrenocorticotropic hormone (ACTH). Resective epilepsy surgery is a consideration in individuals with seizures localizing to one or two tubers. Corpus callosotomy is an option in some children. Some individuals with prolonged seizure freedom while taking medication can successfully discontinue anti-seizure medication (Sparagana et al., 2003). Many TSC patients have intellectual disability, but many have normal intelligence. As seen with early-onset epilepsy in general, intellectual disability in TSC often accompanies epilepsy that manifests earlier in life and that is refractory. The number of subependymal lesions does not correlate with the clinical severity of TSC, but MRI evidence of numerous cortical lesions is associated with more

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TABLE 99.1

Individuals

Neurological Diseases and Their Treatment

Frequency of Lesions in Individuals With Tuberous Sclerosis Versus Other

Lesion Hypomelanotic macules

Tuberous Sclerosis Complex Occur in over 95% of TSC patients, often with many lesions

Other Individuals Occur in up to 5% of the population (but usually fewer than three lesions per person)

Facial angiofibromas

Eventually seen in 75% but less often in children

Seen in individuals with multiple endocrine neoplasia type 1 and in a few sporadic families

Shagreen patch

Up to 48%

Occasional

Ungual fibromas

Seen in 15% but often not until adulthood

Occasionally sporadic or after nail trauma (but typically one lesion)

Rhabdomyomas

One or more tumors seen in 47%–65% but much more common below 2 years Up to 51% of patients with rhabdomyomas have TSC

In 14%–49% of rhabdomyoma patients, there are no other signs of TSC

Renal AML

Often multiple AML occur in up to 80% of TSC patients by age 10

Sporadic AML occur but are typically solitary

Renal cysts

Polycystic kidneys occur in 3%–5% of TSC patients Smaller numbers of renal cysts are present in 15%–20%

There are both dominant and recessive polycystic kidney diseases A few cysts are frequent sporadic findings in adults

Cortical dysplasia/tubers

90%–95% and usually multiple lesions are present (magnetic reso- Sporadic cortical dysplasia (typically one lesion) is common nance imaging yields highest detection rate) among individuals who have epilepsy not due to TSC

Subependymal nodules

83%–93%

Rare, especially if calcified

Subependymal giant-cell tumors Up to 15% (using radiographic criteria)

Rare in the absence of TSC

AML, Angiomyolipoma; TSC, tuberous sclerosis. From Roach, E.S., Sparagana, S.P., 2010. Diagnostic criteria for tuberous sclerosis complex. In: Kwiatkowski, D.J., Whittemore, V.H., Thiele, E.A. (Eds.), Tuberous Sclerosis Complex: Genes, Clinical Features, and Therapeutics. Wiley-VCH Verlag, Weinheim, pp. 21–25. Used with permission.

significant cognitive impairment and seizure intractability. The most abnormal regions seen on MRI tend to coincide with focal abnormalities of the electroencephalogram (EEG). The severity of intellectual disability ranges from borderline to profound intellectual disability. In addition to intellectual disability, many children with TSC have significant behavioral and psychiatric dysfunction. Autism, hyperkinesis, aggressiveness, psychosocial difficulties, and even psychosis can occur, either as isolated problems or in combination. The prevalence of autistic spectrum disorders is 25%–50% and equal between boys and girls. Behavioral problems are frequent and independent of intellectual ability. Mood disorders also are increased. De Vries and colleagues described the array of behavioral and psychiatric symptoms resulting from TSC as tuberous sclerosis associated neuropsychiatric disorders (TAND), and they developed a useful clinical screening tool (de Vries et al., 2015). Computed tomography (CT) best demonstrates the calcified SENs that characterize TSC (Fig. 99.3). CT sometimes shows superficial cerebral lesions, but they are far more obvious with brain MRI (Fig. 99.4). T2-weighted sequences show evidence of abnormal neuronal migration in some patients as high-signal linear lesions running perpendicular to the cortex. SENs along the ventricular surface give the characteristic appearance of “candle guttering.” More than one-fourth of patients with TSC show cerebellar anomalies. SEGAs develop in 6%–14% of patients with TSC. Unlike the more common cortical tubers and SENs, SEGAs can enlarge (Fig. 99.5) and cause symptoms of increased intracranial pressure, particularly if extension into the lateral ventricles creates an obstructive hydrocephalus. Clinical features include new focal neurological deficits, unexplained behavior change, deterioration of seizure control, or symptoms of increased intracranial pressure. Acute or subacute onset of neurological dysfunction may result from sudden obstruction of the ventricular system by an intraventricular SEGA. Rarely, acute deterioration occurs because of hemorrhage into the tumor itself.

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Fig. 99.3 Computed cranial tomography scan from a child with tuberous sclerosis complex demonstrates typical calcified subependymal nodules; a large calcified parenchymal lesion (arrowhead) and low-density cortical lesions (arrows) are seen as well. (Reprinted with permission from Roach, E.S., Kerr, J., Mendelsohn, D., et al., 1991. Diagnosis of symptomatic and asymptomatic gene carriers of tuberous sclerosis by CT and MRI. Ann N Y Acad Sci 615, 112–122.)

SEGAs are usually benign but locally invasive, and early surgery can be curative. Identification of an enlarging SEGA before the onset of symptoms of increased intracranial pressure or appearance of new neurological deficits is ideal. Periodic screening for identifying SEGA

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by lack of sufficient normal myocardium to maintain perfusion. Some patients stabilize after medical treatment with digoxin and diuretics and eventually improve; others require surgery. Echocardiography and electrocardiography (ECG) establish the diagnosis. Arterial aneurysms can occur. Surveillance studies every 6–12 months help monitor existing rhabdomyomas until stabilization or involution occurs. The size of these lesions may increase with hormone exposure—a consideration in the neonate, pubertal individual, and child treated with ACTH for infantile spasms.

Renal Features

Fig. 99.4 Noncontrast T2-weighted magnetic resonance imaging scan from a child with tuberous sclerosis demonstrates extensive high-signal cortical lesions typical of tuberous sclerosis.

may improve surgical outcome. Recent work suggests that rapamycin and the oral mTOR inhibitor everolimus inhibit the growth of SEGAs. Everolimus has approval from the US Food and Drug Administration (FDA) for the treatment of SEGAs, renal angiomyolipomas, and, most recently, seizures due to TSC (Krueger et al., 2013). There also have been reports of improvement in pulmonary lymphangioleiomyomatosis (LAM) and facial angiofibromas (Franz, 2013).

Retinal Features The frequency of retinal hamartomas in TSC varies from almost negligible to 87% of patients, probably reflecting the expertise and technique of the examiner. Pupillary dilatation and indirect ophthalmoscopy are important, particularly in children who may be uncooperative. Findings vary from classic mulberry lesions adjacent to the optic disc (Fig. 99.6) to plaque-like hamartoma or depigmented retinal lesions. Most retinal lesions are clinically insignificant, but some patients have visual impairment caused by large macular lesions, and very few patients have visual loss caused by retinal detachment, vitreous hemorrhage, or hamartoma enlargement. Occasionally, patients have a pigmentary defect of the iris. Funduscopic examination is valuable at the time of diagnosis, to monitor existing abnormalities or to evaluate for new symptoms.

Cardiac Features Approximately two-thirds of individuals with TSC have a cardiac rhabdomyoma, but few demonstrate clinical symptoms. Cardiac rhabdomyomas are hamartomas, tend to be multiple, and involute with time. These lesions sometimes are evident on prenatal ultrasound testing (Fig. 99.7), usually after 24 weeks, gestational age. Most individuals who develop cardiac dysfunction present soon after birth with heart failure. A few children later develop cardiac arrhythmias or cerebral thromboembolism from the rhabdomyomas. The cause of congestive heart failure is either by obstruction of blood flow via intraluminal tumor or

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Renal angiomyolipomas occur in up to three-fourths of patients with TSC, usually presenting by 10 years of age. Most of these lesions are histologically benign tumors with varying amounts of vascular tissue, fat, and smooth muscle (Fig. 99.8). Bilateral tumors and multiple tumors in a kidney are common. The prevalence and size of renal tumors increase with age, and tumors larger than 4 cm are much more likely to become symptomatic than smaller tumors. Renal cell carcinoma or other malignancies can affect TSC patients less commonly and at younger ages than the general population. Coalescing angiomyolipomas can contribute to end-stage renal disease. Endovascular embolization of the larger renal angiomyolipomas prevents hemorrhage and other complications (Ewalt et al., 2005). Rapamycin and everolimus limit the growth of these tumors, at least transiently. Single or multiple renal cysts are also a feature of TSC; these tend to appear earlier than the renal tumors. Ultrasound or cranial CT easily identifies larger cysts, and the combination of renal cysts and angiomyolipomas is characteristic of TSC. Individual renal cysts may disappear. Surveillance imaging is recommended, at least every 2–3 years—more frequently in those with existing or symptomatic renal involvement.

Pulmonary Features Pulmonary disease presents after puberty in the form of LAM and is five times more common in females than in males. Pulmonary lesions, symptomatic or asymptomatic, can be demonstrated in almost half of women with TSC who undergo chest CT. Baseline pulmonary function testing, 6-minute walk test, and high-resolution CT of the chest are recommended in all symptomatic patients and asymptomatic females at age 18 years. Spontaneous and recurrent pneumothorax, dyspnea, cough, and hemoptysis are typical symptoms of pulmonary TSC. Of those who develop symptoms, 10%–12% die within 10 years of symptom onset from complications of pulmonary TSC (Cudzilo et al., 2013). Tamoxifen and progesterone may be helpful in some patients, and mTOR inhibitors have been additional treatment options.

NEUROFIBROMATOSIS TYPE 1 Neurofibromatosis type 1 (NF1), or von Recklinghausen disease, is the most common of the neurocutaneous syndromes, occurring in approximately 1 in 3000 people. Inheritance is autosomal dominant, but approximately half of NF1 cases result from a spontaneous mutation. The clinical features are highly variable. A mutation of the 60-exon NF1 gene on chromosome 17q11.2 causes NF1. The NF1 gene product, neurofibromin, is a tumor-suppressor GTPase-activating protein functioning to inhibit Ras-mediated cell proliferation. Despite identification of approximately 100 mutations of NF1 in various regions of the gene, none correlates to a specific clinical phenotype (Pasmant et al., 2012). Several patients have developed a somatic NF1 mutation affecting only a limited region of the body. With this mosaic NF1, one extremity may have café-au-lait lesions, subcutaneous neurofibromas, and other signs of NF1, but the rest of the body is unaffected (Garcia-

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Fig. 99.5 A, Noncontrast T1-weighted magnetic resonance imaging scan from a child with tuberous sclerosis shows an irregular mass (arrow) with a central signal void caused by calcification protruding into the left frontal horn. B, Another scan with gadolinium a few months later shows contrast enhancement and minimal tumor growth.

Fig. 99.7 Prenatal ultrasound study reveals a large cardiac rhabdomyoma (arrow) and two smaller rhabdomyomas (arrowheads) in a child who subsequently proved to have tuberous sclerosis. (Reprinted with permission from Weiner, D.M., Ewalt, D.E., Roach, E. S., et al., 1998. The tuberous sclerosis complex: a comprehensive review. J Am Coll Surg 187, 548–561.) Fig. 99.6 A retinal astrocytoma (mulberry lesion) adjacent to the optic nerve is typical of those found in tuberous sclerosis. (Reprinted with permission from Roach, E.S., 1992. Neurocutaneous syndromes. Pediatr Clin North Am 39, 591–620.)

Romero et al.,). Similarly, some patients with germline mosaicism have no outward manifestations of NF1 but have multiple affected offspring. If several characteristics are present and the physician is astute, the diagnosis of NF1 is obvious, especially when another family member is affected. The diagnosis is difficult when the clinical features are atypical and the family history is negative. Very young children may have fewer apparent lesions, making definitive diagnosis difficult. Diagnostic criteria (Box 99.2) help to resolve some of these questionable cases, but specific gene testing is replacing the use of clinical criteria. Screening

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for the NF1 gene is technically difficult because the gene is large and several different mutations are causative. Commercially available studies have a 30% false-negative rate.

Cutaneous Features Cutaneous lesions of NF1 (Fig. 99.9) include café-au-lait spots, subcutaneous neurofibromas, plexiform neurofibromas, and axillary freckling. Café-au-lait spots are flat, hyperpigmented areas that vary in shape and size. They typically are present at birth but increase in size and number during the first few years of life. Later in childhood, skin freckling, 1–3 mm in diameter, often occurs symmetrically in the axillae (Crowe sign) and other intertriginous regions. Most children with six or more café-au-lait spots as their only diagnostic criterion will go on to meet diagnostic criteria, usually by age 6 years.

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peripheral nerve sheath tumors (MPNSTs). MPNSTs carry poor 5-year survival rates despite treatment with surgery, chemotherapy, and radiation. PNFs and MPNSTs are difficult to distinguish radiographically and sometimes even pathologically.

Neurological Features

Fig. 99.8 A large angiomyolipoma of the lower pole of a kidney removed at surgery; several smaller angiomyolipomas (arrows) can be seen in the same specimen. (Reprinted with permission from Weiner, D.M., Ewalt, D.E., Roach, E.S., et al., 1998. The tuberous sclerosis complex: a comprehensive review. J Am Coll Surg 187, 548–561.)

Diagnostic Criteria for Neurofibromatosis

BOX 99.2

Neurofibromatosis Type 1 (Any Two or More) Six or more café-au-lait lesions more than 5 mm in diameter before puberty and more than 15 mm in diameter afterward Freckling in the axillary or inguinal areas Optic glioma Two or more neurofibromas or one plexiform neurofibroma A first-degree relative with neurofibromatosis type 1 Two or more Lisch nodules A characteristic bony lesion (sphenoid dysplasia, thinning of the cortex of long bones, with or without pseudoarthrosis) Neurofibromatosis Type 2 Bilateral eighth nerve tumor (shown by magnetic resonance imaging, computed tomography, or histological confirmation) A first-degree relative with neurofibromatosis type 2 and a unilateral eighth nerve tumor A first-degree relative with neurofibromatosis type 2 and any two of the following lesions: neurofibroma, meningioma, schwannoma, glioma, or juvenile posterior subcapsular lenticular opacity

Systemic Features

Data derived from Neurofibromatosis. Conference statement, 1988. National Institutes of Health Consensus Development Conference. Arch Neurol 45, 575–578.

Neurofibromas are benign tumors arising from peripheral nerves. These tumors are composed predominantly of Schwann cells and fibroblasts but contain endothelial, pericyte, and mast cell components. Neurofibromas can develop at any time; their size and number often increase after puberty. Plexiform neurofibromas often occur on the face and can cause substantial deformity. Patients with plexiform tumors of the head, face, or neck and those who presented before 10 years of age are more likely to do poorly (Needle et al., 1997). Plexiform neurofibromas have a 5%–13% lifetime risk of malignant degeneration into malignant

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NF1 affects the nervous system in several ways, but the clinical features vary even within the same family. Tumors occur in the brain, spinal cord, and peripheral nerves. Compared to the general population, there is higher incidence of learning disability and attention disorders. Accompanying moyamoya syndrome predisposes to stroke. Optic nerve glioma (Fig. 99.10) is the most common CNS tumor caused by NF1. Approximately 15% of patients with NF1 have unilateral or bilateral optic glioma. The growth rate of these tumors varies, but they tend to behave less aggressively in patients with NF1 than those without NF1. When symptomatic, the presenting features are optic atrophy, progressive vision loss, pain, or proptosis. Precocious puberty is a common presenting feature of chiasmatic optic nerve tumors in children with NF1. Management options include observation with serial brain MRI or treatment with radiation, chemotherapy, or small-molecule therapies that specifically target signaling pathways downstream of activated Ras. Radiation is less favored, especially given possible exacerbation of vasculopathy in this population. Ependymomas and meningiomas of the CNS occur in patients with NF1 less often than in patients with neurofibromatosis type 2. Neurofibromas and schwannomas are common but not always symptomatic; they develop on either cranial nerves or spinal nerve roots. The symptoms from these tumors (discomfort, pain, numbness, weakness, and bowel/bladder dysfunction) reflect their size, location, and rate of growth. Macrocephaly is seen in half of NF1 patients, typically attributable to megalencephaly related to increases in white-matter volume. Macrocephaly is independent of hydrocephalus accompanying aqueductal stenosis, which also occurs in this disorder. Approximately 60%– 78% of patients with NF1 have increased signal lesions within the basal ganglia, thalamus, brainstem, and cerebellum on T2-weighted MRIs (Fig. 99.11). These areas are not routinely visible with CT. The origin and significance of these radiographic lesions are unclear, and they are referred to at times as unidentified bright objects (UBOs). Whether these MRI lesions correlate with the likelihood of cognitive impairment is still debatable; radiographic findings do not correlate with neurological deficits. Patients with NF1 tend to have full-scale intelligence quotient (IQ) scores within the low-normal range and to exhibit behavioral problems. Deep gray-matter radiological findings tend to decrease with time, while cortical and subcortical findings do not decrease or increase.

Lisch nodules are pigmented iris hamartomas (Fig. 99.12). They are pathognomonic for NF1. Lisch nodules do not cause symptoms; their significance lies in their implications for the diagnosis of NF1. Lisch nodules are often not apparent during early childhood, so their absence does not exclude the diagnosis of NF1. Rarely, children with NF1 have retinal hamartomas, but these usually remain asymptomatic. Dysplasia of the renal or carotid arteries occurs in a small percentage of patients with NF1. Renal artery stenosis causes systemic hypertension. Another potential cause of hypertension is pheochromocytoma. Several forms of cerebral artery dysplasia occur, most commonly moyamoya syndrome, which promotes cerebral infarction in children and brain hemorrhage in adults. Arterial aneurysms occur as well.

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Fig. 99.9 A, Typical café-au-lait spots and axillary freckling in an individual with neurofibromatosis type 1. B, Plexiform neurofibroma in a boy with neurofibromatosis type 1. (B, Reprinted with permission from Roach, E.S., 1988. Diagnosis and management of neurocutaneous syndromes. Semin Neurol 8, 83–96.)

Fig. 99.10 Computed cranial tomography scan from a child with neurofibromatosis type 1 shows bilateral optic nerve gliomas, larger in the right optic nerve (arrow) than the left. (Reprinted with permission from Roach, E.S., 1992. Neurocutaneous syndromes. Pediatr Clin North Am 39, 591–620.)

The most common skeletal manifestations in NF1 consist of short stature and macrocephaly. Other skeletal abnormalities include longbone dysplasia (resulting in pathological fractures and subsequent pseudoarthrosis), scoliosis, and bony erosion secondary to adjacent tumor. Dysplasia of the sphenoid wing is common. A mimic of NF1 is LEOPARD syndrome (lentigenes, ECG conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal (male) genitalia, retardation of growth, deafness) is an autosomal dominant F ECF

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Fig. 99.11 Coronal T2-weighted magnetic resonance imaging scan shows bilateral high-signal lesions in the basal ganglia, abnormalities typical of neurofibromatosis type 1.

disorder whose features also include café-au-lait spots and obstructive cardiomyopathy. The café-au-lait spots and cardiac abnormalities may suggest NF1. Legius syndrome is another autosomal dominant NF-like syndrome; it is characterized by similar cutaneous features but little tumorigenesis. 02 .4.(1( 4 (

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Fig. 99.12 Lisch Nodules of the Iris in a Patient With Neurofibromatosis Type 1.

NEUROFIBROMATOSIS TYPE 2 Designated fully a separate entity from NF1 in the late 20th century, neurofibromatosis type 2 (NF2) is characterized by bilateral vestibular schwannomas and often is associated with other brain or spinal cord tumors. Similar to NF1, the inheritance is autosomal dominant. Some suggest the diagnosis of NF2 based on multiple meningiomas or nonvestibular schwannomas even without family history or classic bilateral vestibular schwannomas. NF2 occurs in only 1 in 35,000 to 50,000 people. A mutation of the NF2 gene on chromosome 22 causes NF2. The NF2 protein product is schwannomin or merlin, moesin-ezrin-radixinlike protein. The NF2 gene is a tumor suppressor. Dysfunction of the NF2 gene accounts for the occurrence of multiple central nervous system (CNS) tumors in patients with NF2. Several different mutations have been documented in the NF2 gene. The clinical severity may be related to the nature of the NF2 mutation; missense mutations that allow some protein function tend to produce milder clinical forms, whereas frameshift and nonsense mutations that produce stop codons preventing the production of any protein often cause severe disease (Halliday et al., 2017).

Clinical Features Patients with NF2 have few cutaneous lesions, and these tend to be subtle. Instead, patients often have multiple types of CNS tumors (thus, the designation of central NF). Café-au-lait spots and subcutaneous neurofibromas are less common than in NF1. Some patients exhibit presenile posterior subcapsular cataracts. Most patients who meet established diagnostic criteria for NF2 (see Box 99.2) eventually develop bilateral vestibular schwannomas, previously termed acoustic neuromas (Fig. 99.13). Symptoms of NF2 typically develop in adolescence or early adulthood but can begin in childhood. Common complaints with large acoustic tumors include hearing loss, tinnitus, vertigo, facial weakness, poor balance, and headache. Unilateral hearing loss is relatively common in the early stages. Consider screening with annual auditory brainstem responses or brain MRI. Other CNS tumors occur much less often than vestibular schwannomas. The term MISME syndrome (multiple inherited schwannomas, meningiomas, and ependymomas) applies to this disorder. The clinical F ECF

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Fig. 99.13 Cranial magnetic resonance imaging scan from a child with neurofibromatosis type 2 shows bilateral vestibular tumors (arrows). As these grow larger, there is an increased likelihood of symptoms. (Reprinted with permission from Roach, E.S., 1992 Neurocutaneous syndromes. Pediatr Clin North Am 39, 591–620.)

features of these tumors depend primarily on their location within the brain and spinal cord. Schwannomas of other cranial nerves occur in some patients. Meningiomas, ependymomas, and astrocytomas also occur with increased frequency. Patients with NF2 may develop multiple simultaneous tumor types, and baseline imaging at the time of diagnosis should include the brain and spinal cord. Merlin is a novel regulator of TSC/mTORC1 signaling, so mTOR inhibitors are being evaluated in the management of NF2 tumors (James et al., 2009) and also have been under study for the treatment of plexiform neurofibromas in NF1.

STURGE-WEBER SYNDROME The characteristic features of Sturge-Weber syndrome (SWS) are a facial cutaneous angioma (port-wine nevus) and an associated leptomeningeal and brain angioma. The findings usually are ipsilateral but can be bilateral or even contralateral. In addition to the facial nevus, other findings include intellectual disability, seizures, contralateral hemiparesis and hemiatrophy, and homonymous hemianopia (Thomas-Sohl et al., 2004). However, the clinical features are variable, and individuals with cutaneous lesions and seizures but with normal intelligence and no focal neurological deficits are common. The syndrome occurs sporadically and in all races. A somatic mutation in GNAQ has been identified in patients with port-wine stains with or without SWS. This activating mutation disrupts the q class of G-protein alpha subunits and contributes to reduced GTPase activity; this results in increased cell signaling activity (Shirley et al., 2013).

Cutaneous Features The nevus typically involves the forehead and upper eyelid but also may involve both sides of the face and extend onto the trunk and limbs (Fig. 99.14). Nevi that involve only the trunk, or facial nevi that spare the upper face, rarely are associated with an intracranial angioma. The facial angioma is usually obvious at birth; it may thicken over time and develop a nodular texture. Reactive hypertrophy of adjacent bone and connective tissue may occur. Some children have the characteristic neurological and radiographic features of SWS, yet have no skin lesions. More frequently, the typical cutaneous and ophthalmic findings are present without clinical or radiographic evidence of an intracranial lesion. Only 10%–20% of children with a port-wine nevus of

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Neurological Diseases and Their Treatment Epilepsy eventually develops in 72%–80% of patients with SWS with unilateral lesions and in 93% of patients with bihemispheric involvement. Although some begin in adult life, 75% of seizures begin during the first year, 86% by age 2, and 95% before age 5. Focal motor seizures or generalized tonic-clonic seizures are the most typical seizure type initially associated with SWS. Other initial seizure types are infantile spasms, myoclonic seizures, and atonic seizures. The first few seizures are often focal, even in patients who later develop generalized tonic-clonic seizures or infantile spasms. Seizures can be refractory or may remain well controlled with medication for long intervals. The neurological impairment caused by SWS depends in part on the site of the intracranial vascular lesion. Because the occipital region frequently is involved, visual-field deficits are common. Hemiparesis often develops acutely in conjunction with the initial flurry of seizures. Although often attributed to postictal weakness, hemiparesis may be permanent or persist longer than typical of a postictal deficit. Some children develop sudden weakness without seizures, either as repeated episodes of weakness similar to transient ischemic attacks or as a single stroke-like episode with persistent neurological deficit. Not all patients have permanent focal neurological signs. Early developmental milestones may be normal, but mild to profound mental deficiency eventually develops in approximately half of patients. Only 8% of the patients with bilateral brain involvement are intellectually normal. Behavioral concerns are frequent, even in patients who are not intellectually disabled. The clinical condition eventually stabilizes, resulting in residual hemiparesis,

the forehead have a leptomeningeal angioma. Although the leptomeningeal angioma is typically ipsilateral to a unilateral facial nevus, bilateral brain lesions occur in at least 15% of patients, including some with a unilateral cutaneous nevus.

Ocular Features Glaucoma is the main ophthalmological condition associated with SWS. The risk of developing glaucoma has two age peaks, the first in infancy and the second in late childhood. Amblyopia and buphthalmos (enlarged globe) are present in some newborns. In others, the glaucoma becomes symptomatic later and, if untreated, causes progressive blindness. Periodic measurement of the intraocular pressure is mandatory, particularly when the nevus is near the eye. Patients with SWS also may develop choroid angiomas or heterochromasia of the iris ipsilateral to the nevus.

Neurological Features Epilepsy, intellectual disability, and focal neurological deficits are the principal neurological abnormalities of SWS. Seizures often begin in conjunction with hemiparesis or other focal deficits. Seizure onset before age 2 years increases the likelihood of future intellectual disability and refractory epilepsy. Intellectual disability is likely in children with refractory seizures, whereas children who never experience seizures usually have normal intelligence. Few children who have normal cognition at age 3 years will later develop severe intellectual impairment.

A

B Fig. 99.14 Two patients with the classic distribution of the port-wine nevus of Sturge-Weber syndrome on the face and eyelid. A, The nevus has developed a nodular texture. B, Episcleral or conjunctival angiomas can occur on the affected side.

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Diagnostic Studies Most children with a facial port-wine nevus do not have an intracranial angioma. Neuroimaging studies help distinguish children with SWS from those with isolated cutaneous lesions. Although gyral calcification is a typical feature of SWS, the tram-track appearance first described on standard radiographs is uncommon and is almost never present in neonates. CT shows intracranial calcification much earlier (Fig. 99.15)

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than standard skull radiographs. Extensive cerebral atrophy is apparent even with CT, but MRI more readily shows subtle atrophy. MRI with gadolinium contrast (Fig. 99.16) effectively demonstrates the abnormal intracranial vessels in most patients with SWS. Positron emission tomography (PET) demonstrates reduced metabolism of the brain adjacent to the leptomeningeal lesion. However, patients with recent-onset seizures may have increased cerebral metabolism near the lesion. Single-photon emission computed tomography (SPECT) shows reduced perfusion of the affected brain. Both PET and SPECT often reveal vascular changes extending well beyond the area of abnormality depicted by CT (Maria et al., 1998). Although functional imaging is not necessary for all patients, it may help initially to establish a diagnosis and may help characterize the extent of abnormality before surgery. Cerebral arteriography is no longer routine in the evaluation of SWS but is sometimes useful in atypical patients or prior to surgery for epilepsy. The veins are more abnormal than the arteries, with enlarged, tortuous, subependymal, and medullary veins and sparse superficial cortical veins. Failure of the sagittal sinus to opacify after ipsilateral carotid injection may be due to obliteration of the superficial cortical veins by thrombosis; the abnormal deep venous channels probably have a similar origin as they form collateral conduits for nonfunctioning cortical veins. Microscopic hemorrhages are sometimes evident on pathology specimens, although significant intracranial hemorrhage is rare.

Treatment

Fig. 99.15 Computed tomographic scan from a typical patient with Sturge-Weber syndrome; the occipital gyriform calcification pattern (arrow) is easily seen. (Reprinted with permission from Garcia, J.C., Roach, E.S., McClean, W.T., 1981. Recurrent thrombotic deterioration in the Sturge-Weber syndrome. Childs Brain 8, 427–433.)

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Generally, the more extensive the intracranial lesion, the more difficult it is to control seizures with medication. Resection of a localized brain vascular lesion or hemispherectomy can often improve seizure control and may promote better intellectual development (Bourgeois et al., 2007). Despite general agreement on the efficacy of surgical resection, debate remains concerning patient selection and the timing of surgery. Almost one patient in five has bilateral cerebral lesions, limiting the surgical options unless one hemisphere is clearly responsible for most of the seizures. Often the patient selected for surgery is

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Fig. 99.16 A, Magnetic resonance imaging study from a child with Sturge-Weber syndrome; this T1-weighted axial view without contrast infusion is normal. B, Scan on the same child with gadolinium reveals leptomeningeal and intraparenchymal angioma.

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one with refractory seizures, clinical dysfunction (e.g., hemiparesis, hemianopia) of the area selected for resection, and failure to respond to an adequate trial of anticonvulsants. Patients with less extensive lesions should have a limited resection rather than a complete hemispherectomy. The limited resection preserves as much normal brain as possible, even at the risk of having to do another operation later. Corpus callosotomy is useful for patients with refractory tonic or atonic seizures and extensive disease. In effect, the surgical considerations in children with SWS are similar to those used with other patients with epilepsy. Low-dose aspirin has been offered to patients with SWS in an effort to minimize the burden of stroke-like episodes, seizures, or cognitive impairment (Lance et al., 2013). Aspirin is generally well-tolerated, but its efficacy has not been established.

VON HIPPEL-LINDAU SYNDROME Von Hippel-Lindau (VHL) syndrome is an autosomal dominant inherited disorder characterized by hemangioblastomas arising in the retina and CNS, as well as visceral cysts and tumors. Hemangioblastomas may occur sporadically but are usually multiple and more likely to occur in young persons. Current prevalence estimates of this disorder are approximately 1 in 40,000. Hemangioblastomas are benign slow-growing vascular tumors that cause symptoms from hemorrhage or local mass effect. Histologically, hemangioblastomas are composed of endothelium-lined vascular channels surrounded by stromal cells and pericytes. Mast cells are present and may produce erythropoietin. The initial symptoms of VHL usually arise from effects of the vascular anomalies in the CNS, but some patients may present with pheochromocytoma or renal, pancreatic, hepatic, or epididymal tumors. One classification system categorizes patients according to whether pheochromocytoma is present. The most common pattern of VHL findings includes retinal and CNS hemangioblastomas and pancreatic cysts (Lonser et al., 2003).

imaging of the entire spinal cord. Arteriography is not necessary for diagnosis but is valuable in demonstrating the feeding vessels if surgical resection is planned. Endolymphatic sac tumors occur in 10%–15% of these individuals. Sometimes they are bilateral. Presenting symptoms can be abrupt change in hearing accompanying hemorrhage or vertigo and tinnitus (Butman et al., 2008).

Neurological Features

Ocular Features

In the CNS, the most common site of hemangioblastomas is the cerebellum in approximately half of patients (Fig. 99.17), followed by spinal and medullary sites. Cerebral hemangioblastomas are present in less than 5% of patients with VHL. The cerebellar hemispheres are affected far more frequently than the cerebellar vermis. Cerebellar hemangioblastomas typically present in the second decade of life. Early symptoms of cerebellar and brainstem hemangioblastomas include headache, the most common symptom, followed by ataxia, nausea and vomiting, and nystagmus. Symptoms are often intermittent or slowly progressive, but up to 20% of patients have an acute onset of symptoms following mild head trauma. Spinal hemangioblastomas typically present with focal back or neck pain and sensory loss or weakness. Because of their typical intramedullary location, spinal hemangioblastomas frequently lead to syringomyelia. The conus medullaris and the cervicomedullary junction are the most common sites. Brainstem hemangioblastomas tend to arise in the area postrema in the medulla, where they may be associated with syringobulbia. Occasionally, hemangioblastomas occur in the cerebral hemispheres or sites near the third ventricle, such as the pituitary gland or its stalk, the hypothalamus, or optic nerve. The incidence of cerebellar hemangioblastomas increases with age, and 84% of patients with VHL will develop at least one such tumor by age 60 years (Maher et al., 1990). Hemangioblastomas are best visualized using contrast-enhanced MRI. Routine screening of the brain and spinal cord should include precontrast and postcontrast T1-weighted images with thin sections through the posterior fossa and spinal cord and surface coil

Childhood onset of symptoms is unusual, but retinal hemangioblastomas may occur in children as young as 1 year. Retinal hemangioblastomas may be asymptomatic, especially if they occur in the periphery of the retina. Vision loss occurs when the lesions are large and centrally located, even in the absence of hemorrhage. Arteriovenous shunting leads to fluid extravasation. Hemorrhage may lead to retinal injury and detachment, glaucoma, uveitis, macular edema, and sympathetic ophthalmitis.

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Fig. 99.17 Magnetic resonance imaging showing multiple cerebellar hemangioblastomas in a patient with Von Hippel-Lindau syndrome.

Systemic Features Renal cysts are present in more than half of individuals with VHL, although, as with CNS and retinal hemangioblastomas, the patients may be asymptomatic. Extensive renal cysts rarely lead to renal failure. Of greater concern is renal cell carcinoma, which develops in more than 70% of patients and is the leading cause of death. These tumors are usually multiple and tend to occur at a younger age than sporadic renal cell carcinoma (Ashouri et al., 2015). Simple renal cysts arise from distal tubular epithelium, whereas renal cell carcinoma tumors arise from proximal tubular epithelium. Pheochromocytomas occur in 7%–19% of patients and may be the only clinical manifestation of VHL, even in carefully screened individuals. Tumors may be bilateral and occur outside the adrenal glands. Symptoms of pheochromocytoma include episodic or sustained hypertension, severe headache, and flushing with profuse sweating— or even hypertensive crises, stroke, myocardial infarction, and heart

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CHAPTER 99 Neurocutaneous Syndromes failure. Diagnostic laboratory investigation demonstrates excessive catecholamine concentrations in serum and urine. Cysts and tumors of the pancreas and epididymis are also features of VHL. Pancreatic tumors include nonsecretory islet cell tumors, simple cysts, serous microcystic adenomas, and adenocarcinomas. Pancreatic cysts are the most common of these lesions and are asymptomatic unless they obstruct the bile duct or become numerous enough to cause pancreatic insufficiency. Islet cell tumors coincide frequently with pheochromocytomas, possibly because both tumors derive from neural crest cells. Epididymal cystadenomas also may be asymptomatic but palpable and cause discomfort.

Molecular Genetics Confirming initial suspicions, the VHL gene is a tumor-suppressor gene located on chromosome 3p25–26. A mutation in the VHL gene also occurs in many sporadic clear-cell renal carcinomas that present later in life, as compared with those with VHL disease. This gene plays a role in the function of hypoxia-induced factor HIF2α. This regulation contributes to increased vascularization and upregulation of proangiogenic genes and other oxygen-sensitive genes via hypoxia response elements (HREs). These genes include vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), transforming growth factor alpha (TGF-α), glucose transporter-1 (GLUT1), carbonic anhydrase IX, and erythropoietin (EPO), among others. In particular, VEGF is important in angiogenesis; its level in ocular fluid of patients is significantly higher than in unaffected subjects. Recognition of these affected genes has focused trials of certain therapies (Clark & Cookson, 2008). Hundreds of known mutations exist. Despite complex genotype-phenotype relationships, some clinical correlations are possible. Missense mutations in this gene are associated with pheochromocytoma, whereas nonsense, frameshift, and splice-site mutations as well as deletions predominate in families without pheochromocytomas. Microdeletions and microinsertions, nonsense mutations, or deletions appear in 56% of families with VHL type 1, whereas missense mutations account for 96% of those responsible for VHL type 2 (Chen et al., 1995). Specific mutations in codon 238 account for 43% of the mutations responsible for VHL type 2, and one group of patients (type 2C) appears to be at low risk for any feature of VHL except pheochromocytoma.

Treatment Careful screening (Box 99.3) is the most important aspect of management of VHL. Screening is mandatory for all first-degree relatives in a family with VHL or pheochromocytoma. Other indications for clinical screening include pancreatic cysts, multiple or bilateral renal cell tumors, retinal hemangiomas, and cerebellar hemangioblastomas. Availability of molecular analysis for the VHL gene reduces the number of asymptomatic relatives requiring surveillance; only relatives who have inherited the VHL mutation need annual screening.

HEREDITARY HEMORRHAGIC TELANGIECTASIA Hereditary hemorrhagic telangiectasia (HHT), also known as RenduOsler-Weber syndrome or Osler-Weber-Rendu syndrome, is a highly penetrant autosomal dominant disorder characterized by telangiectasias of the skin, mucous membranes, and various internal organs. The prevalence is 1 in 10,000. Two different genes are responsible for most cases. One gene on chromosome 9q33–34 (HHT1) encodes for endoglin (ENG), a TGF-β binding protein. The other gene, on chromosome 12q13 (HHT2), encodes for activin A receptor type II-like 1 kinase, or ACVRL1. In some, a SMAD4 gene mutation leads to juvenile

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BOX 99.3

Affected Patient Annual physical examination and urine testing Annual direct and indirect ophthalmoscopy with fluorescein angioscopy or angiography Cranial magnetic resonance imaging (MRI) or computed tomography (CT) every 3 years to age 50 and every 5 years thereafter Annual renal ultrasound, with abdominal CT scan every 3 years (more frequently if multiple renal cysts are discovered) Annual 24-h urine collection for vanillylmandelic acid At-Risk Relative Annual physical examination and urine testing Annual direct and indirect ophthalmoscopy from age 5 years Annual fluorescein angioscopy or angiography from age 10 years until age 60 Cranial MRI or CT every 3 years from age 15 to 40 and every 5 years until age 60 Annual renal ultrasound, with abdominal CT scan every 3 years from age 20 to 65 years Annual 24-h urine collection for vanillylmandelic acid

polyposis and HHT. Up to 30% of cases arise from spontaneous mutations. The clinical features and the age at presentation are highly variable. Diagnostic criteria known as the Curacao criteria include spontaneous recurrent epistaxis, visceral manifestation, and an affected first-degree relative; these were formulated in 2000 (Shovlin, 2000). Consensus guidelines regarding surveillance in 2009 recommend sequence analysis of ENG and ACVRL1 in index cases to guide testing at-risk family members or to assist diagnosis in individuals who do not meet the requisite three of the four clinical criteria (Faughnan et al., 2011) Cutaneous telangiectasias most often occur on the face, lips, and hands and are less common on the trunk. Telangiectasias of the nasal mucosa often cause epistaxis well before other complications of the disease occur and can be severe enough to contribute to iron-deficiency anemia. Approximately one-third of patients have conjunctival telangiectasias, and 10% have retinal vascular malformations, although vision loss from these lesions is uncommon. Telangiectasias are not prominent during the first decade, but they tend to enlarge and multiply thereafter. Widespread vascular dysplasia of the lungs, gastrointestinal tract, or genitourinary system, depending on which site is predominantly affected, can produce hemoptysis, hematemesis, melena, or hematuria. Other involved organs and tissues can include the thyroid, diaphragm, liver, pancreas, spleen, vertebrae, or aorta. Pulmonary arteriovenous malformations (AVMs) occur in 15%–20% of patients, and 60%–90% of all pulmonary AVMs are associated with HHT. Screening includes chest radiograph, arterial blood gas on oxygen, and bubble contrast echocardiogram to evaluate for pulmonary shunting. Repeat screening is helpful every 5 years or at times when the number and size of AVMs increase, such as during puberty or pregnancy. Other tests include chest CT and pulmonary angiography.

Neurological Features Neurological complications are common. Frequent complaints include headache, dizziness, and seizures. Less common complications include paradoxical embolism with stroke, intraparenchymal or subarachnoid hemorrhage, and meningitis or brain abscess. Paradoxical embolism via a pulmonary arteriovenous fistula (AVF) leads to cerebral infarction. Rarely, a clot may form within the

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fistula itself before migrating into the arterial circulation. Intermittent symptoms with subsequent improvement result from repeated small emboli. The cause of transient ischemic attacks during hemoptysis is air embolism from a bleeding pulmonary AVF. Approximately 1% develop cerebral abscess or meningitis, probably because septic microemboli bypass the normal filtration of the pulmonary circulation via a pulmonary AVF. Vascular anomalies may be found anywhere in the brain, spinal cord, or meninges, and more than one type of lesion may be present in the same patient—making this a diagnosis for consideration in patients with multiple cerebrovascular malformations. Approximately one-fourth of HHT patients are likely to have a cerebral vascular malformation. AVMs, high-flow pial fistulae, and telangiectasias are most common; cavernous malformations, venous angiomas, and vein of Galen malformations also occur, but less commonly. Screening should begin with MRI and MR angiography (MRA) of the brain, although cerebral angiography is most sensitive. Angiography every 5 years with interim surveillance is recommended. MRI is the best procedure for patients with known AVMs.

Treatment As with most of the neurocutaneous syndromes, treatment of HHT is limited to the management of complications. Because many of the neurological complications of the disease arise secondary to a pulmonary AVF, resection or embolization of the fistula is essential. Treatment of cerebral AVMs is embolization, excision, or radiosurgery. Periodic transfusion and chronic iron administration may be necessary. To reduce risk of brain abscess in cases of undiagnosed pulmonary AVM, antibiotic prophylaxis is a recommendation prior to dental procedures (Faughnan et al., 2011).

HYPOMELANOSIS OF ITO Hypomelanosis of Ito (HI) is a heterogeneous and complex neurocutaneous disorder affecting the skin, brain, eye, skeleton, and other organs. Ito named the disorder incontinentia pigmenti achromians, but the present name is hypomelanosis of Ito to avoid confusion with incontinentia pigmenti. It is the third most frequent neurocutaneous disease after NF1 and the TSC. HI is usually a sporadic disorder with minimal recurrence risk.

Cutaneous Features The skin findings are distinctive and in fact are the only constant feature of HI. Hypopigmented whorls, streaks, and patches are present at birth and tend to follow Blaschko lines, pathways demarcating embryonic skin development. In HI, the hypopigmented skin lesions are usually multiple, involve several body segments, and may be unilateral or bilateral. They may be observable at birth but commonly develop in infancy, depending on the degree of skin pigmentation. Wood’s lamp examination may enable detection of hypopigmented lesions. The degree or distribution of skin depigmentation does not appear to correlate with either the severity of neurological symptoms or associated organ pathology. The hypopigmented lesions follow Blaschko lines in two-thirds of patients and are patchy in others. Other skin findings in patients with HI include café-au-lait spots, cutis marmorata, aplasia cutis, nevus of Ota, trichorrhexis, focal hypertrichosis, and nail dystrophy. Electron microscopy of the hypopigmented lesions consistently shows a marked reduction of melanocytes (Cavallari et al., 1996). In the proximity of preserved melanocytes, the basal keratinocytes contain a nearly normal content of melanosomes. Depigmented areas contain an increased number of Langerhans cells.

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Many different cytogenetic anomalies occur in HI. Most patients are mosaic for aneuploidy or unbalanced translocations, with two or more chromosomally distinct cell lines either within the same tissue or between tissues. Genetic alterations in HI include ring chromosome 22, mosaic trisomy 18, 18/X translocation, and others. Mosaicism for sex chromosome aneuploidy also occurs. Many individuals have normal lymphocyte karyotypes, but it is important to recognize that mosaicism may be tissue specific, so karyotype abnormalities may be demonstrable in fibroblasts but not in lymphocytes.

Neurological Features The frequency of neurological abnormalities in patients with typical skin lesions ranges from 50% to 80% (Nehal et al., 1996). Epilepsy and intellectual disability are the most common neurological abnormalities. Approximately half of patients with HI have seizures, usually with onset in the first year of life. Focal seizures are most common. Macrocephaly is more common than microcephaly. Generalized cerebral or cerebellar hypoplasia is the most common abnormality on imaging. Severe cortical neuronal migration anomalies, hemimegalencephaly, and lissencephaly occur as well. Hemimegalencephaly may be ipsilateral or contralateral to the cutaneous hypopigmentation. Extensive periventricular white-matter lesions are another common finding. Small periventricular cysts and gray-matter heterotopias occur as well. About a third of patients with HI have normal cranial MRI studies.

Systemic Features Some 50%–70% of patients with HI have noncutaneous defects. Ocular findings include microphthalmia, heterochromia iridis, dacryostenosis, pannus, corneal opacities, cataract, optic atrophy, retinal detachment, and pigmentation anomalies of the retina. The most common musculoskeletal anomaly is hemihypertrophy, but other anomalies include short stature, pectus carinatum and excavatum, cleft palate, butterfly vertebrae, scoliosis, and clinodactyly and polysyndactyly. Dental anomalies are frequent, including conical or hypoplastic teeth, hypoplastic dental enamel, and cleft lip and palate. Cardiac defects include tetralogy of Fallot, pulmonary stenosis, and septal defects. Disorders of endocrine and renal development occur infrequently.

INCONTINENTIA PIGMENTI Incontinentia pigmenti (IP) is a rare X-linked dominant condition affecting the skin, eyes, and CNS. Skeletal and dental anomalies are common and variable. A transitory leukocytosis (predominantly eosinophilic) of uncertain clinical significance can occur. Skin biopsy was instrumental in making the diagnosis in the past, but now gene testing is widely available. Skin biopsy from hyperpigmented regions shows free melanin granules in the dermis.

Cutaneous Features The skin manifestations are characteristic. Skin abnormalities progress in stages any time from the newborn period to adulthood. The duration of each stage is variable and may overlap with other stages. The lesions typically evolve from blister (stage 1) to verrucous (stage 2) to linear and pigmented (stage 3) and finally to atrophic and hypopigmented (stage 4) (Fig. 99.18). Skin lesions develop along Blaschko lines. The blister or bullous stage often presents in the neonatal period and is often evaluated as an infectious process. Verrucous transformation is most typical during infancy, and abnormalities of the nails and teeth as they erupt become notable. The hyperpigmented stage is prominent in childhood and adulthood but begins to fade in the second or third decade. The hypopigmented or atretic stage may demonstrate loss of

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Fig. 99.18 Features of incontinentia pigmenti change over time from blister-like and verrucous in the infant (A) to hyperpigmented in an older individual (B).

normal hair and subcutaneous structures in addition to changes in coloration. Not all stages occur in all individuals, especially the hypopigmented stage. Abnormalities of hair include alopecia in areas that may have been previously affected or unaffected by skin pigmentation changes. Scalp hair may be thin or coarse. Abnormalities of eyebrows may be present as well. Nails may be brittle or demonstrate pits; these findings may wax and wane and raise concern for fungal infection. Tooth abnormalities may include abnormal shape or malpositioning. IP carries an increased risk of retinal detachment. This is most likely to occur in early childhood and is rare after 6 years of age. Dilated funduscopic examination demonstrates retinal neovascularization as a precursor to detachment. Frequent surveillance ophthalmological examination is important, especially early in life, and may be helpful in making the diagnosis in at-risk family members not otherwise symptomatic.

Neurological Features Neurological abnormalities have been overestimated in the past, and the incidence appears less with laboratory confirmation available. Seizures occur more frequently in this population. Most affected females have normal intelligence. Affected males are more likely to have developmental delay. Neurological abnormalities are more likely

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to occur in individuals with ocular abnormalities. Some demonstrate cerebral or cerebellar atrophy.

Genetics Transmission is X-linked dominant, and nuclear factor kappa B (NF-κB) essential modulator (NEMO) is the causative gene—more recently termed IKBKG (Greene-Roethke, 2017). Deletion in exons 4–10 is the responsible mutation in 80%–90% of patients (Nelson, 2006). This protein is involved in prevention of apoptosis. The mutation is expected to be lethal in males; however, males with somatic mosaicism or an additional X chromosome, as in Klinefelter syndrome, have survived. These individuals demonstrate immunodeficiency and ectodermal dysplasia rather than the characteristic skin findings described.

ATAXIA-TELANGIECTASIA Ataxia-telangiectasia (AT) is a neurodegenerative disorder that begins in early childhood as a slowly progressive ataxia. Telangiectasias (dilated small blood vessels), immunodeficiency, and cellular sensitivity to ionizing radiation develop later. The distinctive skin lesions predominantly involve the sclerae, earlobes, and bridge of the nose, with less common involvement of the eyelids, neck, and antecubital

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and popliteal fossae. The combination of these telangiectasias in a child with progressive ataxia is pathognomonic for AT. The most striking non-neurological feature of AT is an increased frequency of sinopulmonary infections and a dramatically increased risk for malignancy of the lymphoreticular system, especially leukemia and lymphoma. The estimated prevalence of AT, an autosomal recessive disorder, ranges from 1 in 40,000 to 1 in 100,000. The gene frequency is as high as 1% in the general population.

Cutaneous Features Telangiectasias typically do not develop until age 3–6 years, well after the onset of ataxia. Two other dermatological features of AT that may be overlooked are hypertrichosis and occasional gray hairs. Hypertrichosis is noticeable particularly over the forearms. These often-overlooked features in the context of a child with slowly progressive ataxia provide clues to the correct diagnosis. Progeric changes such as poikiloderma, loss of subcutaneous fat, and sclerosis also have been associated. Abnormal radiosensitivity may underlie reports of basal cell carcinomas in young adults. Cutaneous granulomas, commonly associated with immunodeficiency states such as severe combined immunodeficiency and X-linked hypogammaglobulinemia, may appear as the initial cutaneous manifestation of AT (Chiam et al., 2011).

Neurological Features Ataxia, the first manifestation of AT, appears when the child learns to walk in the second year of life. Truncal ataxia predominates early in the course of the disorder, affecting sitting, balance, and gait. Muscle strength is normal, and attainment of early gross motor milestones is usually on time. The ataxia is slowly progressive, and children typically require a wheelchair by the age of 12 years. As the child matures, limb ataxia, intention tremor, and segmental myoclonus become apparent. Choreoathetosis may be difficult to distinguish from dysmetria and intention tremor, but it may dominate the clinical picture in older children. At times, the choreoathetosis may resemble segmental myoclonus of the limbs or trunk. Progressive dystonia of the fingers may appear in the second and third decades of life. Axial muscles are affected, and a stooped posture gradually develops. Progressive dysarthria is present. Abnormal eye movements are nearly universal in children with AT. Voluntary ocular motility is impaired; nystagmus and apraxias of voluntary gaze such as disorders of smooth pursuit and limitation of upgaze are the most common abnormalities. Oculomotor apraxia may precede appearance of the telangiectasias but is often misidentified as an attention-seeking behavior. Strabismus is seen in many young children with AT, but it is often transitory and does not warrant corrective surgery. In adult patients with AT, the neurological features include progressive distal muscular atrophy and fasciculations, with relative preservation of proximal strength. The gradual loss of vibration and position sense indicates involvement of the spinal cord dorsal columns, and neuropathological and electrophysiological studies reveal a primarily axonal peripheral polyneuropathy (Verhagen et al., 2007). Serial brain imaging in older children and adults shows nonprogressive cerebellar atrophy. Autopsy studies confirm the radiographic impression of cerebellar degeneration, with reduced numbers of Purkinje cells, granular and basket cells of the cortex, and neurons in the nuclei of the vermis. Degenerative changes are more extensive in adults, involving the substantia nigra, brainstem nuclei, and spinal cord. Relative sparing of the cerebral cortex is associated with fewer significant neuropsychological deficits (Hoche et al., 2014).

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Immunodeficiency and Cancer Risk Approximately 10%–15% of patients with AT develop a lymphoid malignancy by early adulthood (Taylor et al., 1996). T-cell malignancies are more common than B-cell tumors, although both are more frequent than in the general population. This increased risk of T-cell tumors may be due to the increase in chromosomal rearrangement observed in T lymphocytes from patients with AT. T-cell tumors may occur at any age, whereas B-cell lymphomas tend to arise in older children. AT is in a family of disorders (including Nijmegen breakage syndrome, Bloom syndrome, and Fanconi anemia) characterized by specific cellular defects in response to deoxyribonucleic acid (DNA)damaging agents. Other tumor types reported in association with AT include dysgerminoma, gastric carcinoma, liver carcinoma, retinoblastoma, and pancreatic carcinoma. In fact, nonlymphoid tumors, primarily carcinomas, represent approximately 20% of all malignancies in patients with AT. Cerebellar astrocytoma, medulloblastoma, and glioma also have been linked to AT in case reports. Frequent sinopulmonary infections are another characteristic of AT. A third of patients have a potentially severe immune deficiency. Recurrent or chronic sinusitis, bronchitis, pneumonia, and chronic progressive bronchiectasis were frequent causes of death in previous years but now usually respond to antibiotic treatment. The thymus gland is often small or absent on chest radiography, and at autopsy may be only rudimentary.

Laboratory Diagnosis Useful laboratory tests in the diagnosis of AT include serum α-fetoprotein, immunoglobulins (Igs), and cellular radiosensitivity tests. Nearly all patients with AT have an elevated α-fetoprotein level, which is utilized as a screening diagnostic test. Approximately 80% have decreased serum immunoglobulin—IgA, IgE, or IgG, especially the IgG2 subclass. Characteristic cellular features are reduced life span in culture, cytoskeletal abnormalities, chromosomal instability, hypersensitivity to ionizing radiation and radiomimetic agents, defective radiationinduced checkpoints at the G1, S, and G2 phases of the cell cycle, and defects in signal transduction pathways (Rotman & Shiloh, 1997). The gene associated with AT, ataxia telangiectasia mutated (ATM), is a large gene located at chromosome 11q22–23, and more than 100 ATM mutations occur widespread throughout the ATM gene. Although the function of the ATM gene product is not clear, it belongs to a family of large proteins involved in cell cycle progression and checkpoint response to DNA damage. One postulation is that oxidative stress specifically activates ATM by initiating signal transduction pathways responsible for protecting cells from such insults (Savitsky et al., 1995). Thus, the production of reactive oxygen species by ionizing radiation may play an important role in mutagenesis in cells with absent or abnormal ATM. The high risk of malignancy in AT underscores the importance of early diagnosis in affected individuals and subsequent routine surveillance for leukemia and lymphoma. Treatment of the neurological deficits is symptomatic at present. Whether neuroprotective medications or medications that modulate neuronal growth factors can slow neurodegeneration in AT is unknown. Treatment options include vitamin E, α-lipoic acid, and folic acid for their theoretical role in reduction in chromosomal breaks and subsequent translocations or inversions. Genetic counseling and prenatal diagnosis are available.

EPIDERMAL NEVUS SYNDROME The term epidermal nevus syndrome (ENS) encompasses several disorders that have in common an epidermal nevus and neurological

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CHAPTER 99 Neurocutaneous Syndromes manifestations such as epilepsy or hemimegalencephaly. The syndrome name represents the predominant cell type of the nevus; for example, nevus verrucosus (keratinocytes), nevus comedonicus (hair follicles), and nevus sebaceous (sebaceous glands). Several subtypes of ENS exist and should be differentiated from one another: nevus sebaceous syndrome (Schimmelpenning-Feuerstein-Mims syndrome), Proteus syndrome, CHILD (congenital hemidysplasia with ichthyosiform nevus and limb defects) syndrome, Becker nevus associated with extracutaneous involvement (pigmented hairy ENS), nevus comedonicus syndrome, and phakomatosis pigmentokeratotica (Happle, 1995). Terms such as Schimmelpenning syndrome, organoid nevus syndrome, and Jadassohn nevus phakomatosis describe combinations of neurological findings and sebaceous nevi. It is probably best to consider ENS a heterogeneous group of disorders characterized by epidermal and adnexal hamartomas and other organ system involvement.

Cutaneous Features Epidermal nevi are linear or patchy slightly raised lesions that typically present at birth but may appear first in early childhood. The most common location is on the head or neck. Only 16% of congenital nevi subsequently enlarge, compared with 65% of nevi arising after birth. Nevi on the head and neck rarely enlarge, whereas more than half of lesions elsewhere extend beyond their original boundaries. Most nevi contain more than one tissue type, complicating dermatological classification; the nevus name typically reflects the predominant tissue. Verrucous nevi are the most common type.

Neurological Features Neurological involvement is variable but more likely when other extracutaneous disease is present. The location of the nevus appears to correlate with the likelihood of neurological symptoms, with neurological complications of ENS most often occurring in the setting of an epidermal nevus on the face or scalp (Asch & Sugarman, 2018). Cognitive deficits are common, and seizures occur in more than half of those affected. Usually ipsilateral to the nevus, focal epileptiform discharges and focal slowing are the most common EEG abnormalities. Infantile spasms with hypsarrhythmia may occur. Other neurological symptoms include cranial nerve palsies, hemiparesis (especially in patients with hemimegalencephaly), microcephaly, and behavior problems. Spina bifida and encephaloceles rarely occur. Cerebrovascular anomalies occur in approximately 10% of patients with ENS. Intracranial blood vessels may be dysplastic, dilated, or occluded. A few patients have had AVMs and aneurysms. Ischemia or hemorrhage from intracranial blood vessel anomalies may result in porencephaly, infarctions, and dystrophic calcification.

Other Features Tumors occur with moderate frequency in association with ENS. The nevus itself may undergo malignant transformation, often into a basal cell carcinoma. Extracutaneous tumors have included astrocytomas, Wilms tumors, rhabdomyosarcomas, and gastrointestinal carcinomas, among others. Skeletal abnormalities are quite frequent but often secondary to neurological dysfunction that alters skeletal development. Certain skeletal anomalies may be a primary part of ENS, such as abnormal vertebrae. Limb anomalies include clinodactyly, limb reduction defects, syndactyly, polydactyly, bifid thumbs, and talipes equinovarus. Half of patients with ENS have ocular abnormalities such as colobomas. Disorders of globe growth include either microphthalmia or macrophthalmia. Retinal lesions such as scarring, degeneration, and detachment may occur. Strabismus and lipodermoid lesions of the conjunctivae are more frequent but less serious findings.

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Approximately 10% of patients with ENS have cardiovascular and genitourinary malformations. Single reports describe hypoplastic left-sided heart, ventricular septal defect, coarctation of the aorta, pulmonic stenosis, patent ductus arteriosus, and dilated pulmonary artery. Horseshoe kidney, cystic kidneys, duplicated collecting system, and ureteropelvic junction obstruction also occur.

Neuroimaging Megalencephaly ipsilateral to the epidermal nevus is the most frequent finding on neuroimaging, but bilateral involvement is common also. In some patients, megalencephaly results from asymmetrical growth of the skull, with the brain being of normal size. MRI of the skull may show a widened diploic space. Often, enlargement of the calvarium and the ipsilateral cerebral hemisphere are present together. In addition, several types of cerebral dysplasia are associated with ENS, also primarily ipsilateral to the epidermal nevus. Focal pachygyria is the most common type of cortical dysplasia in ENS. The surface of the affected hemisphere may be smooth, the cortical mantle thickened, and the adjacent white matter abnormal.

NEUROCUTANEOUS MELANOSIS Neurocutaneous melanosis (NCM) is a congenital disorder of melanotic cell development that involves the CNS, especially the leptomeninges (Agero et al., 2005). Congenital melanocytic nevi may occur without CNS involvement, and, conversely, melanin is found normally in the CNS in the absence of congenital nevi. NCM is apparently not hereditary and affects male and female subjects with equal frequency. The incidence of NCM is unknown, but it is very uncommon, with only 100–200 cases reported in the literature. Although the precise pathogenesis is not well understood, a disorder involving neural crest cell differentiation and melanocyte embryogenesis is suspected. The prominent involvement of the leptomeninges and skin over the spine supports the suggestion that the primary defect is abnormal migration of nevus cell precursors, although the embryological origin of nevus cells has not been determined. Alternatively, melanin-producing cells may be produced in excessive numbers. It has also been speculated that nevi located over the spine result from an error early in nevus cell migration or differentiation, whereas nevi are restricted to the extremities if the error occurs later in development (Pavlidou et al., 2008).

Cutaneous Features The characteristic lesions are dark to light brown hairy nevi present at birth (Fig. 99.19). Multiple small nevi (satellite nevi) usually are present around one giant nevus that most commonly appears on the lower trunk and perineal area (swimming trunk nevus). A giant nevus is absent in 34% of patients with NCM. Approximately one-third of patients have a large nevus over the upper back (cape nevus). The giant nevi may fade over time, but satellite nevi continue to appear during the first few years of life. Diagnostic criteria for NCM have been suggested: (1) large or multiple (three or more) congenital nevi (large is ≥20 cm in an adult, 9 cm on the scalp of an infant, or 6 cm on the body of an infant); (2) no evidence of cutaneous melanoma, except in patients in whom the examined portions of the meningeal lesions are benign; and (3) no evidence of meningeal melanoma, except in patients in whom the examined areas of the cutaneous lesions are benign (Marghoob et al., 2004). Some authors argue that a definitive diagnosis of NCM requires histological confirmation of the CNS lesions. However, in the context of the

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Fig. 99.20 Leptomeningeal Melanosis at Autopsy in a Patient With Neurocutaneous Melanosis. (Photo courtesy Dr. John Bodensteiner. Reprinted with permission from Miller V.S. 2004. Neurocutaneous melanosis, In: Roach E.S., Miller V.S. (Eds.), Neurocutaneous Disorders. Cambridge University Press, Cambridge, pp. 71–76.)

Fig. 99.19 Large, Dark, Hairy Nevus Covering most of the back of an Infant with Neurocutaneous Melanosis.

typical melanocytic cutaneous nevi and characteristic neuroimaging findings, leptomeningeal or brain biopsy is unnecessary. Biopsy of a congenital nevus reveals extension of the nevus cells into the deep dermis or even the subcutis between collagen bundles and around nerves, hair follicles, and blood vessels. Nevus cells tend to form cords or nests. Sheets of nevomelanocytes in the dermis may display a few mitoses and large atypical cells positive for S100 and HMB45 antibodies and formaldehyde-induced green-specific fluorescence. The occurrence of atypical mitoses in the dermis may constitute an early stage of malignant melanoma. The greatest risks in NCM are the high incidence of malignant transformation of melanotic cells and spinal and intracranial pathology.

Neurological Features Neurological symptoms may result from leptomeningeal melanosis, intracranial melanoma, or intracerebral or subarachnoid hemorrhage. Malformations of the vertebral column, spine, and brain also may impair neurological function. The median age of neurological complications is 2 years, but infants may be affected (DeDavid et al., 1996). Leptomeningeal melanosis is probably the most common cause of neurological symptoms, especially in children. This tends to occur at the base of the brain along the interpeduncular fossa, ventral brainstem, upper cervical cord, and ventral surface of the lumbosacral cord. Marked leptomeningeal melanosis (Fig. 99.20) is present in the vast majority of patients with NCM and associated with interruption of cerebrospinal fluid (CSF) flow. This leads to hydrocephalus and increased intracranial pressure with typical symptoms of irritability, vomiting, seizures, and

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papilledema. In infants, symptoms may include rapidly increasing head circumference or tense anterior fontanelle. Cranial nerve deficits such as limitation of upgaze and lateral gaze are common. Myelopathy occurs when leptomeningeal proliferation affects the spinal cord or spinal nerves. The likelihood of symptomatic neurological involvement correlates with location of large nevi. Large congenital melanocytic nevi occur in a posterior and midline position in nearly 80% of affected patients (Agero et al., 2005). In one series, all 33 patients with neurological symptoms had a nevus over the back, whereas none of 26 patients with nevi restricted to the limbs had neurological abnormalities. Patients occur with leptomeningeal melanosis confirmed by biopsy and CNS involvement but without skin lesions.

Laboratory Findings CSF from patients with neurological symptoms may show a mild pleocytosis and elevated pressure and protein. CSF cytopathology shows numerous round cells with abundant cytoplasm and ovoid nuclei, and light brown cytoplasmic granules (presumably melanin) may be seen. The most characteristic histological feature is the presence of numerous irregular fingers projecting from the cell body, which may aid in diagnosis of NCM.

Neuroimaging Approximately half of neurologically asymptomatic children with NCM have abnormal cranial neuroimaging study results. Cranial MRI demonstrates lesions with T1 shortening in the cerebellum, in the anterior temporal lobe (especially the amygdala), and along the basilar meninges (Fig. 99.21). Some of these lesions also show T2 shortening. The pons, medulla, thalami, and base of the frontal lobe often are affected (Ramaswamy et al., 2012). Gadolinium-enhanced MRIs rarely may show enhancement of the pia-arachnoid. In one study, five of six children with neurological symptoms of increased intracranial pressure showed leptomeningeal thickening and enhancement. Conversely, asymptomatic children never showed leptomeningeal thickening. Inferior vermian hypoplasia and Dandy-Walker malformation have been reported. Spinal MRI study results are usually normal. It may be difficult to distinguish radiological evidence of CNS melanoma from benign melanin deposits. Serial imaging studies are the best way to follow clinically suspect MRI lesions. Certain neuroimaging findings help distinguish benign intracranial melanosis from

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Fig. 99.22 Cutaneous hyperelasticity of the anterior chest in a patient with Ehlers-Danlos syndrome without cerebrovascular disease.

Fig. 99.21 T1-weighted cranial magnetic resonance imaging scan showing leptomeningeal melanosis over the cerebellum (arrow) and focal melanosis or melanoma in the temporal lobe (arrowhead).

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Fig. 99.23 A, Computed tomographic scan with contrast from an 18-year-old patient with headache and a family history of type IV Ehlers-Danlos syndrome reveals a giant aneurysm (arrow) of the right intracavernous carotid artery. B, Right internal carotid angiogram confirms the giant aneurysm of the intracavernous carotid artery. (Reprinted with permission from Roach, E.S., Zimmerman, C.F., 1995. Ehlers-Danlos syndrome, In: Bogousslavsky, J., Caplan, L.R. (Eds.), Stroke Syndromes. Cambridge University Press, London, pp. 491–496.)

melanoma; necrosis, perilesional edema, contrast enhancement, and hemorrhage are features of melanoma. Unfortunately, melanoma may not exhibit any of these findings until late in its course when metastasis is likely to have already occurred.

EHLERS-DANLOS SYNDROME At least 10 subtypes of Ehlers-Danlos syndrome (EDS) exist, defined by the clinical features, inheritance pattern, and even specific molecular defects. Together these syndromes are characterized by fragile or hyperelastic skin (Fig. 99.22), hyperextensible joints, vascular lesions, easy bruising, poor wound healing, and excessive scarring. Some patients develop peripheral neuropathy caused by lax F ECF

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ligaments, and others may present with neonatal hypotonia or weakness. Neuromuscular kyphoscoliosis can develop. However, vascular lesions such as aneurysm (Fig. 99.23) and arterial dissection are the most serious threat to the nervous system. (See also Chapter 65 and 104.) More than 80% of EDS patients have type I, II, or III, and the other subtypes are individually uncommon. Type IV most often leads to neurovascular complications, and its prevalence is 1 in 50,000 to 500,000. Often, a delay in the diagnosis of type IV EDS occurs because of a decreased incidence of hyperelastic skin or hyperextensible joints compared to other types. Transmission of all familial type IV EDS cases with a documented abnormality of type III collagen is autosomal dominant. Various defects of the COL3A1 gene (which codes

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for the α1 chain of type III collagen) on chromosome 2 have been identified (Schwarze et al., 1997). Mutations of this gene are rare in patients with aneurysm without type IV EDS (Hamano et al., 1998).

Neurovascular Features There is a risk of aneurysms, and the most commonly affected intracranial vessel is the internal carotid artery, typically in or just beyond the cavernous sinus. Rupture of the aneurysm can occur spontaneously or during vigorous activity. Rupture within the cavernous sinus may create a carotid-cavernous fistula. Less often, the aneurysm occurs in other intracranial arteries and presents with subarachnoid hemorrhage. Most individuals become symptomatic in early adulthood, but some begin in childhood and adolescence. Some patients develop a fistula after minor head trauma, but most occur spontaneously and even without an aneurysm. Clinical features of carotid-cavernous fistula include proptosis, chemosis, diplopia, and pulsatile tinnitus. The vascular fragility of type IV EDS makes both standard angiography and intravascular occlusion of the fistula difficult. Arterial dissection occurs in both intracranial and extracranial arteries, and the initial features depend primarily on which artery is affected. One patient with a vertebral dissection developed a painful pulsatile mass of the neck. Dissection of an intrathoracic artery secondarily can occlude cervical vessels, and distal embolism from a dissection can cause cerebral infarction. Surgery is difficult because the arteries are friable and difficult to suture, and handling the tissue leads to tears of the artery or separation of the arterial layers. Type IV EDS should be considered in children and young adults with arterial dissection.

CEREBROTENDINOUS XANTHOMATOSIS Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive disorder of bile acid synthesis characterized by tendon xanthomas, cataracts, and progressive neurological deterioration (Box 99.4). The underlying defect consists of the enzyme, sterol 27-hydroxylase, whose gene (CYP27A1) is located on chromosome 2q. The enzyme deficiency leads to deposits of cholesterol and cholestanol, a metabolic derivative of cholesterol, in virtually every tissue, particularly the Achilles tendons, brain, and lungs. Bile acid production decreases markedly, which leads to reduced chenodeoxycholic acid (CDCA) concentration in bile. Excretion of bile acid precursors increases in bile and urine. Serum cholesterol levels are typically not elevated in CTX syndrome.

Neurological Features Personality changes and decline in school performance may be the earliest neurological manifestations of this syndrome. Progressive loss of cognitive function typically begins in childhood, but some patients remain intellectually normal for many years. EEG shows nonspecific characteristics of metabolic encephalopathy such as slowing. Seizures may occur. Ataxia with gait disturbance, dysmetria, nystagmus, and dysarthria are common. Psychosis with auditory hallucinations, paranoid ideation, and catatonia occur rarely, but examination for cataracts and tendon xanthomas should be included in the evaluation of patients with new-onset psychosis. Parkinsonism may be the only neurological symptom. Cranial MRI typically shows involvement of the dentate nuclei (Gallus et al., 2006). Other findings include cerebral and cerebellar atrophy and diffusely abnormal white matter, presumably reflecting sterol infiltration with demyelination. Focal lesions of the cerebral white matter and globus pallidus are sometimes demonstrable on MRI. Peripheral neuropathy is a prominent feature of CTX, with signs of pes cavus, areflexia, and loss of vibration perception. Sural nerve

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Clinical Features of Cerebrotendinous Xanthomatosis

BOX 99.4

Neurological Progressive dementia Ataxia Nystagmus Dysarthria Hyperreflexia Bulbar symptoms Palatal and pharyngeal myoclonus Peripheral neuropathy Electroencephalographic abnormalities Parkinsonism Cerebral and cerebellar atrophy Cataracts Behavioral Abnormalities Personality changes Irritability Agitation Aggressiveness Paranoid ideation Auditory hallucinations Catatonia Musculoskeletal Xanthomas Osteoporosis and bone fractures Large paranasal sinuses

biopsy may show reduced densities of both myelinated and unmyelinated axons, and teased fibers show axonal regeneration and remyelination. Large-diameter myelinated nerve fibers particularly are affected. Schwann cells contain foamy macrophages and lipid droplets. Shortlatency somatosensory evoked potentials may show prolonged central conduction times with tibial nerve stimulation, but normal conduction velocities with median nerve stimulation. Brainstem auditory evoked potentials and visual evoked potentials are abnormal in approximately half of patients studied. These electrophysiological parameters correlate with the ratio of serum cholestanol to cholesterol concentration and may improve with treatment with CDCA.

Xanthomas The Achilles tendon is the most common site of tendon xanthomas, but the quadriceps, triceps, and finger extensor tendons also show xanthomatous involvement. Tendon xanthomas usually appear after the age of 20 years but may occur earlier. A substantial number of patients never develop xanthomas. Compared with xanthomas found in patients with familial hypercholesterolemia or hyperlipoproteinemia, these xanthomas appear similar grossly but contain high amounts of cholestanol and little cholesterol. The presence of early-onset cataracts, progressive dementia, and tendon xanthomas is pathognomonic of CTX syndrome (Salen & Steiner, 2017). The differential diagnosis includes Marinesco-Sjögren syndrome multiple sclerosis, hereditary spastic paraparesis, olivopontocerebellar atrophy, and spinocerebellar degeneration.

Other Clinical Features Onset of cataracts by age 10 years and chronic diarrhea are a characteristic combination in CTX. Cataracts can be bilateral and asymptomatic.

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Osteoporosis may lead to an increased risk of skeletal and vertebral fractures. Large paranasal sinuses occur in association with CTX. Renal disorders reported in patients with CTX include nephrolithiasis, nephrocalcinosis, and renal tubular acidosis.

Treatment Treatment of CTX focuses on lowering cholestanol levels, primarily with CDCA. Other lipid-lowering agents such as cholestyramine or β-hydroxymethylglutarate-CoA inhibitors are not as effective alone, but the latter in combination with CDCA constitutes the most effective treatment. Long-term therapy can lead to striking improvement in neurological function, resolution of peripheral and intracranial xanthomas, and improvement of EEG and peripheral nerve conduction abnormalities as well as visual and somatosensory evoked potentials. It may be that early treatment is required, which ideally would begin before onset of clinical symptoms in individuals with a family history of CTX. The possibility that early treatment may improve the neurological symptoms of CTX underscores the importance of careful screening and genetic counseling of asymptomatic relatives of patients with this disorder. Treatment with cholic acid is also an option and may produce fewer side effects (Mandia et al., 2019).

PROGRESSIVE FACIAL HEMIATROPHY Progressive facial hemiatrophy (Parry-Romberg syndrome) occurs sporadically. The relationship of this disorder to en coup de sabre, morphea, and linear scleroderma is still debated (Peterson et al., 1995). Traditionally, progressive facial hemiatrophy involves the upper cranium, whereas en coup de sabre tends to affect the lower face as well. Scleroderma and morphea affect other parts of the body. However, understanding of pathogenesis is poor, and they may prove to have a similar origin. An arbitrary distinction based on the anatomical distribution does have at least one practical use: as a rule, only patients whose upper face and head are affected are likely to develop cerebral complications.

Fig. 99.24 Unilateral atrophy of the skin and subcutaneous tissue (arrows) in a young boy with progressive hemifacial atrophy.

Clinical Features Progressive facial hemiatrophy is characterized by unilateral atrophy of the skin, subcutaneous tissue, and adjacent bone (Fig. 99.24). The atrophic area is characteristically oblong or linear and sometimes begins as a raised erythematous lesion. The lesion sometimes begins after trauma to the area. The atrophy eventually stabilizes, leaving facial disfigurement. Epilepsy is probably the most common neurological problem associated with progressive facial hemiatrophy. Some patients develop a usually mild hemiparesis. Less common neurological features include cognitive impairment, cranial neuropathy, or even brainstem signs. Cerebral calcifications and white-matter lesions are common neuroimaging findings (Fig. 99.25); abnormalities typically lie beneath the cutaneous lesion (Fry et al., 1992). Understanding of the cause of progressive facial hemiatrophy and related disorders is poor. Proposed mechanisms (e.g., cortical dysgenesis, dysfunction of the sympathetic nervous system, chronic localized meningoencephalitis) are inadequate to explain all of the clinical features.

KINKY HAIR SYNDROME (MENKES DISEASE) Kinky hair syndrome, also known as Menkes disease or trichopoliodystrophy, is an X-linked recessive disorder of connective tissue and neuronal metabolism caused by inborn disorders of copper metabolism:namely, impaired cellular export of copper, leading to accumulation in all tissues except the liver and brain. The estimated frequency is

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Fig. 99.25 Computed tomographic scan revealing right frontal encephalomalacia and calcification in a patient with progressive facial hemiatrophy.

1 in 40,000 to 1 in 298,000 live births. In the classic form of kinky hair syndrome, the neurological symptoms begin in the first year of life, and the course is rapidly progressive, with death by the third year of life in more involved cases. Death is commonly due to infection, cerebrovascular complications, or the neurodegenerative process. Documented cases of late-onset cases and apparently asymptomatic individuals are in the literature. Clinical features in affected girls are similar to but

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B Fig. 99.26 A, Brittle, light-colored hair seen in kinky hair syndrome. B, Hair shaft from a patient with kinky hair syndrome.

milder than those seen in typical neonatal-onset cases; genetic analysis reveals inactivation of the normal X chromosome.

Cutaneous Features Connective tissue abnormalities are a major feature of kinky hair syndrome and include loose skin, hyperextensible joints, bladder diverticula, and skeletal anomalies. The enzyme lysyl oxidase has copper-dependent steps that are impaired in the establishment of elastin and collagen cross-linking. Keratin cross-linking and melanin production also depend on copper, and copper deficiency leads to characteristic cutaneous features. The hair is light-colored and brittle and on microscopic examination (Fig. 99.26) appears as pili torti (twisted hair) and trichorrhexis nodosa (complete or incomplete fractures of the hair shafts at regular intervals). Trichorrhexis nodosa is not pathognomonic of kinky hair syndrome; it also occurs in biotinidase deficiency and argininosuccinic aciduria. Skin may be diffusely hypopigmented or normal.

Other Clinical Features Kinky hair syndrome covers a clinical continuum from nearly normal to the severe classic infantile-onset form (Box 99.5). Newborns may be more prone to cephalohematomas or spontaneous bone fractures and develop temperature instability, diarrhea, and failure to thrive in early infancy. Sympathetic adrenergic dysfunction, including hypotension, hypothermia, anorexia, and somnolence, is attributable to the impairment of dopamine β-hydroxylase that requires copper for the synthesis of norepinephrine and other neurotransmitters. One variant of kinky hair syndrome is the occipital horn syndrome in which connective tissue symptoms predominate, and cognitive and motor involvement is variable. This disorder is named for the characteristic exostoses (“orbital horns”) resulting from calcification of the trapezius and sternocleidomastoid muscles at their attachment to the occipital skull.

Neurological Features In early-onset cases, hypotonia develops in the first few weeks to months and gradually develops into spastic quadriparesis with clenched fists, opisthotonus, and scissoring. Seizures are a prominent feature of this disorder, appearing by age 2–3 months, and may be focal or generalized. Myoclonic seizures are especially common. Developmental delay and regression appear between ages 4 and 6 months in the classic form. Intracranial and extracranial blood vessels may be tortuous, kinked, and dilated (Kim & Suh, 1997); the cause may be defective or deficient elastin fibers in the walls of these blood vessels. Neuropathological studies show diffuse neuronal loss and gliosis that is particularly

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Neurological and Systemic Features of Infantile-Onset Kinky Hair Syndrome

BOX 99.5

Premature birth, low birth weight Neonatal jaundice Hypothermia Decreased facial expression Prominent forehead Full cheeks Narrow palate Hypopigmented skin Cutis laxa Pili torti Inguinal hernia Hepatomegaly Deafness Bladder diverticula Joint laxity Skeletal anomalies: Pectus excavatum Wormian skull bones Metaphyseal spurring of long bones Ataxia Seizures Intracranial hemorrhage Neuroimaging findings: Cerebellar and cerebral atrophy White-matter abnormalities Subdural fluid collections Dilated and tortuous intracranial and extracranial blood vessels Cerebral edema

prominent in the cerebrum and cerebellum. Microscopic findings include abnormal dendritic arborization in the cerebellar cortex.

Neuroimaging Cranial MRI and CT studies show diffuse cerebral atrophy with secondary subdural fluid collections, which may be large enough to cause mild compression of the ventricular system. The presence of large subdural fluid collections and metaphyseal fractures in an infant can lead to the erroneous diagnosis of child abuse. In older children, MRI studies typically reveal diffuse white-matter signal abnormalities suggestive of demyelination and gliosis, whereas in infants the white matter may

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CHAPTER 99 Neurocutaneous Syndromes be only focally affected. Diffuse brain atrophy, subdural effusions or hemorrhages, infarction, or edema also may be present. MRI shows tortuous intracranial blood vessels, better seen by MRA or conventional angiography. Skull radiographs may show wormian bones.

Genetic Studies A gene involved in transmembrane copper transport, ATP7A (also referred to as MNK), has been implicated in both kinky hair syndrome and occipital horn syndrome. ATP7A maps to Xq13.3 and is highly homologous to the gene implicated in Wilson disease. ATP7A mRNA is present in several cell types and organs except liver, which explains the clinical observations that liver does not accumulate excess copper and is largely unaffected in kinky hair syndrome. Infantile-onset kinky hair syndrome results from extensive mutations of ATP7A (e.g., large deletions, frameshift mutations), whereas occipital horn syndrome is associated with promoter and splicing efficiency mutations, possibly leading to reduced levels of an otherwise normal protein product. Mutations of the ATP7A gene in the patients with the occipital horn syndrome have been base pair substitutions affecting normal messenger ribonucleic acid (mRNA) splicing (Tumer & Horn, 1997). Copper deficiency impairs the function of multiple enzymes that require copper as a cofactor: tyrosinase, cytochrome C oxidase, dopamine β-hydroxylase, and Cu/Zn superoxide dismutase, among others.

Diagnosis and Treatment When suspected clinically, low serum copper and ceruloplasmin support the diagnosis. Plasma catecholamine analysis to evaluate for dopamine β-hydroxylase deficiency also may be helpful. Specialized centers can determine intracellular accumulation of copper. The large size of the ATP7A gene and the variety of mutations make detection of a specific genetic defect difficult, unless previously established for a given family. Carrier status is difficult to assess, although prenatal testing for copper content in chorionic villi or cultured amniotic-fluid cells is available. The focus of treatment approaches is to restore copper to normal levels in brain and other tissues. Careful medical care is particularly important in extending the life span. Copper histidine administered parenterally (subcutaneously) is the most promising treatment, and substantial clinical improvement in a small number of patients has been reported. Undoubtedly, response to copper histidine treatment partly depends on the specific mutation of ATP7A involved. Such correlations are not yet well characterized. Aggressive copper replacement beginning in early infancy may be necessary to significantly improve neurological outcome (Tang et al., 2008). Replacement therapy does not appear to help the connective tissue abnormalities in kinky hair syndrome. Preservation of some residual activity of adenosine triphosphatase (ATPase) may be required for significant clinical efficacy from copper replacement treatment, since it did not normalize neurological outcome in two children with the Q724H splicing mutation, which yields a nonfunctioning ATPase.

XERODERMA PIGMENTOSUM Xeroderma pigmentosum (XP) is a group of uncommon neurocutaneous disorders characterized by susceptibility to sun-induced skin disorders and variable (but typically progressive) neurological deterioration. Inheritance of XP is autosomal recessive, often in the setting of parental consanguinity, and occurs in 1 in 30,000 to 1 in 250,000 or higher. It occurs more frequently in Japan and Egypt than in the United States and Europe. Several gene mutations involving nucleotide excision repair and DNA transcription have been associated with

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XP and related syndromes such as Cockayne syndrome, trichothiodystrophy, and De Sanctis-Cacchione syndrome.

Complementation Groups Complementation analysis has been important in understanding the genetic basis of XP. If two particular cell types with different metabolic abnormalities are fused, the cell produced may function normally. These two cell types have different complementation groups and presumably have a different genetic basis. In XP, eight complementation groups have been identified (XP-A through XP-G and a variant group). Although some general genotype–phenotype correlations among these complementation groups exist, considerable clinical overlap exists between them (Copeland et al., 1997). Complementation groups XP-A, XP-C, and XP-D are the most common. Despite the few individuals with XP-B available, cloning of the responsible gene (XPBC) was successful. The XPBC gene is located on chromosome 2q21 and encodes a protein that is a component of the basal transcription factor TFIIH/BTF2. This protein helps regulate both DNA transcription initiation and nucleotide excision repair. Mutations in the XPCC gene, located on chromosome 3p25.1, cause XP-C. Patients with XP-C generally do not have prominent neurological dysfunction. The XPCC gene codes for a protein involved in global genome repair, but full understanding of its exact role is lacking. Complementation group D is the third most common complementation group. Characteristic of the abnormalities are mild to severe neurological dysfunction. The gene associated with XP-D is at chromosome 9q13. The gene product in XP-D is a component of TFFIIH/ BTF2, as is XP-B, and accordingly, XP-B and XP-D have similar clinical features. Complementation group E (XP-E) is uncommon and associated with mild neurological and cutaneous symptoms. The precise localization and function of the XP-E gene of its associated protein, XPEC, has not been determined. No neurological symptoms occur in patients from complementation groups F or G or the variant group.

Related Syndromes De Sanctis-Cacchione syndrome is a variant of XP in which patients have severe and progressive cognitive deficiency, dwarfism, and gonadal hypoplasia. Trichothiodystrophy and similar syndromes link to XP complementation groups B and D. Patients with trichothiodystrophy have brittle hair and nails because of sulfur-deficient matrix proteins, ichthyosis, and intellectual disability. Patients with photosensitivity (P), ichthyosis (I), brittle hair (B), impaired intelligence (I), possibly decreased fertility (D), and short stature (S) fit into the PIBI(D) S syndrome. DNA repair studies of patients with trichothiodystrophy demonstrate reduced ultraviolet-induced DNA repair synthesis, and one patient assigned to XP-D. A variant of trichothiodystrophy is Tay syndrome, in which dysplastic nails and lack of subcutaneous fatty tissue are characteristic. Low birth weight, short stature, and intellectual disability are also features of this disorder. Cockayne syndrome combines cutaneous sunlight sensitivity, dwarfism, intellectual disability, microcephaly, dental caries, peripheral neuropathy, and sensorineural deafness. The combined features of XP and Cockayne syndrome within complementation groups XP-B, XP-D, and XP-G indicate that there is considerable clinical heterogeneity and phenotypical overlap within the subsets of these complementation groups. Trichothiodystrophy may present with congenital ichthyosis (collodion baby) but persistent ichthyosis of the scalp, trunk, palms, and soles is the main feature.

Cutaneous and Ocular Features Cutaneous and ocular features of XP result primarily from ultraviolet light exposure (Box 99.6). The onset of cutaneous symptoms in XP is

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Cutaneous and Ocular Features of Xeroderma Pigmentosum

BOX 99.6

Cutaneous Features Sunlight sensitivity Freckling Atrophy Xerosis and scaling Telangiectasia Actinic keratosis Angioma Keratoacanthoma Fibroma Malignant tumors Basal cell carcinoma Squamous cell carcinoma Melanoma Fibrosarcoma Ocular Features Eyelids Atrophy leading to loss of lashes, ectropion, entropion Neoplasm Conjunctiva Conjunctivitis Inflammatory lesions such as pinguecula Pigmentation, telangiectases, dryness Symblepharon, inflammatory nodules Neoplasm Cornea Exposure keratitis leading to corneal clouding, dryness, ulceration, scarring, and vascularization Neoplasm Iris Iritis, synechiae, atrophy

Treatment

usually early; the median age of onset is 1–2 years, typically freckling or erythema and bullae formation after sun exposure. Nearly half of patients develop malignant skin lesions, with the median age of first skin neoplasm being only 8 years. The estimated incidence of non-melanoma skin cancer under the age of 20 years is 10,000-fold greater than that observed for the general US population (DiGiovanna & Kraemer, 2012). Light-skinned infants develop erythema and bullae after even brief sun exposure. Sun exposure also induces prominent macule formation (freckling or solar lentigenes), which over time enlarge and coalesce. Telangiectasias and epidermal and dermal atrophy develop in later years, and the skin becomes dry. Actinic keratosis, angiomas, keratoacanthomas, and fibromas also occur. Ocular tissues are particularly susceptible to ultraviolet damage. Keratitis and conjunctivitis with photophobia are common in patients with XP. Atrophy of the eyelids leads to loss of lashes and ectropion or entropion. Neoplasms of the eyelid, conjunctiva, and cornea include squamous cell carcinoma, epithelioma and basal cell carcinoma, and melanoma. The tip of the tongue, gingiva, and palate also are susceptible to sun exposure. Most of what is known about the neurological features in XP comes from studies of Japanese patients with XP-A. Research indicates that the severity of neurological symptoms correlates with particular

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mutations within the XPAC gene, and presumably this is true in other types of XP (Maeda et al., 1995). The principal neurological symptoms in XP-A are progressive dementia, sensorineural hearing loss, tremor, choreoathetosis, and ataxia. Progressive dementia begins in patients with XP-A during the preschool years, and IQ scores after 10 years of age are invariably less than 50. Sensorineural hearing loss has a later onset, but most patients older than 10 years have hearing impairment. Cerebellar signs develop at approximately the same time as the hearing loss. Microcephaly is present in about half of patients. EEG studies most often show nonspecific generalized slowing, but focal slow waves and focal spike discharges occasionally occur. Peripheral neuropathy is a prominent feature that may begin in the first decade of life. Deep tendon reflexes are absent in nearly all patients older than 6 years. Motor nerve conduction velocities are normal during the first 3 years of life but slow by 6 years. Similarly, all patients older than 6 years had either absent or prolonged sensory nerve conduction velocities. Electromyography shows a neuropathic pattern with large, prolonged, polyphasic motor unit potentials and incomplete recruitment of motor units. Nerve biopsy may show an age-dependent decrease of myelinated fibers, which was associated with rare acute axonal degeneration, sparse axonal regeneration, rare axonal atrophy, and few onion bulb formations, consistent with a neuropathic process. Neural tissue lacks exposure to sun-induced DNA damage. Therefore, the cause of neurodegeneration in patients with XP remains unexplained. The high frequency of neurological symptoms in XP-B and XP-D but not in XP-C, XP-F, XP-G, and the variant group supports the notion that one cause of the neurological dysfunction in XP is dysfunction of DNA transcription rather than nucleotide excision repair. Deficits in excision repair may closely link to skin cancer susceptibility. In addition, recent work suggests that in XP, the cause of neurological injury is partly defective repair of lesions produced in nerve cells by reactive oxygen species generated as by-products of an active oxidative metabolism. Specifically, two major oxidative DNA lesions, 8-oxoguanine and thymine glycol, are excised from DNA in vitro by the same enzyme system responsible for removing pyrimidine dimers and other bulky DNA adducts.

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Cancer surveillance and avoidance of precipitating factors is the most important aspect of health screening of individuals with XP. There is hope that gene therapy will reduce cancer risk and perhaps improve neurological outcomes. In vitro studies offer hope that, eventually, recombinant retroviruses can transfer and stably express the human DNA repair genes in XP cells to correct defective DNA repair (Zeng et al., 1997). Using the recombinant retroviral vector LXSN, successful transfer of human XP-A, XP-B, and XP-C–complementary DNAs (cDNAs) into primary and immortalized fibroblasts obtained from patients with XP-A, XP-B, and XP-C occurred. After transduction, monitoring of the complete correction of DNA repair deficiency and functional expression of the transgenes included ultraviolet survival, unscheduled DNA synthesis, and recovery of RNA synthesis. In a similar study, XP-FR2 cells expressed a high level of XP-F protein and ERCC1 protein following the cloning of XP-F cDNA into a mammalian expression vector plasmid and introduction into group F XP (XP-F) cells. The XP-FR2 cells expressed a high level of XP-F protein and ERCC1 protein. They showed ultraviolet resistance comparable to that in normal human cells and had normal levels of ultraviolet-induced unscheduled DNA synthesis and normal capability to remove DNA adducts. This demonstrates that the nucleotide excision repair defect in XP-F cells is fully corrected by overexpression of XP-F cDNA alone.

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OTHER NEUROLOGICAL CONDITIONS WITH CUTANEOUS MANIFESTATIONS Many other conditions with cutaneous stigmata also manifest neurological symptoms primarily or secondarily. Fabry disease is an X-linked lysosomal disorder with prominent cutaneous angiokeratoma corporis diffusum, sensory neuropathy, and risk of stroke (see Chapters 68 and 106). A connective tissue disorder known as pseudoxanthoma elasticum demonstrates characteristic skin plaques, and vascular involvement leads to cerebrovascular compromise (see Chapter 65). WyburnMason syndrome (or Bonnet-Dechaume-Blanc syndrome) is a rare sporadic neurocutaneous syndrome characterized by retinal, facial, and intracranial AVMs.

syndromes remains of utmost importance. Regardless of which sign or symptom manifests first, the pathophysiology arising from angiogenic proliferation or loss of tumor suppression function has guided prognosis across multiple body systems. Imaging technology has enabled surveillance of involvement at presymptomatic stages. Significantly, the understanding of affected genes and gene protein function has not only advanced the phenotypic breadth of clinical involvement but also has begun to expand the availability of interventions that might slow or halt progression across multiple systems and syndromes. The complete reference list is available online at https://expertconsult. inkling.com/.

CONCLUSIONS Neurocutaneous syndromes long have been defined on the basis of cutaneous features and neurological involvement guiding diagnosis of a syndrome—and the awareness of clinical features accompanying these

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100 Epilepsies Bassel W. Abou-Khalil, Martin J. Gallagher, Robert L. Macdonald

OUTLINE Seizures and Epilepsy Definitions, 1614 Ictal Phenomenology, 1614 Glossary of Seizure Terminology and Other Definitions, 1614 Classification of Seizures, 1615 Other Seizure Terminology, 1617 Seizure Types, 1618 Focal Seizures (Partial Seizures), 1618 Generalized Seizures, 1622 Classification of Epilepsies and Epileptic Syndromes, 1623 Select Epilepsies, Epileptic Syndromes, and Related Disorders, 1624 Causes and Risk Factors, 1633 Seizure Precipitants, 1636 Epidemiology of Epilepsy and Seizures, 1636 Descriptive Epidemiology, 1636 Epidemiology of the First Unprovoked Seizure, 1636 Morbidity and Mortality, 1636 Morbidity and Comorbidity, 1636 Mortality in Epilepsy, 1637 Pathophysiology and Mechanisms, 1638 Typical Absence Seizures, 1638 Hippocampal Focal-Onset Seizures, 1639 Differential Diagnosis, 1640 Psychogenic Nonepileptic Seizures, 1640 Syncope, 1641 Migraine, 1642 Sleep Disorders, 1642

Paroxysmal Movement Disorders, 1642 Evaluation and Diagnosis, 1642 Evaluation of Recent-Onset Seizures and Epilepsy, 1642 Evaluation of Drug-Resistant Seizures and Epilepsy, 1644 Evaluation of Patients for Epilepsy Surgery, 1645 Medical Therapy, 1649 Initiating Therapy, 1649 Antiseizure Medication Considerations Based on Age and Gender, 1652 Pharmacoresistance, Tolerance, and Seizure Aggravation, 1652 Medication Adverse Effects, 1655 Therapeutic Drug Monitoring, 1655 Discontinuation of Antiseizure Medication Therapy, 1656 Surgical Therapy, 1656 Timing, 1656 Presurgical Evaluation, 1657 Surgical Approaches, 1657 Surgical Results and Predictors of Surgical Freedom, 1658 Other Therapies, 1658 Dietary Therapy, 1659 Vagus Nerve Stimulation, 1659 Other Stimulation Therapies, 1660 Radiosurgery, 1661 Quality-of-Care Standards in the Management of Epilepsy, 1661 Seizure Clusters and Status Epilepticus, 1661

SEIZURES AND EPILEPSY DEFINITIONS

occurring over the next 10 years, or (3) diagnosis of an epilepsy syndrome (Fisher et al., 2014). A variety of seizure types exist, and epilepsy is not a single entity but rather a collection of disorders/diseases that have in common the occurrence of seizures. Hence, a need exists for classification of seizures and of epilepsies and epileptic syndromes. The classification is important for communication and diagnostic purposes, but also for evaluating drug specificity and prescribing the most appropriate therapy. The diagnosis of certain seizure types can predict response to therapy and prognosis. The newest classification has three levels, starting with classification of seizure types (Scheffer et al., 2017). The classification of seizures requires a description of signs and symptoms during a seizure.

Seizures are transient events that include symptoms and/or signs of abnormal excessive hypersynchronous activity in the brain (Fisher et al., 2005). The traditional definition of epilepsy required the occurrence of two unprovoked seizures. It is known that the risk of seizure recurrence after two unprovoked seizures is greater than 60% (Hauser et al., 1998), and treatment would normally be initiated with an antiseizure medication (ASM) in that setting. There are situations where the risk of seizure recurrence after a single seizure is equally high, suggesting an enduring predisposition to have recurrence. Treatment would normally be initiated in these situations, and there was a desire to include this in the definition of epilepsy. In 2014, the International League Against Epilepsy (ILAE) revised the definition of epilepsy as a disease of the brain with (1) at least two unprovoked (or reflex) seizures occurring greater than 24 hours apart, or (2) one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures,

ICTAL PHENOMENOLOGY Glossary of Seizure Terminology and Other Definitions The terms frequently used in the description of seizures follow. Whenever possible, the definition is derived from the glossary of

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CHAPTER 100 Epilepsies descriptive terminology for ictal semiology, reported by the ILAE task force on classification and terminology (Blume et al., 2001). The term ictal semiology means the signs and symptoms associated with seizures. Motor manifestations refer to involvement of the musculature, usually with an increase in muscle contraction that produces a movement. A motor manifestation can also be negative, associated with a decrease in muscle contraction. The term positive motor can be used to specifically indicate an increase in muscle contraction. Several qualifiers for motor manifestation exist. Elementary motor refers to the contraction of a muscle or group of muscles that is usually stereotyped and does not include multiple phases. Elementary motor manifestations include tonic, which means a sustained increase in muscle contraction lasting up to minutes. Tonic activity includes epileptic spasms that are a sudden flexion and/or extension which is more sustained than a myoclonic jerk but yet very short in duration, affecting predominantly proximal or truncal muscles. Postural manifestation suggests tonic activity that results in a posture. This will usually involve contraction of more than one muscle. Versive manifestation indicates a sustained or forced deviation of the eyes or the head to one side (Fig. 100.1). This may be associated with a truncal rotation. Dystonic posturing is a sustained contraction that results in an abnormal posture with a rotating or twisting motion (Fig. 100.2). A myoclonic jerk or myoclonus refers to a very brief involuntary contraction usually lasting less than 100 ms. This can affect any distal or proximal body part and may also be generalized. Negative myoclonus refers to an interruption of tonic muscle activity for less than 500 ms without prior positive contraction. Negative myoclonus may produce a jerk-like motion in association with a transitory loss of posture of that body part. Negative myoclonus would not be visible if the affected body part were resting. Clonic activity refers to a regularly repetitive jerking that is prolonged. Clonic activity is further described as being without a march if it remains confined to the same body part from beginning to end. Clonic activity has a Jacksonian march if it spreads through contiguous body parts on the same side, reflecting horizontal spread of seizure activity over the motor strip. Tonic-clonic activity is a sequence of initial tonic posturing that evolves to a clonic phase. Atonic activity refers to a sudden decrease or loss of muscle tone usually lasting more than 1 second. This can affect the head, trunk, or limbs, usually bilaterally. However, focal atonic activity can also occur. Astatic refers to a loss of erect posture; an astatic seizure is synonymous with a drop attack. Automatisms are repetitive motor activities that are more or less coordinated and resemble a voluntary movement but are not purposeful. Automatisms usually occur in association with altered sensorium, and the individual is usually amnestic to their occurrence. Automatisms may be an inappropriate continuation of previously ongoing activity. This is referred to as perseverative automatisms. Automatisms that start after seizure onset are called de novo automatisms. Automatisms may be reactive—for example, fumbling with an object that was present or newly placed in the patient’s hand. Automatisms can be described by the part of the body affected. Some of the most common are oroalimentary automatisms, which include lip smacking, chewing, swallowing, and other mouth movements (Video 100.1). Ictal spitting and ictal drinking can be considered forms of oroalimentary automatisms. Automatisms affecting the distal extremities are manual or pedal. Manual or pedal automatisms can be bilateral or unilateral. Gestural automatisms include extremity movements such as those used to enhance speech. More recently, introduced categories for upper extremity automatisms are manipulative and nonmanipulative (Kelemen et al., 2010). Manipulative automatisms involve picking and fumbling motions, typically reflecting interaction with the environment (see Video 100.1). Nonmanipulative upper extremity automatisms tend to be rhythmic and do not involve interaction with the environment (Video 100.2). Distal nonmanipulative upper-extremity

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automatisms have been described with the acronym RINCH (rhythmic ictal nonclonic hand) movements (Kuba et al., 2013; Lee et al., 2006; Zaher et al., 2020). Hyperkinetic automatisms imply an inappropriately rapid sequence of movements that predominantly involve axial and proximal limb muscles. The resulting motion can be thrashing, rocking, pelvic thrusting, kicking, or bicycling motions. Seizures with hyperkinetic automatisms are often referred to as hypermotor (Video 100.3). Gelastic refers to abrupt laughter or giggling (Video 100.4), while dacrystic refers to abrupt crying, both inappropriate. Seizures may include a variety of subjective or sensory phenomena. Sensory phenomena are described as elementary if they involve a single primary sensory modality with unformed phenomena. This is applied predominantly to visual or auditory hallucination. Elementary visual phenomena could consist of flickering or flashing lights and other simple patterns such as spots, scotomata, or visual loss. Elementary auditory phenomena include buzzing, ringing, or humming sounds or single tones, but may also be negative, with loss of hearing. Somatosensory phenomena can include tingling and other paresthesias, shock-like sensations, numbness, pain, or a sense of movement or a desire to move a body part. Somatosensory phenomena can remain confined to the same body part or could also have a Jacksonian march, in which case the sensation moves to adjacent body parts on the same side, reflecting spread of the seizure discharge in the sensory cortex. Olfactory hallucinations are most often disagreeable and usually difficult to characterize. A variety of gustatory hallucinations can occur, particularly with a metallic taste. A cephalic sensation is a sensation in the head that can be described variably, including tingling, fullness, pressure, or lightheadedness. The category of experiential phenomena is wide and includes affective experiences such as fear, sadness, elation; dysmnesic phenomena such as feelings of familiarity (déjà vu) or unfamiliarity (jamais vu); and complex hallucination (such as seeing people or hearing music) and illusions (alterations of perception). Dyscognitive describes events in which the predominant feature is alteration of cognition including perception, attention, memory, or executive function. The most recent classification of seizures reorganized experiential phenomena into cognitive category and emotional or affective category (Fisher et al, 2017). Autonomic phenomena are very common in seizures. They may be subjective, including an epigastric sensation, nausea, a feeling of palpitation, or a feeling of flushing, or can be objective, including pupillary dilation, piloerection, pallor or flushing, vomiting, and even flatulence.

CLASSIFICATION OF SEIZURES Two classifications developed by the ILAE were used widely: the Clinical and Electroencephalographic Classification of Epileptic Seizures published in 1981 (Commission on Classification and Terminology of the International League Against Epilepsy, 1981; Box 100.1) and the Classification of Epilepsies and Epileptic Syndromes introduced in 1989 (Commission on Classification and Terminologyof the International League Against Epilepsy 1989; Box 100.2). These classifications were recently revised based on advances made in the last three decades (Fisher et al., 2017; Scheffer et al., 2017). The current chapter uses the newer terminology but offers the corresponding older established terminology. The 1981 classification of seizures has a major dichotomy based on whether seizures start in one part of one hemisphere or in both hemispheres simultaneously. Seizures that start in one part of one hemisphere are classified as partial (or partial-onset) seizures, whereas those that start in both hemispheres simultaneously are classified as generalized (or generalized-onset) seizures. Partial-onset seizures are subclassified as simple partial if there is no impairment of consciousness, complex partial if there is impairment or loss of consciousness at any point in the seizure, and partial seizures evolving to generalized

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Fig. 100.1 Versive eye and head turning in transition to bilateral tonic posturing in a subject with right frontal lobe seizures. Note the associated neck extension.

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Fig. 100.2 Dystonic posturing (DP): variable pattern demonstrated in four patients with temporal lobe epilepsy. Left to right: top, right arm DP, left arm DP; bottom, right arm DP, right arm DP.

tonic-clonic (GTC) convulsions. Simple partial seizures can have motor signs, somatosensory or special sensory symptoms, autonomic symptoms and signs, or psychic symptoms. Under the heading of generalized seizures were included generalized absence (typical or atypical), myoclonic, clonic, tonic, tonic-clonic, and atonic seizures. Acknowledging that some seizures cannot be classified into partial or generalized onset, the classification also includes a category of unclassified seizures. One important criticism of the 1981 classification is that it requires both clinical and electroencephalographic (EEG) information, and assumptions on correlation of clinical and EEG features may be incorrect. A purely semiological classification of epileptic seizures was proposed, based solely on observed clinical features (Luders et al., 1998). The semiological seizure classification includes somatotopic modifiers to define the somatotopic distribution of the manifestations and allows demonstration of evolution of ictal manifestations using arrows to link sequential manifestations (Luders et al., 1998). Although this classification was not adopted by the ILAE, it is considered an optional seizure classification system that is useful for localization purposes in epilepsy surgery centers. The latest ILAE revision of the seizure classification (Figure 100.3) has maintained the division of seizures based on generalized or focal onset but has recommended replacing the term partial with focal (Fisher et al., 2017). The latest revision updated the definition of focal seizures as “originating within networks limited to one hemisphere,” with the possibility of the seizures being discretely localized or more widely distributed, and possibly originating in subcortical structures. Generalized seizures were defined as “originating at some point within, and rapidly engaging, bilaterally distributed networks,” which do not

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necessarily include the entire cortex (Fisher et al., 2017). The revised concepts acknowledge that generalized seizures can be asymmetrical (Fisher et al., 2017). The category of focal-onset seizures underwent major changes. The terms “simple partial” and “complex partial” were abandoned. Level of consciousness during seizures can still be used to classify focal-onset seizures, if it is known, but it is no longer obligatory. The aspect of consciousness chosen for classification is the patient’s awareness during a seizure. Focal seizures are focal aware seizures (FAS) if awareness is totally preserved for the whole duration of the seizure or focal impaired awareness seizures (FIAS) if there is any alteration of awareness during any part of the seizure. Secondarily generalized seizures were renamed focal to bilateral tonic-clonic seizures (FBTCS). The term “generalized” was reserved for seizures that are generalized from onset. Another important level of classification for focal seizures is by the first clinical manifestation at onset. Thus, focal seizures can be classified as motor or nonmotor, or if possible with the specific initial sign or symptom under these headings (Fig. 100.3). As an exception, for a seizure to be classified as behavior arrest seizure, behavior arrest has to be the dominant clinical feature for the whole duration of the seizure. The other major change in the classification is that it allows some classification of unknown onset seizures. The new classification allows some seizure types such as tonic or myoclonic to be focal or generalized. Table 100.1 summarizes some of the key terminology changes between the old and the new classifications.

Other Seizure Terminology Convulsion is an old term typically used to denote a GTC seizure. It may also be used to indicate a seizure with prominent motor

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BOX 100.1

1981 International League Against Epilepsy Classification of Epileptic Seizures

BOX 100.2

I. Partial (Focal, Local) Seizures A. Simple partial seizures (consciousness not impaired) 1. With motor symptoms 2. With somatosensory or special sensory symptoms 3. With autonomic symptoms 4. With psychic symptoms B. Complex partial seizures (with impairment of consciousness) 1. With simple partial onset followed by impairment of consciousness 2. With impairment of consciousness at onset C. Partial seizures evolving to secondarily generalized seizures 1. Simple partial seizures evolving to generalized seizures 2. Complex partial seizures evolving to generalized seizures 3. Simple partial seizures evolving to complex partial seizures evolving to generalized seizures II. Generalized Seizures (Convulsive or Nonconvulsive) A. Absence seizures 1. Typical absence seizures 2. Atypical absence seizures B. Myoclonic seizures C. Clonic seizures D. Tonic seizures E. Tonic-clonic seizures F. Atonic seizures III. Unclassified Epileptic Seizures

1. Localization-related (focal, local, partial) epilepsies and syndromes 1.1. Idiopathic (with age-related onset) 1.2. Symptomatic 1.3. Cryptogenic 2. Generalized epilepsies and syndromes 2.1. Idiopathic (with age-related onset, listed in order of age appearance) 2.2. Cryptogenic or symptomatic (in order of age) 2.3. Symptomatic 2.3.1. Nonspecific etiology 2.3.2. Specific syndromes 3. Epilepsies and syndromes undetermined as to whether they are focal or generalized 3.1. With both generalized and focal seizures 3.2. Without unequivocal generalized or focal features 4. Special syndromes 4.1. Situation-related seizures (Gelegenheitsanfälle) 4.1.1. Febrile convulsions 4.1.2. Isolated seizures or isolated status epilepticus 4.1.3. Seizures occurring only when there is an acute metabolic or toxic event

From Commission on Classification and Terminology of the International League Against Epilepsy, 1981. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 22, 489–501.

activity. Convulsive is an adjective indicating the presence of prominent motor activity such as tonic or clonic or both. Nonconvulsive refers to a seizure or status epilepticus without prominent clonic or tonic motor activity. The term is most commonly used with status epilepticus to indicate that seizure activity is predominantly affecting consciousness or behavior, with minimal or no motor activity. The term grand mal is also an old term that is usually synonymous with GTC seizure. The term is discouraged in scientific writing because it does not specify whether the onset is focal or generalized. Patients may use the term grand mal simply to indicate a big seizure, and the neurologist has to convert this term into official terminology. The term petit mal is an old synonym for childhood absence epilepsy (CAE) but is also used to describe absence seizures. Again, the term is commonly used by patients to indicate a small seizure, which may actually be a focal seizure. A primary generalized seizure or primarily generalized seizure is a synonym for generalized-onset seizure. Primary generalized epilepsy is a synonym for idiopathic generalized epilepsy (IGE). Secondarily generalized seizure is an old term for a focal seizure that evolves to bilateral tonic-clonic activity. This is to be distinguished from secondary generalized epilepsy, which is a synonym of symptomatic generalized epilepsy, an old term for generalized epilepsy of structural/metabolic etiology, where most seizures are usually of generalized onset. The term secondary generalized epilepsy should be discouraged because of confusion with secondarily generalized seizure.

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1989 International League Against Epilepsy Classification of Epilepsies and Epileptic Syndromes

From Commission on Classification and Terminology of the International League Against Epilepsy, 1989. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 30, 389–399.

SEIZURE TYPES Focal Seizures (Partial Seizures) Focal Aware Seizures (Simple Partial Seizures) FAS are seizures in which awareness is not altered at any point in the course of the seizure. FAS of purely subjective nature are often referred to as auras or isolated auras. The manifestations of FAS depend on the brain region involved in the ictal discharge. However, it is important to recognize that the seizure activity may originate in silent areas, and the first clinical manifestations may reflect seizure spread to other brain regions. Nevertheless, FAS and auras may have important lateralizing and localizing value. For example, focal clonic or tonic activity is usually contralateral to the hemisphere involved in seizure activity. Somatosensory auras, visual auras, and auditory auras are often useful in suggesting localization and lateralization of the epileptogenic zone. However, some auras are nonspecific and may be seen with a variety of localizations. Auras are typically short in duration, lasting seconds to minutes. Some patients may experience a prodrome, a difficult-to-describe feeling that a seizure may occur. Prodromes may last hours or even days and have to be distinguished from auras. On the other hand, auras may occasionally be prolonged, in which case they are called aura continua, which is a form of focal nonconvulsive status epilepticus without impairment of consciousness.

Focal Impaired Awareness Seizures (Complex Partial Seizures) FIAS are characterized by altered awareness during the seizure. Impairment may be very subtle, manifesting with slight confusion, fuzziness, or slowing of responses. A patient may have some recollection of events or total amnesia for the event. FIAS may start with an aura or may start with loss of awareness. It is sometimes difficult to determine if awareness was impaired. The patient may be totally

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ILAE 2017 classification of seizure types: basic version Focal onset Aware

Generalized onset

Unknown onset Motor

Motor

Impaired awareness

Tonic-clonic Other motor

Tonic-clonic Other motor

Nonmotor (absence)

Nonmotor

Motor onset nonmotor onset Unclassified

focal to bilateral tonic-clonic

ILAE 2017 classification of seizure types: expanded version Focal onset Aware

Generalized onset

Impaired awareness

Unknown onset Motor

Motor

tonic-clonic epileptic spasms

tonic-clonic clonic tonic myoclonic myoclonic-tonic-clonic myoclonic-atonic atonic epileptic spasms

Motor onset automatisms atonic clonic epileptic spasms hyperkinetic myoclonic tonic

NonMotor behavior arrest

Unclassified

Nonmotor (absence) typical atypical myoclonic eyelid myoclonia

Nonmotor onset autonomic behavior arrest cognitive emotional sensory

focal to bilateral tonic-clonic

Fig. 100.3 The 2017 ILAE Operational Classification of Seizure Types.

TABLE 100.1 Select Terminology in New Versus Old Seizure and Epilepsy Classifications 1981 Terminology

2017 Terminology

Seizure Classification Partial seizure Simple partial seizure Complex partial seizure Secondarily generalized seizure

Focal seizure Focal aware seizure Focal impaired awareness seizure Focal to bilateral tonic-clonic seizure

Epilepsy Classification Localization related epilepsy Idiopathic generalized epilepsy

Cryptogenic epilepsies Symptomatic epilepsies

Benign Epilepsies undetermined as to whether focal or generalized

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Focal epilepsy Idiopathic generalized epilepsy or genetic generalized epilepsy (both terms are acceptable) Epilepsies of unknown cause Structural/metabolic epilepsies secondary to specific structural or metabolic lesions or conditions, but which do not fit a specific electroclinical pattern. Self-limited or pharmacoresponsive (1) Combined generalized and focal (if both seizure categories coexist) or (2) Unknown (if the seizure type cannot be determined) HE @ @AE C

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conscious but unable to respond verbally because of aphasia or unable to respond or react because of motor inhibition. Impaired awareness seizures may arise from any lobe but most commonly arise from the temporal lobe; the frontal lobe is the second most common site of seizure origin. The most common type of motor activity in this seizure type is automatism, described earlier. The different seizure manifestations in seizures arising from different lobes of the brain are discussed in the next section.

Focal to Bilateral Tonic-Clonic Seizures (Partial Seizures Evolving to Generalized Tonic-Clonic Activity) These seizures may start as focal aware or FIAS. The transition to bilateral tonic-clonic activity usually involves versive head turning in a direction contralateral to the hemisphere of seizure onset (see Fig. 100.1), and focal or lateralized tonic or clonic motor activity. The pattern of evolution may be clonic-tonic-clonic in some instances. The bilateral tonic phase may be asymmetrical, with flexion on one side and extension on the other. This has been called figure-of-four posturing (Kotagal et al., 2000; Fig. 100.4). Some asymmetry and asynchrony may also occur in the clonic phase, resulting in a slight degree of sideto-side head jerking (Niaz et al., 1999). The evolution from tonic to clonic activity is gradual and not always simultaneous in all affected body parts. A phase of high-frequency tremor has been referred to as the tremulous or vibratory phase of the seizure (Theodore et al., 1994). Clonic activity typically decreases in frequency over time, with longer

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Fig. 100.4 A, Figure-of-four posturing, usually seen in transition from focal to generalized activity. The sign lateralizes seizure activity contralaterally to the extended upper extremity (left hemisphere on the left, right hemisphere on the right).

intervals between jerks toward the termination of the seizure. The clonic activity may end on one side of the body first so that clonic activity may then appear lateralized to one side. In addition, there may be a late head turn ipsilateral to the hemisphere of seizure origin (Wyllie et al., 1986). After the motor activity stops, the individual is usually limp and has a loud snoring respiration often referred to as stertorous respiration (Video 100.5). During the course of recovery, there may be variable agitation. The speed of recovery is expected to be slower with longer and more severe seizures.

Focal Seizure Semiology in Relation to Localization Focal seizures of temporal lobe origin. Temporal lobe seizures most often are of mesial temporal amygdalohippocampal origin, in association with the pathology of hippocampal sclerosis. Patients commonly have isolated auras, and FIAS tend to start with an aura. The most common aura is an epigastric sensation frequently with a rising character (French et al., 1993). Other auras occur less commonly and include fear, anxiety, and other emotions, déjà vu and jamais vu, nonspecific sensations, and autonomic changes such as palpitation and gooseflesh. Olfactory and gustatory auras are uncommon and are more likely with tumoral mesial temporal lobe epilepsy (MTLE). FIAS may start with an aura or with altered consciousness. With nondominant temporal lobe seizures, the patient may remain responsive and verbally interactive. However, recollection of conversations is unusual. Altered consciousness is often associated with an arrest of motion and speech. Speech arrest is not synonymous with aphasia and does not distinguish dominant and nondominant temporal lobe seizures. Automatisms are one of the most prominent manifestations, and oroalimentary automatisms are the most prevalent. Extremity automatisms also occur and are most commonly manipulative, with picking or fumbling (see Video 100.1). This type of automatism is not of direct lateralizing value. However, the contralateral upper extremity is commonly involved in dystonic posturing (Kotagal et al., 1989) or milder degrees of posturing and immobility (Fakhoury and AbouKhalil, 1995; Williamson et al., 1998). This reduces the availability of the contralateral arm for automatisms, so manipulative automatisms tend to be ipsilateral, involving the unaffected upper extremity. F ECF

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Nonmanipulative automatisms typically consist of rhythmic movements either distally or proximally. These tend to be contralateral, often preceding overt dystonic posturing (Kuba et al., 2013; Lee et al., 2006; Zaher et al., 2020). Head turning occurs commonly. Early head turning is not usually forceful. It typically occurs at the same time as dystonic posturing and is most often ipsilateral (Fakhoury and Abou-Khalil, 1995; Williamson et al., 1998). Late head turning most often occurs during evolution to bilateral tonic-clonic activity (see Video 100.5). This is usually contralateral to the side of seizure origin (Williamson et al., 1998). Well-formed ictal speech may occur during seizures of nondominant temporal lobe origin (Gabr et al., 1989). Verbal output may at times be tinged with a fearful tone. FIAS of temporal lobe origin usually last between 30 seconds and 3 minutes. Postictal manifestations may be helpful in lateralizing the seizure onset. Postictal aphasia is commonly seen after dominant temporal lobe seizures (Gabr et al., 1989). In one study, patients with dominant left temporal seizure origin were unable to read a test sentence correctly in the first minute after seizure termination, but patients with nondominant right temporal lobe origin were able to read the test sentence within 1 minute of seizure termination (Privitera et al., 1991). Seizures of lateral temporal origin or neocortical temporal origin are much less common than those of mesial temporal origin. They cannot be reliably distinguished based on their semiology, but certain features suggest lateral temporal origin. Auditory auras are the most common auras referable to the lateral temporal cortex, usually implying involvement of the Heschl gyrus. Other types of auras referable to the lateral temporal cortex are vertigo and complex visual hallucinations (usually posterior temporal). Oroalimentary automatisms are less common, and the pattern of contralateral dystonic posturing and ipsilateral extremity automatisms is also less common (Dupont et al., 1999). Early contralateral or bilateral facial twitching may be seen as a result of propagation to the frontal operculum (Foldvary et al., 1997). Seizures of lateral temporal origin tend to be shorter in duration and have a greater tendency to evolve to bilateral tonic-clonic activity than seizures of mesial temporal origin. Seizures originating in the temporal lobe may have hypermotor semiology characteristic of frontal lobe origin, due to propagation to the frontal lobe (Vaugier et al., 2009; Yu et al., 2013). This is commonly seen with seizure origin in the temporal pole (Wang et al., 2008). 02 .4.(1( 4 (

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Focal seizures of frontal lobe origin. Many different seizure types can originate in the frontal lobe, depending on site of seizure origin and propagation. FAS can be motor with focal clonic activity, can originate in the motor cortex, or can be the result of spread to the motor cortex. These seizures may or may not have a Jacksonian march. Asymmetrical tonic seizures or postural seizures are usually related to involvement of the supplementary motor area in the mesial frontal cortex anterior to the motor strip. The best-known posturing pattern is the fencing posture in which the contralateral arm is extended and the ipsilateral arm is flexed. Tonic posturing may involve all four extremities and is occasionally symmetrical. When these seizures originate in the supplementary motor area, consciousness is usually preserved (Morris et al., 1988). Supplementary motor seizures are an important exception to the rule that bilateral motor activity during a seizure should be associated with loss of consciousness. Supplementary motor seizures are usually short in duration and frequently arise out of sleep. They tend to occur in clusters and may be preceded by a sensory aura referable to the supplementary sensory cortex. The pattern of posturing described with supplementary motor area seizures can occur as a result of seizure spread to the supplementary motor area from other regions of the brain. In that case, consciousness is frequently impaired. Subjective FAS may also occur with frontal lobe origin, the most common being a nonspecific cephalic aura. FIAS of frontal lobe origin tend to be very peculiar. They may be preceded by a nonspecific aura (most commonly cephalic) or they may start abruptly, often out of sleep. Their most characteristic features are hyperkinetic automatisms with frenzied behavior and agitation (Jobst et al., 2000; Williamson et al., 1985). These are often referred to as hypermotor seizures. There may be various vocalizations including expletives. The manifestations can be so bizarre as to suggest a psychiatric origin (Video 100.6). The seizure duration is short, often less than 30 seconds, and postictal manifestations are brief or nonexistent, further adding to the risk of misdiagnosis as psychogenic seizures. Frontal lobe FIAS arise predominantly from the orbitofrontal region and from the mesial frontal cingulate region. However, they can arise from other parts of the frontal lobe. It may be difficult to determine the region of origin in the frontal lobe based on the seizure manifestations. It has been suggested that the presence of tonic posturing on one side points to a mesial frontal origin, as does rotation along the body axis, which sometimes leads to turning prone during the seizure (Leung et al., 2008; Rheims et al., 2008). Ictal pouting, also known as “chapeau de gendarme,” tends to arise in the anterior cingulate region (Souirti et al., 2014). Seizures originating in the frontal operculum are associated with profuse salivation, oral facial apraxia, and sometimes facial clonic activity (Williamson and Engel, 2008). Seizures originating in the dorsolateral frontal lobe may involve tonic movements of the extremities and versive deviation of the eyes and head. The head deviation preceding evolution to bilateral tonic-clonic activity is contralateral, but earlier head turning can be in either direction (Remi et al., 2011). Seizures may begin with forced thinking. Focal seizures of frontal origin may at times resemble absence seizures (So, 1998). It is important to recognize that seizures originating in the frontal lobe can propagate to the temporal lobe and produce manifestations typical of mesial temporal lobe seizures. Focal seizures originating in the parietal lobe. The bestrecognized seizure type that originates in the parietal lobe is focal seizure with somatosensory manifestations. The somatosensory experience can be described as tingling, pins and needles, numbness, burning, or pain. The presence of a sensory march is most suggestive of involvement of the primary sensory cortex. Sensory phenomena arising from the second sensory area and the supplementary sensory

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area are less likely to have a march. Somatosensory auras tend to be contralateral to the hemisphere of seizure origin, but they may be bilateral or ipsilateral when arising from the second or supplementary sensory regions. Other auras of parietal lobe origin are a sensation of movement in an extremity, a feeling of the body bending forward or swaying or twisting or turning, or even a feeling of an extremity being absent (Salanova et al., 1995a, 1995b). Some patients may complain of inability to move a limb. Vertigo has been reported, as well as visual illusions of objects going away or coming closer or looking larger (Siegel, 2003). Some patients may have initial auras suggesting spread to the occipital or temporal lobe. Seizures involving the dominant parietal lobe may produce aphasic manifestations. Motor manifestations tend to reflect seizure spread to the frontal lobe. These include tonic posturing of the extremities, focal motor clonic activity, and version of the head and eyes (Cascino et al., 1993; Ho et al., 1994; Williamson et al., 1992a). Negative motor manifestations may occur, with ictal paralysis (Abou-Khalil et al., 1995). Seizures may spread to the temporal lobe, producing oroalimentary or extremity automatisms (Siegel, 2003). In one study, motor manifestations were more likely with superior parietal epileptogenic foci, and oroalimentary and extremity automatisms more likely with inferior parietal epileptogenic foci (Salanova et al., 1995a). Visual manifestations seemed more likely with posterior parietal lesions. Focal seizures originating in the occipital lobe. The bestrecognized occipital lobe seizure semiology is that of FAS with visual manifestations (Salanova et al., 1992). The most common are elementary visual hallucinations that are described as flashing colored lights or geometrical figures. These are usually contralateral but may move within the visual field. Complex visual hallucinations with familiar faces or people may also occur. Negative symptoms may be reported, with loss of vision in one hemifield. Ictal blindness may occur, with loss of vision in the whole visual field. Objective seizure manifestations include blinking, nystagmoid eye movements, and versive eye and head deviation contralateral to the seizure focus. This version may occur while the patient is still conscious or could be a component of impaired awareness seizures. Seizure manifestations that are related to seizure spread to the temporal or frontal lobe are very common. Oroalimentary automatisms are typical of seizures that spread to the temporal lobe, whereas asymmetrical tonic posturing typifies spread to the frontal lobe; both types of spread can be seen in the same patient (Williamson et al., 1992b). Spread to the temporal or frontal lobe is so common with occipital lobe seizures that it is at times reported in most patients (Jobst et al., 2010b). Ictal semiology cannot distinguish seizures originating from the mesial versus lateral occipital region (Blume et al., 2005). Evolution of occipital seizures to bilateral tonic-clonic activity is commonly reported.

Focal Seizures Originating in the Insular Cortex Insular epilepsy is uncommon and frequently unrecognized because of the inability to record directly from the insula with scalp electrodes. Subjective symptoms that should suggest seizure origin in the insula include laryngeal discomfort, possibly preceded or followed by a sensation in the chest or abdomen, shortness of breath, and paresthesias around the mouth or also involving other contralateral body parts (Isnard et al., 2004). Objective seizure manifestations include dysarthria/dysphonia, sometimes evolving to complete muteness. With seizure progression in some patients, tonic spasm of the face and upper limb, head and eye rotation, and at times generalized dystonia occur (Isnard et al., 2004). Hypersalivation is also very common and can be impressive. Insular-onset seizures may spread to other brain regions and can be disguised as temporal lobe, parietal lobe, or frontal lobe epilepsy (Jobst et al., 2019; Ryvlin, 2006; Ryvlin et al., 2006).

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Generalized Seizures

Generalized Absence Seizures Typical absence seizures are characterized by a sudden blank stare with motor arrest, usually lasting less than 15 seconds (Commission on Classification and Terminology of the International League Against Epilepsy, 1981). The individual is usually unresponsive and unaware. The seizure ends as abruptly as it starts, and the patient returns immediately to a baseline level of function with no postictal confusion but may have missed conversation and seems confused as a result (Video 100.7). If the only manifestation is altered responsiveness and awareness, with no associated motor component, the absence seizure is classified as simple absence. Most often, generalized absence seizures include mild motor components and are classified as complex absence. The most common motor components are automatisms such as licking the lips or playing with an object that was held in the hand before the seizure. Other motor components include clonic, tonic, atonic, and autonomic manifestations. Clonic activity may affect the eyelids or the mouth. An atonic component may manifest with dropping an object or slight head drop or drooping of the shoulders or trunk. Tonic components may manifest with slight increase in tone. The EEG hallmark of a typical generalized absence seizure is generalized 2.5- to 4-Hz spike-and-wave activity with a normal interictal background (Fig. 100.5). Atypical absence seizures are diagnosed primarily based on a slower (0.5 cm retroposition of gnathion relative to nasion

Dental occlusion

Anatomy and measurements Fig. 101.49 Anatomy and Surface Measurements in the Assessment of a Patient with Suspected Obstructive Sleep Apnea. Retrognathia, overjet, and reduced cricomental space are key craniofacial properties that are predictive of obstructive sleep apnea. (From Myers, K.A., Mrkobrada, M., Simel, D.L., 2013. Does this patient have obstructive sleep apnea? The rational clinical examination systematic review. JAMA 310, 731−741.)

insomnia as summarized in Fig. 101.51. (Gaspar et al., 2017; Banno and Kryger, 2007; Cordero-Guevara et al., 2011; Flemons, 2002; Kendzerska et al., 2014; Kohler et al., 2013; Korson and Guilleminault, 2015; Marin et al., 2005; Redline et al., 2010; Somers et al., 2008; Vlachantoni et al., 2013; Zamarion et al., 2013). Several prospective longitudinal studies (Nieto et al., 2000; Peppard et al., 2000; Young et al., 1997) have shown a clear association between OSAS and systemic hypertension, which may be noted in approximately 50% of patients with OSAS. The factors that cause hypertension in OSAS include repeated hypoxemias during sleep at night causing an increased sympathetic activity. OSAS is frequently noted in about 30% of cases of essential hypertension. Several studies have shown improvement of hypertension or reduction of need for antihypertensive medications after effective treatment of OSAS with CPAP titration (Banno and Kryger, 2007; Faccenda et al., 2001; Hla et al., 2002; Kendzerska et al., 2014; Kohler et al., 2013; Pepperell et al., 2002; Vlachantoni et al., 2013; Zamarion et al., 2013). Pulmonary hypertension is also noted in approximately 15%–20% of cases. Cardiac arrhythmias in the form of premature ventricular contractions, ventricular tachycardia, sinus pauses, and third-degree heart block as well as sudden

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cardiac death have been attributed to OSAS. Heart failure, mostly systolic heart failure but also diastolic heart failure (in which the studies are limited), is associated with both obstructive and CSAs, but more CSAs, including Cheyne-Stokes breathing, than obstructive apneas (Arias et al., 2007; Javaheri, 2006; Javaheri and Somers, 2011; Kendzerska et al., 2014; Levy et al., 2013; McNicholas et al., 2007; Randerath and Javaheri, 2015; Somers et al., 2008). The presence of central apnea, including Cheyne-Stokes breathing, increases the mortality in patients with heart failure. Cognitive dysfunction, which is noted in moderately severe to severe OSAS patients (Lim and Pack, 2014), shows improvement after satisfactory treatment with CPAP titration (Atwood and Strollo, 2015). Recently awareness about the presence of depression and insomnia in patients with OSAS has grown, but adequate studies have not been conducted to find the prevalence and impact of these conditions on OSAS (Glidewell, 2013). There has been an increased association between OSAS and impaired quality of life, metabolic syndrome, hypertension, increased risk for metabolic disease, (increased insulin resistance with type 2 diabetes, hypertriglyceridemia, and obesity), depression, cognitive decline, drowsy driving and motor vehicle accidents, and cognitive

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(Modified Mallapati)

Position II

Position I

Allows visualization of the entire uvula and tonsils/pillars

Allows visualization of the uvula but not the tonsils

Position III

Allows visualization of the soft palate but not the uvula

Position IV

Allows visualization of the hard palate only

Grade 1

Grade 2

Grade 3

Grade 4

Within tonsillar fauces

Outside tonsillar fauces, up to 50% of airway to midline

Outside tonsillar fauces, up to 75% of the distance to the midline

Outside tonsillar fauces, > 75% of the lateral airway dimension

Fig. 101.50 New Sleep Medicine Examination. A, The Modified Mallampati classification describes tongue size relative to oropharyngeal size. The test is conducted with the patient in the sitting position, the head held in a natural position, the mouth wide open and relaxed and with the tongue inside the mouth without any protrusion or phonation. The subsequent classification is assigned based upon the pharyngeal structures that are visible. Class I = visualization of the soft palate, fauces, uvula, anterior and posterior pillars. Class II = visualization of the soft palate, fauces, and uvula. Class III = visualization of the soft palate and the base of the uvula. Class IV = soft palate is not visible at all. If the patient phonates, this falsely improves the view. If the patient arches his or her tongue, the uvula is falsely obscured. The test was initially adapted to predict ease of intubation but can be used to predict the potential severity of obstructive sleep apnea. B, Clinical of tonsillar size is based on the following scheme. Grade 1: within tonsillar fauces; Grade 2: outside tonsillar fauces, up to 50% of the airway to the midline; Grade 3: outside tonsillar fauces and up to 75% of the distance to the midline; and Grade 4: >75% of the lateral airway dimension. (Modified from Mallampati, S.R., Gatt, S.P., Gugino, L.D., et al., 1985. A clinical sign to predict difficult tracheal intubation: a prospective study. Can. Anaesth. Soc. J. 32, 429–434.) F ECF

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decline. The mechanisms accounting for OSA include hypoxia, sleep fragmentation, and systemic inflammation (Dumortier and Bricout, 2019; Walia, 2019). (a combination of) (Oyama et al., 2012; Sharma et al., 2011; Zamarion et al., 2013). However, CPAP treatment did not significantly improve glycemia control or insulin resistance in patients with type 2 diabetes and OSAS. Recent studies have also shown an association of OSAS to an increased risk of cancer and cancer mortality (Martinez-Garcia et al., 2014).

Pathogenesis of Obstructive Sleep Apnea Syndrome The factors contributing to the pathogenesis of OSAS include local anatomical, neurological, and vascular factors as well as familial predisposition (Banno and Kryger, 2007; Dempsey et al., 2010; Joosten et al., 2014; Korson and Guilleminault, 2015). Collapse of the pharyngeal airway is the fundamental factor in OSA. During sleep, muscle tone decreases, including that of the upper airway dilator muscles, which maintain upper airway patency. As a result of this decreased tone, these muscles relax, causing increased upper airway resistance and narrowing of the upper airway space. Defective upper airway reflexes may also play a role. Increasing familial occurrence of OSAS in some patients may be related to abnormal craniofacial features. In children, adenotonsillar enlargement and craniofacial dysostosis causing narrow upper airway space are important factors. Neurological factors include reduced medullary respiratory neuronal output and ventilatory control instability which may create excessive response to respiratory muscles (high loop gain) promoting upper airway collapse and obstruction in susceptible individuals. Other neurological factors include autonomic activation during sleep-related breathing events, contributing toward development of hypertension and cardiac arrhythmias. Vascular factors contributing to the pathogenesis and long-term adverse consequences (Banno and Kryger, 2007; Javaheri and Somers, 2011) include increased endothelin 1 (a vasoconstrictor), reduced nitric oxide (a known vasodilator), and increased serum levels of vascular endothelial growth factor (glycoprotein responsible for vascular remodeling and atherosclerosis). It has been shown that after effective CPAP titration, these vascular abnormalities are reversed. Thus, a complex interaction of peripheral upper airway anatomical, central neural, vascular, and genetic factors contributes to the syndrome of upper airway OSAS.

Upper Airway Resistance Syndrome Additional text and eFig. 101.34 are available at http://expertconsult. inkling.com. Central sleep apnea syndrome. Additional text is available at http://expertconsult.inkling.com.

Central Sleep Apnea Syndrome CSAS includes primary CSA, CSA with Cheyne-Stokes breathing, CSA due to high altitude periodic breathing, CSA due to a medical disorder without Cheyne-Stokes breathing, CSA due to drug or substance abuse (e.g., use of opiates) (Javaheri and Randerath, 2014), primary CSA of infancy, primary CSA of prematurity, and treatment emergent CSA (ICSD-III; AASM, 2014). Primary CSAS is rare, and the patient may present with EDS and frequent awakenings due to repeated episodes of central apnea followed by arousals. The patient may also present with insomnia. Cheyne-Stokes breathing as previously highlighted in Fig. 101.44 noted in patients with congestive heart failure (Javaheri, 2006; Javaheri and Somers, 2011; Javaheri and Dempsey, 2013) and sometimes in renal failure. The presence of Cheyne-Stokes breathing in cardiac failure increases mortality. Patients with primary CSA usually are normocapnic or hypocapnic, with Paco2 of 40 mm Hg or lower. The other important point of differentiation is that the cycle length (apnea

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plus ventilatory duration) is more than 45 seconds in Cheyne-Stokes breathing and less than 45 seconds in primary CSA.

Restless Legs Syndrome Clinical Manifestations

RLS is the most common movement disorder but is uncommonly recognized and treated despite a lucid description of the entity in the middle of the last century (Hening et al., 2009; Wijemanne and Jankovic, 2015). Diagnosis is based on clinical grounds and is based on the International Restless Legs Syndrome Study Group (IRLSSG) criteria first established in 1995 (Walters, 1995) and modified slightly in 2003 (Allen et al., 2003), and modified again in 2012 (Allen et al., 2014). These criteria include five essential diagnostic criteria (Box 101.17). In addition, there are supportive clinical features as well as specifiers for clinical significance and clinical course of RLS (Box 101.18). The IRLSSG diagnostic criteria are consensus criteria established by the international experts in RLS after careful deliberation. It is notable that these differ from the AASM (2014) and the Diagnostic and Statistical Manual (DSM-V) diagnostic criteria. The AASM criteria must include the specifier for clinical significance (see Box 101.18), whereas DSM-V (2013) criteria require a frequency of at least three times a week and a duration of at least 3 months for symptoms. This division into three different requirements amongst three groups of physicians is unfortunate but it is hoped that in future these three groups would merge the criteria into uniform and consistent diagnostic criteria to avoid confusion among physicians in different specialties (Video 101.5). RLS is a lifelong sensory-motor neurological disorder (Earley, 2003; Patel et al., 2014) that often begins at a very young age but is mostly diagnosed in the middle or later years. Prevalence of RLS increases with age and plateaus for some unknown reason around age 85 to 90 (Allen et al., 2001; Earley, 2003; Earley et al., 2011). All five essential diagnostic criteria (see Box 101.17) are needed for establishing the diagnosis. The overall prevalence of RLS has been estimated at about 7.2% for all adult populations when severity was not considered, but at 2.7% for moderate to severe cases, particularly those in North American and European populations (Allen et al., 2005; Chokroverty, 2014). The prevalence appears to be much less in some surveys from Asia (32% of 3s REM mini-epochs having any chin or phasic FDS activity

Meets video criteria for RBD in the context of α-synucleinopathy

>32% of 3s REM mini-epochs having any chin or phasic FDS activity in the context of α-synucleinopathy

EMG

Nature Reviews | Neurology Fig. 101.66 The New Concept of Prodromal Rapid Eye Movement Sleep Behavior Disorder. Neurophysiological and behavioral findings on polysomnography and signature EMG (electromyography) findings of augmented tone probably represent the earliest sign of an emergent α-synucleinopathy which progress along a continuum over time. From initially normal findings, patients enter a prodromal stage of rapid eye movement (REM) sleep behavior disorder (RBD) that progresses into isolated RBD, and eventually into RBD with overt α-synucleinopathy. FDS, Flexor digitorum superficialis; RBEs, REM sleep behavioral events. (From Högl, B., Stefani, A., Videnović, A., 2018. Idiopathic REM sleep behaviour disorder and neurodegeneration—an update. Nat. Rev. Neurol. 14, 40–55.)

Kaplan-Meier curve for RBD conversion rates

Survival probability

1.00

0.75

0.50

0.25

0.00

Log-rank p < 0.0001 5

0

10

15

Time Disease type PD MSA DLB MCI Dementia AD Other Fig. 101.67 Rates of neurological-disease-free-survival according to the time of iRBD diagnosis in a sample of 174 patients from Spain utilizing Kaplan-Meier analysis. There is a “dose response” relationship between the years since documenting RBD episodes to phenoconversion to a neurodegenerative disease in the following relationship: 5 years -> 33%, 10 years -> 76%, 14 years -> 91%. Emerging diagnoses were dementia with Lewy bodies (DLB), Parkinson disease (PD), multiple system atrophy (MSA), and mild cognitive impairment (MCI). (From Iranzo, A., Fernández-Arcos, A., Tolosa, E., et al., 2014. Neurodegenerative disorder risk in idiopathic REM sleep behavior disorder: study in 174 Patients. PLoS ONE 9 [2], e89741.)

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PATHOPHYSIOLOGY OF REM SLEEP BEHAVIOR DISORDER Pedunculopontine centers Perilocus coeruleus Stimulation Inhibition Lateral tegmentoreticular tract

Medullary centers Magnocellularis neurons

RBD Lack of pontine-mediated medullar inhibition of spinal motor neurons

Spinal cord Ventrolateral reticulospinal tract

Lack of medullary-mediated spinal motor neuron inhibition

Spinal motor neuron

Skeletal muscle

Lack of REM atonia

REM-associated atonia

Fig. 101.68 The normally generalized muscle atonia during rapid eye movement (REM) sleep results from pontine-mediated peri-locus coeruleus inhibition of motor activity. This pontine activity exerts an excitatory influence on medullary centers (magnocellularis neurons) via the lateral tegmentoreticular tract. These neuronal groups in turn hyperpolarize the spinal motor neuron postsynaptic membranes via the ventrolateral reticulospinal tract. In REM sleep behavior disorder (RBD), the brainstem mechanisms generating the muscle atonia normally seen in REM sleep may be disrupted. The pathophysiology of RBD in humans is based on the cat model. In the cat model, bilateral pontine lesions result in a persistent absence of REM atonia associated with prominent motor activity during REM sleep, similar to that observed in RBD in humans. The pathophysiology of the idiopathic form of RBD in humans is still not very well understood but may be related to reduction of striatal presynaptic dopamine transporters. (Modified with permission from Avidan, A.Y., 2005. Sleep disorders in the older patient, In: Lee-Choing, T. [Guest Ed.], Primary Care: Clinics in Office Practice, vol. 32, Sleep Medicine. Elsevier, St. Louis, pp. 563–586.)

would be ready to enroll patients for treatments trials in the hope of delaying/preventing neurodegenerative diseases before the condition is irreversible (https://www.naps-rbd.org/ https://clinicaltrials.gov/ct2/ show/NCT03623672 Vvidenovic A, Ju Y-eS, Arnulf i, et al. J Neurol Neurosurg Psychiatry 2020;91:740–749.).

Nightmares (Dream Anxiety Attacks) Nightmares are fearful, vivid, often frightening dreams, mostly visual but sometimes auditory, and seen during REM sleep. Nightmares may accompany sleep talking and body movements. These most commonly occur during the middle to late part of sleep at night. Nightmares are mostly a normal phenomenon. Up to 50% of children, perhaps even more, have nightmares beginning at age 3–5 years. The incidence of nightmares continues to decrease as the child grows older, and elderly individuals have very few or no nightmares. Very frightening and recurring nightmares (e.g., one or more per week) are not common and may

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occur in a very small percentage (1 g/day for 6 months (ten Hove et al., 2016). This trial has also provided support for the safe use of acetazolamide up to 4 g daily with weight loss for effective treatment of mild vision loss in IIH, with associated improvements in papilledema, increased ICP, and quality of life (Smith and Friedman, 2017). Other diuretics and topiramate are used in patients who cannot take acetazolamide, although these have not been studied in controlled fashion. The amount of weight loss required for IIH to remit is not known, but up to 15% of weight loss has been reported (Mollan et al., 2018). An ophthalmologist should follow patients together with the neurologist to properly monitor vision. Headache is usually managed according to its phenotype (e.g., migraine or tension-type), when present. Patients who have significant visual field loss at presentation and those that have progressive visual field loss and/or progressive worsening of visual acuity despite medical management may require surgical intervention, traditionally CSF shunting or optic nerve sheath fenestration. Cerebral venous sinus stenting has been reported to improve symptoms of intracranial hypertension. The role of neurovascular

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stenting in IIH, however, has not yet been established. Stenting may be useful for highly selected IIH patients with venous sinus stenosis with an elevated pressure gradient in whom traditional therapies have not been effective (Mollan et al., 2018). Of note, headaches sometimes persist even after proper management of IIH. In the IIHTT, 41% of patients reported a prior history of migraine (Wall et al., 2014). In addition, 37% of headache sufferers at baseline were overusing symptomatic headache medications (Friedman et al., 2017). Possibly, in some cases, persistent headaches may occur on the basis of other processes (e.g., migraine with or without medication overuse headache) different from intracranial hypertension.

Headache Attributed to Low Cerebrospinal Fluid Pressure The headache of low CSF pressure/volume from spinal CSF leaks is characteristically orthostatic, developing or worsening when a person is upright and resolving or significantly improving with recumbency. It most commonly occurs after a LP via loss of CSF volume due to the removal of CSF for diagnostic purposes, and/or continued leakage of CSF through the hole in the arachnoid and dural layers left by the LP needle. Loss of CSF can result in brain sagging and traction on pain-sensitive structures such as bridging veins and sensory nerves. Recumbency removes the effect of gravity, and the traction headache is relieved. The headache that occurs after a spinal tap usually resolves spontaneously within a few days. Spontaneous recovery is estimated to occur in 24% of patients within the first 2 days, an additional 29% of patients within 3–4 days, and an additional 19% within 5–7 days (Turnbull and Shepherd, 2003). The healing process might be hastened when the patient has relative bed rest and good hydration. When these conservative measures fail, relief can usually be obtained by the application of an epidural blood patch. An epidural blood patch consists of approximately 20 mL of the patient’s own venous blood being injected into the epidural space close to the site of the original LP. The resulting compression of the thecal sac and the presumed elevation of subarachnoid pressure presumably explains the resulting headache resolution. The increased pressure resulting from the epidural blood patch presumably causes temporary cessation of the CSF leak, thereby allowing the dura and arachnoid to heal. The success rate of a single epidural blood patch is estimated between 70% and 98% (Turnbull and Shepherd, 2003). Similar low-CSF pressure/volume headaches can occur when a spinal leak spontaneously develops, a condition still often referred to as “spontaneous intracranial hypotension” by some. Although indeed a significant number of patients with this condition have low (sometimes negative) CSF opening pressure when measured via LP, most have normal pressures (Kranz et al., 2016b). Because low CSF volume may better explain the low pressure, headache, and neuroimaging findings seen in spontaneous spinal CSF leaks, “CSF hypovolemia” has been proposed as an alternative term (Mokri, 1999). Skull-based CSF leaks, however, rarely if ever present with the classic syndrome in the setting of spontaneous spinal CSF leaks (Schievink et al., 2012). The remaining discussion pertains to “headaches secondary to spontaneous spinal CSF leaks (SSCSFL),” the authors’ preferred term for this syndrome. Spontaneous spinal CSF leaks are most commonly located in the thoracic or cervico-thoracic regions. Three main types have been identified in observational studies: the dural tear, the meningeal diverticulum, and the CSF-venous fistula (Schievink et al., 2016). Although a precipitating event for symptoms is often absent or uncertain, many patients with SSCSFL recall having a very minor injury, coughing, sneezing, or performing a Valsalva maneuver just prior to onset of

Fig. 102.1 Axial T1-weighted magnetic resonance image with gadolinium in a patient with a spontaneous spinal cerebrospinal fluid leak and orthostatic headache demonstrates diffuse pachymeningeal thickening and enhancement.

Fig. 102.2 Coronal T1-weighted magnetic resonance image with gadolinium of a patient with orthostatic headache secondary to a SSCSFL demonstrates subdural fluid collections and pachymeningeal enhancement.

symptoms. Most commonly headache is orthostatic, but not infrequently can be purely precipitated by Valsalva-like maneuvers (e.g., coughing, sneezing, laughing) or present as a combination of these two. A large series of SSCSFL specifically secondary to CSF-venous fistula reported an even greater percentage of patients experienced Valsalva-induced headache exacerbation or precipitation compared to orthostatic headache, features that should raise suspicion for occult CSF-venous fistula (Duvall et al., 2019). Occasionally, headaches secondary to SSCSFL are preceded by a single “thunderclap headache.” Other common symptoms of SSCSFL include auditory muffling, tinnitus, nausea and vomiting, and neck pain. Patients who have had the condition for a prolonged time can lose the orthostatic component

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eFig. 102.3 Sagittal T1-weighted magnetic resonance image demonstrates brain descent made evident by low cerebellar tonsils, crowding of the posterior fossa, small prepontine cistern, and inferior displacement of the optic chiasm in a patient with a SSCSFL.

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to their headache. Such patients might have constant headaches or so-called “end-of-the-day” headaches (headache starting late in the day and getting worse as the day goes on). As additional cases have been reported in the literature, the clinical picture of CSF leaks has been found to take many forms (Mokri, 2004). When a SSCSFL is suspected, the initial diagnostic test is brain MRI with gadolinium. MRI findings supportive of a diagnosis of SSCSFL include diffuse pachymeningeal gadolinium enhancement, brain sagging (i.e., cerebral and cerebellar tonsillar descent, inferior displacement of the optic chiasm), flattening of the anterior aspect of the pons, and venous dilation (Figs. 102.1 and 102.2; eFig. 102.3). While an “acquired Chiari” from brain sagging can commonly be distinguished fairly easily from a congenital Chiari I malformation, sometimes this can be challenging. Subdural fluid collections (subdural hygromas and subdural hematomas) might occur in up to 50% of patients with SSCSFL (Schievink et al., 2005). The patient with classical symptoms of SSCSFL and classical brain MRI findings of the disorder might not need additional diagnostic tests prior to treatment with conservative measures or epidural blood patch. However, increasing symptom duration associates with decreased prevalence of abnormal dural enhancement; brain MRI can be normal in 20%–30% of cases (Kranz et al., 2016a). When the diagnosis is uncertain a complete spine MRI and/or radioisotope cisternography (RICG) may help establish the presence of a SSCSFL although they rarely localize the exact leak site. Spine MRI findings suggestive of CSF leak include dural enhancement, dilated epidural veins, epidural venous plexus engorgement, and/or epidural fluid collections. Large longitudinal epidural fluid collections often suggest the presence of a high flow or “fast” SSCSFL. On RICG, delayed radioactive tracer ascent to cerebral convexities and/or early isotope tracer appearance in the urinary bladder are findings suggestive of CSF leak. Although measurement of opening pressure via LP can aid diagnosis if low opening pressure is found, LP should be avoided when possible due to the risk of worsening symptoms following the procedure. Importantly, a normal CSF opening pressure does not rule out a spontaneous CSF leak. If RICG is pursued, however, we typically measure opening pressure during the LP part of the procedure. In patients with the typical clinical and radiographic features of SSCSFL, treatment may be conservative with bed rest and hydration for 1–2 weeks. If this is either impractical or ineffective, treatment with an epidural blood patch is warranted. If the CSF leak site is suspected, a “targeted” patch can be attempted close to the suspected leak site, but the patch is often done “blindly” in the lumbar spine when no clear leak site is known or suspected. Although epidural blood patches are effective in a substantial number of patients, many require more than one blood patch, and some require as many as four to six blood patches (Mokri, 2004) with 1–2 months between individual attempts. Patients with SSCSFL who fail to respond to conservative measures are best investigated with myelography, the most effective study at present to identify the precise spinal CSF leak site. Myelography can also be pursued even prior to attempting epidural blood patching in patients with SSCSFL when a more precise diagnosis and a more definitive treatment plan are desired. Conventional computed tomography (CT) myelography is often the first modality used. Dynamic CT myelography is an alternative modality, particularly helpful to localize high-flow leaks. Digital subtraction myelography may be particularly helpful in those with suspected occult CSF-venous fistula and in patients with SSCSFL with negative conventional CT myelogram. If myelography identifies the CSF leak site, targeted epidural blood patching can be attempted. However, CSF-venous fistulas appear to respond poorly to epidural blood patching (Duvall et al., 2019) and are often best managed with surgical repair in centers with expertise. For other resistant leaks that can be precisely localized, surgical repair may also be attempted.

Headache Attributed to Trauma or Injury to the Head and/or Neck Headaches are a common symptom following injuries to the head and neck. Direct causality between the injury and headache is typically difficult to prove, since there are no headache characteristics that are specific or sensitive for a diagnosis of posttraumatic headache. Thus, the interval between trauma and onset of headaches is relied upon for making a diagnosis of a posttraumatic headache. Although controversial, diagnostic criteria stipulate that headaches must begin within the first 7 days following trauma in order to be considered “posttraumatic” or within 7 days of regaining consciousness following a head injury or within 7 days of discontinuing medications that impair the ability to sense or report headache following head injury (IHS, 2018). In addition, the diagnosis of headaches attributed to whiplash requires that there is neck pain and/or headache at the time of whiplash. Posttraumatic headaches are considered “acute” when they have been present for less than 3 months and “persistent” when they last longer than 3 months (IHS, 2018). Posttraumatic headaches can be due to direct or indirect forces to the head and/or neck. Headaches attributed to head injuries are typically subdivided into those associated with mild head injury and those associated with moderate to severe injury. Headache is the most common symptom following mild head injury and headaches might be more common following mild traumatic brain injury compared to moderate or severe injury (Packard, 2005). Other risk factors for the development of posttraumatic headaches might include presence of pre-injury headaches, female sex, and presence of comorbid psychiatric disorders (Stovner et al., 2009). Most often, posttraumatic headaches phenotypically resemble migraine or tension-type headaches and less often resemble cervicogenic headache or occipital neuralgia (Lew et al., 2006). Headache may be an isolated symptom following head trauma or can be part of the post-concussion syndrome, a syndrome consisting of headache, dizziness, fatigue, cognitive dysfunction, psychomotor slowing, insomnia and personality changes (Evans, 2004; Yang et al., 2009). When considering a diagnosis of posttraumatic headache, it is essential to exclude structural traumatic injuries such as cervical spine injuries, skull fractures, intracranial hemorrhages, cerebrospinal fluid leaks, and cervical artery dissections. Treatment of post-concussion syndrome and posttraumatic headache can be difficult, and an evidence base from which to select optimal therapies is absent. Posttraumatic headaches are thus treated according to the primary headache disorder that they most resemble (e.g., a posttraumatic headache that resembles migraine is treated with medications and other therapies typically used to treat migraine). Optimizing treatment requires that coexisting symptoms such as myofascial pain and spasm, sleep disorders, and anxiety be recognized and addressed. Nonpharmacological treatments (e.g., physical therapy, biobehavioral therapy) should be considered in addition to medication therapy.

Headache Attributed to Infection Inflammation of pain-sensitive structures such as the meninges and intracranial vessels produces the severe headache frequently associated with both meningitis and meningoencephalitis. Headache is the most common symptom in acute bacterial meningitis, occurring in nearly 90% of cases (van de Beek et al., 2004). Acute bacterial meningitis characteristically produces a severe holocephalic headache with neck stiffness and other signs of meningismus, including photophobia and irritability. Pain may be retro-orbital and may worsen with eye movement. The presence of the classic triad of fever, neck stiffness, and altered mental status has a low sensitivity for the diagnosis of meningitis; however, nearly all patients present with at least two of these symptoms and/or headache (van de Beek et al., 2004). Jolt accentuation of headache (i.e.,

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CHAPTER 102 Headache and Other Craniofacial Pain worsening of headache with sudden movements) is a common feature of bacterial meningitis but its absence does not rule it out. Chronic meningitis due to fungal or tuberculous infection may lead to headache that may be severe and unrelenting. The headache of intracranial infection is nonspecific but merits consideration, especially in immunocompromised patients. The diagnosis can be confirmed only by examination of the CSF. Further discussion of meningitis can be found in Chapters 4, 75, 76, and 77. Sinusitis, mastoiditis, epidural or intraparenchymal abscess formation, and osteomyelitis of the skull can all cause either focal or generalized headache. The diagnosis is usually suspected in the context of other associated symptoms and signs. After craniotomy, increasing pain and swelling in the operative site may be due to osteomyelitis of the bone flap. Plain skull roentgenograms may reveal the typical mottled appearance of the infected bone, necessitating removal of the flap. Mollaret meningitis is a rare and recurrent aseptic meningitis (see Chapters 76 and 103). The CSF cellular response includes large epithelioid cells (Mollaret cells). The pathogenesis is unknown but may relate to the herpes simplex virus. The condition may recur every few days or every few weeks for months or years. Headache, signs of meningismus, and lowgrade fever accompany each attack. Treatment is mainly symptomatic. Headache can accompany systemic infections due to viruses (e.g., influenza), bacteria (e.g., leptospirosis) and other infectious agents (e.g., Borrelia burgdorferi). These typically nonspecific headaches can be mild or can be a prominent symptom of the systemic infection (Gladstone and Bigal, 2010). Headaches attributable to systemic infections might be a result of the microorganisms activating pain-sensitive structures, release of inflammatory mediators, presence of fever, and/or dehydration.

Headache Attributed to Cranial or Cervical Vascular Disorders Aneurysms and Arteriovenous Malformations

Intracranial aneurysms are rarely responsible for headache unless they rupture or rapidly enlarge. Large aneurysms may produce pain by exerting pressure upon cranial nerves or other pain-sensitive structures. Such pain is most commonly associated with aneurysms of the internal carotid and posterior communicating arteries. Enlargement of an aneurysm may occur shortly before rupture, and the pain is therefore an important clinical sign. Parenchymal arteriovenous malformations (AVMs) should be considered in a patient presenting with a cranial bruit or the classic triad of migraine, seizures, and focal neurological deficits. Headache may be a presenting symptom in about 16% of patients and is often ipsilateral to the AVM. Similar to aneurysms, the pain may increase in intensity and frequency before hemorrhage. Though photophobia and phonophobia are uncommon, large AVMs can be associated with ipsilateral or bilateral throbbing cephalgia, resembling migraine. Occipital AVMs may frequently have migraine characteristics, and it is thought that the occipital location may be linked with cortical spreading depression, causing secondary migraine headaches. The visual disturbances associated with occipital AVMs may resemble migrainous aura. MR or CT angiography can usually exclude the presence of clinically significant aneurysms and AVMs. Both aneurysms and AVMs can produce mild subarachnoid hemorrhages that result in sentinel headaches. Such headaches may be abrupt, mild, and short-lived. More catastrophic subarachnoid hemorrhages classically present as the worst headache the patient has ever had, all the more worrisome when associated with neck stiffness or pain, transient neurological symptoms (e.g., extraocular nerve palsy), or fever. Patients having any suggestion of a sentinel bleeding episode or who describe a recent thunderclap-like headache (see thunderclap headache discussion below) require emergent examination and CT to

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detect the presence of subarachnoid blood. If the CT is normal, perform a LP, looking for blood or xanthochromia.

Subarachnoid Hemorrhage and Thunderclap Headache The term thunderclap headache describes a severe headache occurring with instantaneous onset (within seconds) and without warning, like a clap of thunder. While multiple processes can present like this, a subarachnoid hemorrhage is the most worrisome. Rupture of an intracranial aneurysm or AVM results in a subarachnoid hemorrhage, with or without extension into the brain parenchyma. The headache of a subarachnoid hemorrhage is characteristically explosive in onset and of overwhelming intensity. Patients may relate that they thought they were hit on the head. The headache rapidly generalizes and may quickly be accompanied by neck and back pain. Loss of consciousness may also occur, but many patients remain alert enough to complain of the excruciating headache. Vomiting often accompanies the headache, which may aggravate the pain. Extension of blood into the ventricles and basal cisterns or distortion of the midline structures can each contribute to the rapid development of hydrocephalus, which frequently worsens the headache. Suspicion of the diagnosis is easily confirmed by an unenhanced CT scan that reveals blood in the subarachnoid cisterns or within the parenchyma and often early hydrocephalus. When a CT unequivocally shows blood in the subarachnoid spaces it is not necessary or advisable to perform a LP, because the resultant reduction of CSF pressure may cause herniation of the brain or may remotely induce further bleeding from the aneurysm. Demonstration of subarachnoid hemorrhage generally indicates the need for cerebral angiography. The timing of this procedure and the subsequent mode of treatment are detailed elsewhere (see Chapter 65). The headache that occurs after a subarachnoid hemorrhage may be persistent, lasting up to 7–10 days. Rarely, a chronic daily headache (CDH) may persist for months to years. Movement aggravates a subarachnoid hemorrhage headache, and photophobia and phonophobia are often associated. Therefore, these patients require a dark, quiet room, as well as comfort measures that minimize straining with bowel movements, vomiting, and coughing. Other conditions which can also manifest with thunderclap headache in addition to subarachnoid hemorrhage include cerebral venous sinus thrombosis, cervicocephalic arterial dissection, pituitary apoplexy, acute hypertensive crisis, spontaneous spinal CSF leaks, meningitis, embolic cerebellar infarcts, pheochromocytoma (Angus, 2013; Heo et al., 2009), and reversible cerebral vasoconstriction syndromes (RCVS) (Calabrese et al., 2007; Schwedt, 2013). These entities can be associated with significant neurological morbidity and may not be easily seen on the initial CT image, thus underscoring the need for MRI and magnetic resonance angiography (MRA)/MRV in this group if results of the initial workup are negative. There is also a rarely seen category of thunderclap headache, referred to as primary thunderclap headache, for which there is no underlying cause established (see the section “Other Primary Headaches” later in the chapter).

Subdural Hematoma Bleeding into the subdural space is generally due to tearing of the bridging veins that cross the subarachnoid space to reach the venous sinuses. Chronic subdural hematomas may cause headache via enlargement of the lesion and may present without serious neurological signs for a considerable time. Midline shift was the most influential factor for headache in one study, which has led some to consider that the likely cause of headache may be stretching or twisting of the pain-sensitive meninges and meningeal arteries or veins (Yamada et al., 2018). Changes in personality, alterations in cognitive abilities, subacute dementia, and nonspecific symptoms such as dizziness and excessive sleepiness may

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PART III Neurological Diseases and Their Treatment

be present for weeks or months. Focal seizures, focal weakness, sensory changes, and ultimately, decreasing levels of consciousness may occur. Symptoms of chronic subdural hematoma, including headache and focal neurological symptoms, may fluctuate and occur intermittently, thereby mimicking transient ischemic attacks (TIAs). Headache is the single most common symptom of subdural hematoma and often presents as a severe bitemporal pain. Headache due to subdural hematoma is more common in young people; the cerebral atrophy seen in many elderly patients may be protective in the setting of any space-occupying intracranial lesion. Subdural hematoma should be considered in an elderly person with recent onset of headaches, especially in the context of a traumatic injury of even mild severity. Once suspected, exclude the presence of a subdural hematoma with CT or MRI. Treatment of subdural hematomas is discussed in Chapter 60. Headaches tend to resolve after resolution of the bleed.

Parenchymal Hemorrhage A hemorrhage into the cerebral or cerebellar tissue is a potent source of headache of rapid onset and increasing severity. The intraparenchymal mass causes headache by deforming and shifting the pain-sensitive vascular, meningeal, and neural structures. As the hematoma enlarges, it may obstruct the normal circulation of CSF and lead to increases in ICP. Initially, the pain of a cerebral hemorrhage is often ipsilateral, but it may generalize in the presence of hydrocephalus and elevated ICP. Rupture of the hematoma into the subarachnoid space or leakage of the blood into the basal cisterns through the CSF pathways may cause the headache to intensify and may also be associated with neck stiffness and other signs of meningeal irritation. Disorders leading to cerebral and cerebellar hemorrhages are more thoroughly discussed elsewhere (see Chapter 64). Cerebellar hemorrhages account for about 10% of all intraparenchymal bleeds and are neurological emergencies with potentially fatal outcomes. An enlarging hematoma in the cerebellum rapidly compresses vital brainstem structures and obstructs the outflow of CSF from the ventricular system. This leads to occipital headache followed rapidly by vomiting, impaired consciousness, and various combinations of brainstem, cerebellar, and cranial nerve dysfunction.

Cerebral Ischemia Cerebral infarctions and TIAs may be associated with transient head pain in up to 40% of patients. The headache may be either steady or throbbing and is rarely explosive or severe (Kropp et al., 2013). The location of the pain is a poor predictor of the vascular territory involved, though unilateral headaches tend to be ipsilateral to the infarct. Cerebral ischemia-related headache is more common in younger patients and patients who are female. It is also more common in patients with larger infarcts and infarcts in the posterior cerebral and vertebrobasilar arterial distributions (Kropp et al., 2013). A recent MRI voxel-based symptom lesion-mapping study suggests headache phenotypes may be related to specific ischemic lesion patterns (Seifert et al., 2018). In this study, pulsatile headache occurred with widespread cortical/subcortical strokes, noise sensitivity was associated with cerebellar lesions, nausea was associated with posterior circulation territory infarcts, and cranial-autonomic symptoms were related to parietal lobe, somatosensory cortex, and middle temporal cortical lesions (Seifert et al., 2018). If a large cerebral or cerebellar infarct produces significant mass effect as a result of edema, the associated headache may worsen. Obstruction of the ventricular system frequently results in hydrocephalus and further aggravation of the pain. The pain may be pulsatile and may worsen with straining or the head-low position. Hemorrhagic transformation of an ischemic infarct may be associated with worsening of headache. As the infarct decreases in size and the phase of

hyperemia subsides, headache generally eases, although in some, headache following stroke becomes chronic and often resembles tension-type headache (Hansen et al., 2015). Paroxysmal visual and sensory disturbances commonly associated with migraine aura may mimic symptoms of cerebrovascular disease, occasionally making the differentiation between the two a challenge. The visual aura of migraine is typically a positive phenomenon, perceived with the eyes open or closed. Visual disturbances due to ischemic lesions of the visual pathway or retina are usually associated with negative phenomena such as vision loss or a negative scotoma; however, emboli to the retinal artery can result in showers of bright flashes, and calcarine ischemia can occasionally produce scintillating scotoma. While visual disturbances associated with stroke and TIA are usually abrupt and fixed, the migraine aura tends to march across the visual field over the course of a few minutes and is generally followed by headache after a latent interval. The headache associated with stroke and TIA typically has a more variable relationship to the visual disturbances.

Carotid and Vertebral Artery Dissection Dissection of the cervical portion of the carotid or vertebral arteries is associated with headache, neck pain, or face pain in approximately 80% of patients. The headache may be isolated or associated with an ipsilateral Horner syndrome or stroke symptoms. An ipsilateral Horner syndrome is more common in carotid than vertebral dissections, and the sympathetic hypofunction may be due to interference with the sympathetic fibers around the internal carotid artery as they ascend from the superior cervical ganglion to the intracranial structures. In internal carotid artery dissections, the headache is typically unilateral and ipsilateral to dissection. Facial pain is common and ipsilateral cranial nerve palsies, especially of lower cranial nerves, are not infrequent. Cerebral or retinal ischemic symptoms are the initial manifestations in a minority of patients. Vertebral artery dissections present most often with headache with or without neck pain, followed by a delay of focal CNS ischemic symptoms. In uncomplicated intracranial vertebral artery dissection, the headache usually is acute in onset with a persistent and temporal feature and in many cases the pain appears to be throbbing and severe in the ipsilateral and occipitonuchal area. Additionally, the headache often is aggravated by head flexion/ rotation and relieved by head extension and being supine (Kim et al., 2015). Cervicocephalic arterial dissections can result from intrinsic factors that predispose the vessel to dissection, including fibromuscular dysplasia, cystic medial necrosis, and other connective tissue disorders such as Marfan syndrome or Ehlers-Danlos syndrome. Extrinsic factors such as trivial trauma may play a pathogenic role when superimposed on structurally abnormal arteries. Severe head and neck trauma may occasionally be the proximate cause of dissection. Importantly, in patients >60 years old, pain and mechanical triggers may be absent, making the diagnosis of cervical artery dissection more challenging in these older patients (Traenka et al., 2017). MRI or MRA usually confirms the diagnosis of arterial dissection. At the level of involvement, the lumen of the artery typically appears as a dark circle of flow void of smaller caliber than the original vessel, and the intramural clot appears as a hyperintense and bright crescent or circle (in both T1- and T2-weighted images) surrounding the flow void (eFig. 102.4). Catheter angiography is rarely required. The pain associated with cervicocephalic dissections is of variable duration and may require treatment with potent analgesics. Patients with evidence of distal embolization are usually treated with either antiplatelet agents or anticoagulation.

Giant-Cell Arteritis Giant-cell arteritis is a vasculitis of elderly persons and is one of the most ominous causes of headache in this population. When

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CHAPTER 102 Headache and Other Craniofacial Pain

A

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B

eFig. 102.4 Magnetic resonance images of a patient with right internal carotid artery (ICA) dissection. Large arrow in each figure points to right ICA, which has a smaller flow void than left ICA (small arrows), reflecting narrowed vessel lumen. Region of flow void is surrounded by a hyperintense crescent representing the intramural hematoma.

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CHAPTER 102 Headache and Other Craniofacial Pain

Symptoms of Giant-Cell Arteritis in 166 Patients* TABLE 102.3

Symptom

Patients in whom it Patients with was Initial Symptom (%) Symptom (%)

Headache Polymyalgia rheumatica Malaise, fatigue Jaw claudication Fever Cough Neuropathy Sore throat, dysphagia Amaurosis fugax Permanent vision loss Claudication of limbs Transient ischemic attack/stroke Neuro-otological disorder Scintillating scotoma Tongue claudication Depression Diplopia Tongue numbness Myelopathy

72 58 56 40 35 17 14 11 10 8 8 7 7 5 4 3 2 2 0.6

33 25 20 4 11 8 0 2 2 3 0 0 0 0 0 0.6 0 0 0

*Some patients had coincident onset of more than one symptom. Data from Caselli, R.J., Hunder, G.G., Whisnant, J.P., 1988. Neurologic disease in biopsy-proven giant cell (temporal) arteritis. Neurology 38, 352–359.

unrecognized and untreated, it may lead to permanent blindness. Patients with this disorder most commonly see neurologists for new headaches of unknown cause. Clinical symptoms. The clinical manifestations of giant-cell arteritis result from inflammation of medium and large arteries. Table 102.3 summarizes clinical symptoms in 166 patients examined at the Mayo Clinic between 1981 and 1983 (Caselli et al., 1988). Headache was the most common symptom, experienced by 72% of patients at some time and the initial symptom in 33%. The headache is most often throbbing, and many patients report scalp tenderness. Headache is associated with striking focal tenderness of the affected superficial temporal or, less often, occipital artery. One-third of patients with headache may have no objective signs of superficial temporal artery inflammation. More than half of patients with giant-cell arteritis experience polymyalgia rheumatica, which is the initial symptom in one-fourth. Fatigue, malaise, and a general loss of energy occur in 56% of patients and are the initial symptoms in 20%. Jaw claudication is common and the initial symptom in 4% of patients. Tongue claudication is rare. Amaurosis fugax is one of the most ominous symptoms in giantcell arteritis; 50% of affected patients subsequently become partially or totally blind if untreated. In the Mayo Clinic series, 10% of patients experienced amaurosis fugax, and 35% of those cases were bilateral. Horizontal or vertical diplopia also occurs in giant-cell arteritis. Some 14% of patients have a neuropathy, which is a peripheral polyneuropathy in 48%, multiple mononeuropathies in 39%, and an isolated mononeuropathy in 13%. Limb claudication occurs in 8% of patients and usually involves the upper limbs. TIAs and strokes occur in 7% of patients, and the ratio of carotid to vertebral events is 2 : 1. Vertigo and unilateral hearing loss can occur. An acute myelopathy,

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acute confusional state, and subacute stepwise cognitive deterioration are rare manifestations. Physical findings. About 49% of patients with histologically verified giant-cell arteritis have physical signs of superficial temporal artery inflammation, including erythema, pain on palpation, arterial nodularity and/or thickening, or reduced pulsation on the affected side. Rarely, ischemic necrosis of the scalp and tongue occurs. Almost a third of patients have large-artery bruits or diminished pulses, which usually affect the carotid artery. The upper-limb arteries are more commonly affected than those in the lower limbs. Ocular findings in giant-cell arteritis may be striking. In patients with amaurosis fugax, sludging of blood in the retinal arterioles may be observed. With infarction of the optic nerve, vision loss precedes the funduscopic signs of an anterior ischemic optic neuropathy by up to 36 hours. During the acute stage, there may be optic disc edema, optic disc pallor, and resulting visual field defects which tend to be altitudinal. Optic disc edema is commonly followed by the gradual development of optic atrophy. Restrictions in eye movements may indicate involvement of specific extraocular muscles. Oculosympathetic paresis (Horner syndrome) occasionally occurs. Up to one-third of patients have clinically significant large-artery disease. The most common causes of vasculitis-related death are cerebral and myocardial infarction. In fatal occurrences, vertebral, ophthalmic, and posterior ciliary arteries are involved as often and as severely as the superficial temporal arteries. Rupture of the aorta is rare. In patients with peripheral neuropathic syndromes, ischemic infarction of peripheral nerves due to vasculitis is demonstrable. Intracranial vascular involvement is rare. Laboratory studies, and imaging. The laboratory abnormality most often associated with giant-cell arteritis is elevation of the erythrocyte sedimentation rate (ESR) (mean, 85 ± 32 mm in 1 hour with the Westergren method), which has a sensitivity of about 84%. C-reactive protein levels may be more sensitive than the ESR, though one study showed that both can be normal in 4% of biopsy-proven patients (Kermani et al., 2012). Patients are usually anemic (mean hemoglobin value 11.7 ± 1.6 g/dL) and show a mild thrombocytosis (mean platelet count 427 ± 116 × 103/µL). As all of these laboratory tests are nonspecific, the confirmatory diagnosis rests on a temporal artery biopsy. However, the sensitivity for this procedure is low, with a high false-negative rate of 15%–40% (Chong and Robertson, 2005). Imaging, particularly with temporal artery MRI or ultrasound, may supplement the diagnostic investigation and may be helpful in decision making about proceeding to biopsy. The superficial cranial arteries along with the mural and luminal properties can be investigated with a contrast-enhanced, high-resolution, temporal artery MRI (Bley et al., 2005). Doppler ultrasound has been advocated by some, but its practical value is difficult to assess because of the heterogeneous study findings and high operator dependence for image acquisition (Bienvenu et al., 2016). Currently, temporal artery imaging is not considered to support the diagnosis with as much certainty as temporal artery biopsy (Bienvenu et al., 2016). An angiogram of the aortic arch vessels may show long segments of smoothly tapered stenosis and occlusions of subclavian, brachial, and axillary arteries. Fluorodeoxyglucose positron emission tomography (FDG-PET)/CT may supplement the diagnostic investigation by identifying vessel inflammation. The spatial resolution of FDG-PET is best for vessels greater than 4 mm in diameter, so it is most useful when involvement of larger vessels, such as the aorta or the subclavian, vertebral, and carotid arteries, is suspected. Pathology. The histopathological features of arterial lesions include intimal proliferation with consequent luminal stenosis, disruption of the internal elastic membrane by a mononuclear cell infiltrate, invasion and necrosis of the media progressing to panarteritic involvement by

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PART III Neurological Diseases and Their Treatment

mononuclear cells, giant-cell formation with granulomata within the mononuclear cell infiltrate, and (variably) intravascular thrombosis (eFig. 102.5). Involvement of an affected artery is patchy, with long segments of the normal unaffected artery flanked by vasculitic foci known as skip lesions, which may begin to normalize within days after treatment. For these reasons, biopsy specimens of the superficial temporal artery should be generous (4- to 6-cm-long specimens), multiple histological sections should be taken, and bilateral biopsy considered. Employing these strategies may increase the diagnostic yield of temporal artery biopsy up to 86%. Immunology, etiology, and pathogenesis. Giant-cell arteritis is an idiopathic autoimmune disease. Although vasculitic processes are often systemic, giant-cell arteritis is usually more focal than polyarteritis nodosa and characterized by a mononuclear cell infiltrate with giant-cell formation, suggesting differences in immunopathogenesis. No distinctive antigen has been identified to explain the particular tropism of giant-cell arteritis, although the possibility that the immune reaction is directed against the internal elastic lamina (which is absent from cerebral vessels shortly after they pierce the dura) may explain the paucity of intracranial involvement. Lymphocytes sensitized to the purported antigen infiltrate the internal elastic lamina and release a host of lymphokines which attract a mononuclear cell infiltrate. Activated macrophages release lysosomal proteases and may transform into epithelioid and multinucleate giant cells. T cells themselves, by antibody-dependent cell-mediated cytotoxicity or natural killer cell actions, may also be involved. In addition, the demonstration of antibody and complement deposits at the internal elastic lamina suggests that humoral mechanisms are involved. Epidemiology. The incidence of biopsy-confirmed giant-cell arteritis ranges between 9.5 and 29.1 per 100,000 per year, significantly increases after 50 years of age, and peaks in the eighth decade (Gonzalez-Gay et al., 2009). It is the most common vasculitic process in both Europe and North America, appears to be most common among individuals of Scandinavian descent, and is significantly less common among Asians. The reported female-to-male ratio in giantcell arteritis is as high as 4 : 1. Treatment and management. Once giant-cell arteritis is suspected, histological confirmation should be obtained, and treatment started immediately. Treatment consists of oral corticosteroids given initially in high doses and gradually tapered over months. Treatment should not be withheld pending the result of temporal artery biopsy. Prednisone may be initiated at 40–60 mg/ day and continued for 1 month, after which time, start a cautious taper of less than 10% of the daily dose per week. If, at the time of presentation, ischemic complications are imminent or evolving, parenteral high-dose corticosteroids should be given until these complications stabilize. Intravenous (IV) pulse corticosteroids, typically in the form of methylprednisolone 1000 mg/day for 3 days, has been advocated for patients with transient, partial, or complete vision loss at presentation (Hoffman, 2016). Some studies have shown antiplatelet therapy with low-dose aspirin to be associated with a lower risk for developing visual loss and cerebrovascular infarcts (Nesher et al., 2004). A Cochrane review of the literature published in 2014, however, found that there is no evidence from randomized controlled trials to determine the safety and efficacy of low-dose aspirin as an adjunctive treatment in giant-cell arteritis (Mollan et al. 2014). The adjunctive use of anticoagulants for patients with ischemia may be tried, but their efficacy in this setting is unproven. Disease activity must be monitored both clinically and by monitoring the ESR. A flare of symptoms accompanied by an increase in the ESR mandates increasing the corticosteroid dose at least to the

last effective dose and often boosting it temporarily to a higher level. Relapses generally reflect too rapid a taper, and resumption of a more slowly tapering regimen is indicated after the relapse has stabilized. Some patients may require continuation of low-dose (7.5–10 mg/day) prednisone for several years, although complete withdrawal remains the eventual goal. There is some evidence that treatment with methotrexate 10 mg/wk may be an effective adjunctive treatment that allows for more rapid tapering of the prednisone dose. Recently, the US Food and Drug Administration (FDA) approved the use of tocilizumab as a steroid-sparing agent for giant-cell arteritis treatment. The multitude of well-known adverse effects associated with exogenous corticosteroids (e.g., vertebral body compression fractures, myopathy, a confusional state, among others) may influence management by prompting a more rapid taper, thereby exposing the patient to the risks that accompany a relapse of the vasculitis. Course and prognosis. The clinical onset of giant-cell arteritis may be acute, subacute, or chronic. Although the median duration of symptoms before diagnosis is 1 month, patients may rarely present with a history of up to several years of polymyalgia rheumatica. Within days of corticosteroid treatment, symptoms and laboratory abnormalities may begin to normalize. With tapering doses, relapses may occur and may present as a reactivation of prior symptoms or with new symptoms altogether. Neurological complications, including neuropathies and cerebrovascular events, are not always preventable by corticosteroid administration and have a median onset of 1 month after initiation of treatment. Similarly, large-artery involvement can occur up to 7 months after initiation of treatment. Although the occurrence of amaurosis fugax often brings a patient with undiagnosed giant-cell arteritis to medical attention, permanent loss of vision rarely occurs with adequate treatment. In patients with acute and incomplete loss of vision, some visual function may return with immediate institution of corticosteroid therapy, but this is rare.

Headache Associated With Disorders of Homeostasis Sleep apnea may result in both an independent headache type and may also be an aggravating factor among individuals with migraine. Individuals with nocturnal or morning-predominant headaches should be asked about sleep apnea risk factors, such as snoring and observed apneic episodes. A body mass index greater than 35 kg/m2, and neck circumference greater than 40 cm, further increase the likelihood of obstructive sleep apnea. The mechanism may involve hypercarbia and/or hypoxemia. Despite common belief, mild to moderate hypertension does not directly cause headache, as demonstrated by a lack of correlation between headache diaries and 24-hour ambulatory blood pressure analysis. Conversely, hypertensive emergency is commonly associated with headache, where a diagnosis of posterior reversible encephalopathy syndrome should also be considered. In a patient with a short-duration headache associated with diaphoresis and palpitations, the possibility of pheochromocytoma should be pursued. Similarly, headache may be a sign of pre-eclampsia during pregnancy. Cardiac cephalalgia occurs as a direct result of myocardial ischemia and may present in the complete absence of chest pain. The headache is characteristically brought on by exertion, improved with rest, and unlike most primary headache disorders, improved by nitroglycerin. Failure to identify this diagnostic entity may be associated with dire consequences. A cardiac evaluation should be considered in patients over the age of 50 who present with new headaches (especially if exertional) and vascular risk factors.

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CHAPTER 102 Headache and Other Craniofacial Pain

1754.e1

eFig. 102.5 Transverse section of temporal artery showing narrowed lumen (arrowhead) and giant cells (two arrows) in relation to the elastic lamina (hematoxylin and eosin stain, ×100) (Micrograph courtesy R. Jean Campbell, MBChB.)

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CHAPTER 102 Headache and Other Craniofacial Pain

Headache Caused by Disorders of the Cranium, Neck, Eyes, Ears, Nose, Sinuses, Teeth, Mouth, or Other Facial or Cranial Structures Ocular Causes of Headache

In the absence of injection of the conjunctiva or other obvious signs of eye disease, headache and eye pain rarely have an ophthalmic cause. The maxim is that a white eye is rarely the cause of a monosymptomatic painful eye. Acute angle-closure glaucoma is a rare but often dramatic event. The patient may present with extreme eye and frontal head pain with associated vomiting. The sclera is injected, the cornea is cloudy, the globe is stony hard, and unlike cluster headache, the pupil is fixed in mid-position. Refractive errors, imbalance of external eye muscles, amblyopia, and “eyestrain” are not causes of headache in most instances. In children and teenagers, however, refractive errors, especially hyperopia, can produce dull frontal and orbital headaches from straining to achieve accommodation at school. Myopic children are unaffected. Trochleitis may produce a periorbital headache and be either idiopathic or secondary to an autoimmune disorder. The headache is characteristically aggravated by vertical ductions of the eye, as the tendon of the superior oblique muscle runs through this structure. Cluster headache, migraine, and other primary headaches, as well as carotid artery dissection, can cause orbital and retro-orbital pain. Each is discussed elsewhere in this chapter.

Nasal Causes of Headache and Facial Pain Acute purulent rhinosinusitis causes local and referred pain. The distribution of the pain depends on the sinuses involved. Maxillary sinusitis causes pain and tenderness over the cheek. Frontal sinus disease produces frontal pain; sphenoid and ethmoidal sinusitis causes pain behind and between the eyes, and the pain may refer to the vertex. Acute rhinosinusitis is commonly associated with fever, purulent nasal discharge, and other constitutional symptoms. The pain is worse when the patient bends forward and is often relieved as soon as the infected material drains from the sinus. Chronic rhinosinusitis is considered to be a risk factor for CDH, where the headache most often resembles chronic tension-type headache in features (Aaseth et al., 2010). Intracranial infections may occur as a complication of untreated sinusitis. Acute infection involving the sphenoid sinus can be especially dangerous because of its close proximity to the cavernous sinus. Commonly, migraine headaches are erroneously diagnosed as sinus headaches, because they are associated with cranial autonomic symptoms, have prominent facial involvement, and/or are triggered (e.g., by a change in altitude/weather, an exposure to pollens, or a seasonal predilection). Most patients with a diagnosis of “sinus headaches” have migraine headaches (Cady et al., 2005). Malignant tumors of the sinuses and nasopharynx can produce deep-seated facial and head pain before involving cranial nerves or otherwise becoming obvious. Trigeminal sensory loss is an important neurological sign which is associated with neurological involvement, often by perineural spread. MRI scanning is the optimal technique for detecting these cryptic lesions.

Temporomandibular Joint Disorders In 1934, Costen first drew attention to the temporomandibular joint (TMJ) as a cause of facial and head pain. Until recently, Costen syndrome was a rare diagnosis. During the past 2 decades, however, interest in disorders of the TMJ, the muscles of mastication, and the bite as they relate to headaches has been increasing. Painful temporomandibular dysfunction is most common between the ages of 35 and

1755

45, after which spontaneous resolution is often seen. Mechanical disorders of the joint, alterations in the way the upper and lower teeth relate, and congenital and acquired deformities of the jaw and mandible can all produce head and facial pain and are very occasionally responsible for the episodic and chronic pain syndromes seen by neurologists. The neurologist evaluating head or facial pain should be familiar with the criteria for identification and localization of TMJ disorders. Temporomandibular joint pain should relate directly to jaw movements and mastication and commonly associates with tenderness in the masticatory muscles or over the TMJ on palpation. Anesthetic blocking of tender structures should confirm presence and location of the pain source. A sudden change in occlusal relationship of the teeth, restriction of mandibular movement, and interference with mandibular movement (clicking, incoordination, and crepitus) are all symptoms and signs suggestive of TMJ dysfunction. Bruxism, teeth clenching, and chronic gum chewing are important in the production of pain in the masseter and temporalis muscles. Arthritis and degenerative changes in the TMJ, loss of teeth, ill-fitting dentures or lack of dentures, and other dental conditions can all lead to the TMJ or myofascial pain dysfunction syndrome, which manifests as facial and masticatory muscle pain. Head pain and facial pain, even when associated with the above-discussed criteria, require full evaluation, which should include a detailed history and examination, appropriate radiographs, and laboratory studies to exclude other more serious causes. If TMJ dysfunction is thought to be the source of pain, further evaluation and treatment are in the province of the appropriate dental specialist. Even when TMJ dysfunction is believed to be responsible for facial or head pain, conservative management with analgesics, anti-inflammatory agents, application of local heat, and nonsurgical techniques to adjust the bite generally provide relief. Before using surgical modalities on the TMJ or mandibles, the diagnosis must be secure and other causes of head and facial pain excluded by appropriate investigations.

Other Dental Causes of Craniofacial Pain Pulpitis and root abscess generally produce dental pain that a patient can localize. The cracked tooth syndrome results from an incomplete tooth fracture, most commonly involving a lower molar. The initial pain is usually sharp and well localized, but thereafter the pain is often diffuse and hard to locate. After a fracture, the tooth is sensitive to cold. Pain may be felt in the head and face ipsilateral to the damaged tooth. With time, infection develops in the pulp, leading to extreme and well-localized pain. Confirmation of the diagnosis and treatment of the cracked tooth require the expertise of a dentist.

Headaches and the Cervical Spine Cervicogenic headache is often a controversial diagnosis with potential medicolegal implications. Many common cervical spine pathologies, such as degenerative spondylosis, occur just as often in individuals with or without headache. Therefore, the diagnosis rests on establishing the cervical spine as a pain generator either through clinical signs, or a diagnostic nerve block. Cervicogenic headache should be strongly suspected as a diagnosis when there is occipital headache, especially when unilateral, and associated with constant neck pain. Migraine in particular frequently presents with pain in the occipital and nuchal regions, which are innervated by the greater occipital nerve. Furthermore, muscle hypersensitivity and tenderness, restriction of neck movements, and hyperalgesia may accompany the pain. Similarly, pain of cervical origin or cervicogenic headache is prominent in the occipital region but may also spread to trigeminal

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PART III Neurological Diseases and Their Treatment

territories. The referral of pain observed in cervicogenic headache and migraine reflects the convergence of trigeminal and cervical afferents onto the same neurons in the trigeminal-cervical complex. Despite this anatomical overlap, the provocation or exacerbation of the headache by neck movement, a persistent rather than intermittent headache, and lack of photophobia, phonophobia, and nausea, are features that may be helpful in distinguishing cervicogenic headache from migraine. Diagnostic blocks performed accurately and under controlled conditions are the only currently available means by which a cervical source of pain can be established. A positive response to occipital nerve block should be interpreted with caution, however, given the fact that many primary headaches, including migraine and cluster headache, may respond to this procedure. The use of intra-articular steroids and long-acting anesthetics may provide relief that can last several months, and complete relief of headache can occasionally be achieved by radiofrequency neurotomy in patients whose headache stems from the C2 to C3 zygapophysial joint (Bogduk, 2004). Physical therapy may also be helpful in the treatment of cervicogenic headache.

Medication Overuse Headache Overuse of acute medications by patients with frequent headache may lead to a daily headache syndrome, now known as medication overuse headache (MOH). Previously referred to as rebound or medicationinduced headache, this syndrome is induced and maintained by the very medications used to relieve the pain. Diagnostic criteria according to ICHD-3 are designed to improve sensitivity, requiring only the presence of chronic daily headache (CDH) in the setting of exposure to an overused analgesic (IHS, 2018). The risk for development of medication overuse headache varies with individual substances. Opioids, butalbital-containing compounds, and some combination analgesics appear to have the highest risk; triptans carry moderate risk, and nonsteroidal antiinflammatory drugs (NSAIDs) the lowest risk. In fact, migraine prevention guidelines include recommendations for daily NSAID exposure in the preventive treatment of migraine (Silberstein et al., 2012). Further, there is longitudinal epidemiological evidence that NSAID use among individuals with 72 hours, treatment often needs to start earlier if associated with significant uncontrolled vomiting and/or dehydration. In this model, if IV access is present, initial treatment consists of IV hydration, IV ketorolac 30 mg, and a neuroleptic antiemetic of choice (commonly prochlorperazine, metoclopramide, or promethazine) as needed. Specific status migrainosus treatment protocols using neuroleptic antiemetics have been published (Bell et al., 1990; Fisher, 1995; Lane et al., 1989; McEwen et al., 1987; Richman et al., 2002; Tek et al., 1990; Wang et al., 1997). To avoid extrapyramidal reactions with neuroleptic antiemetics, consideration can be given to pretreating with 1 mg oral (PO), intramuscular (IM), or IV benztropine mesylate. Benztropine is typically given to patients with a history of an extrapyramidal reaction to the chosen antiemetic, but not routinely. If IV access is not available, IM ketorolac with or without promethazine may be a good alternative. Patients with significant dehydration, complex coexisting medical problems and those requiring prolonged parenteral treatment may need to be hospitalized (Garza and Cutrer, n.d.). If initial measures fail and proper expertise is available, consideration can be given to extracranial nerve blocks directed to the area or areas of pain such as occipital, supraorbital, or auriculotemporal nerves and/or the sphenopalatine ganglion. If DHE is needed for a patient in a short-term stay setting

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CHAPTER 102 Headache and Other Craniofacial Pain

eTABLE 102.6

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Subcutaneous and Intranasal Serotonin (5-HT) Agonists HEADACHE RESPONSE (%)*

Drug

Dose (mg)

1h

2h

4h

Recurrence of Headache (%)†

Dihydroergotamine Subcutaneous Intranasal

1 2

57 46

73 47–61

85 56–70

18 14

Sumatriptan Subcutaneous Intranasal

6 20

70 55

75 60

83 NA

35–40 35–40

Zolmitriptan Intranasal

5

55

70

78

25

NA, Not available. *Headache response is defined as a reduction of headache severity from moderate or severe pain to mild or no pain. †Recurrence of headache within 24 h after initial headache response.

eTABLE 102.7

Oral Serotonin (5-HT) Agonists HEADACHE RESPONSE (%)*

Drug

Dose (mg)

1h

2h

4h

Recurrence of Headache (%)†

Almotriptan Eletriptan

12.5 20 40 2.5 1 2.5 5 10 25 50 100 2.5 5

35 20 30 NA 19 21 30 37 NA NA NA 38 44

57 49 60 42 42 48 60 67–77 52 50 56 64 66

NA NA NA 61 51 67 NA NA 68 70 75 75 77

23 30 22 10–25 17–28 2.5 30–35 10 35–40 50 100 31 5

Frovatriptan Naratriptan Rizatriptan Sumatriptan

Zolmitriptan

Note: Composite data from product information inserts and literature. NA, Not available. *Headache response is defined as a reduction in headache severity from moderate or severe pain to mild or no pain. †Recurrence of headache within 24 h after initial headache response.

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PART III Neurological Diseases and Their Treatment

Status migrainosus confirmed

Initial treatment

Yes Resolved?

Dismiss and outpatient follow-up

No Consider extracranial nerve clocks

Yes Resolved?

Dismiss and outpatient follow-up

No

No

Administer DHE according to clinical setting

Contraindications to dihydroergotamine (DHE)?

Yes No IV valproic acid

Resolved?

Yes

Yes Resolved?

Dismiss and outpatient follow-up

Dismiss and outpatient follow-up

No Current opioid overuse?

Yes Neurology consult

IV opiate of choice

Yes Resolved?

Dismiss and outpatient follow-up

No Neurology consult Fig. 102.6 Status Migrainosus Management Recommendations for Adult Patients at our Institution. IV, Intravenous.(Adapted from (Garza and Cutrer, n.d.). Used with permission of Mayo Foundation for Medical Education and Research, all rights reserved.)

such as the emergency room, it is administered as a 0.5 mg IV test dose and if tolerated may repeat DHE 0.5 mg IV 30–60 minutes later (total 1 mg). If inpatient, however, DHE is administered instead with IV 0.5– 1.0 mg doses (depending on tolerance every 8 hours as needed (“Raskin protocol”) (Raskin, 1990) for up to 2–5 days or via continuous IV DHE infusion (“Ford protocol”) (Ford and Ford, 1997). In the latter,

DHE initiates at 3 mg in 1000 mL normal saline and is administered IV at 42 mL/h but if significant nausea the rate is reduced to 21–30 mL/h (may continue up to 7 days if needed). Patients getting IV DHE are commonly pretreated with IV metoclopramide (with or without benztropine mesylate as discussed above) if no other antiemetic has been given, and the antiemetic is repeated as needed while on IV DHE

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CHAPTER 102 Headache and Other Craniofacial Pain treatment. When used, IV valproic acid starts with a loading dose of 15 mg/kg in D5W (5% dextrose in water) or normal saline at 20 mg/min and is followed by 5 mg/kg every 8 hours as needed (Schwartz et al., 2002). An alternative IV valproic acid protocol is 1 g in 250 mL normal saline over 1 hour (Edwards et al., 2001). A very common valproic acid IV dosing, however, is 500 mg at 20 mg/min × 1 dose (after 1000 mL normal saline) (Garza and Cutrer, n.d.). One of the main goals of this approach is to avoid opiate/opioid use as much as possible when managing status migrainosus, to minimize the risk of medication overuse headache. Dexamethasone (10 mg IV) may be given prior to dismissal to help prevent headache recurrence (Garza and Cutrer, n.d.).

Prophylactic Treatment A preventive program is appropriate when attacks occur weekly or several times a month, or when they occur less often but are very prolonged and debilitating. The most effective prophylactic agents available typically reduce headache frequency by at least 50% in approximately 50% of patients. Preventive medications are generally titrated gradually to the minimum effective or maximum tolerated dosage. This target dosage is maintained for at least 3 months, and if there is a beneficial response, the medication is continued until there has been clinical stabilization for at least 6–12 months. The full benefit of a preventive medication may take up to 6 months to be realized. In a clinical trial evaluating the impact of discontinuing preventive therapy, patients taking topiramate were randomized for 6-months to either continue topiramate or switch to a placebo (Diener et al., 2007a). Remarkably, although patients continuing topiramate tended to have overall better headache outcomes, patients switching to placebo maintained improvements, compared to their pre-treatment baseline. Therefore, a discussion regarding treatment discontinuation is reasonable after 6 months if patients are doing well. Multiple guidelines exist for the selection of preventive therapies for episodic migraine, including the American Academy of Neurology (AAN)/American Headache Society (AHS), Canadian Headache Society and the European Federation of Neurological Societies (Loder et al., 2012). The levels of recommendation made by the AAN/AHS are based on the strength of efficacy data alone, while the Canadian and European guidelines factor in a balance of potential benefits and harms. First-line therapies, including topiramate, divalproex, metoprolol, and propranolol are given first-line recommendation status by all guidelines (Loder et al., 2012). In our practice, a process of shared decision making with consideration for the strength of available clinical trial data, potential side effects, and individual patient treatment preferences and goals is employed. Table 102.8 lists some commonly used migraine preventive medications in our practice.

TABLE 102.8

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β-Adrenergic blockers. β-Adrenergic antagonists are widely used for prophylaxis of migraine headaches (Silberstein et al., 2012). Propranolol in doses of 80–240 mg/day, if tolerated, should be given a trial of 2–3 months. Compliance increases with the use of a long-acting form of propranolol given once daily. Side effects are not usually severe. Lethargy or depression may occur and may be a reason for discontinuation of the medication. Hypotension, bradycardia, impotence, insomnia, and nightmares can all occur. As with all β-adrenergic blocking agents, propranolol should be discontinued slowly to avoid cardiac complications. It is contraindicated in persons with a history of asthma or severe depression and should be used with caution in patients using insulin or oral hypoglycemic agents, because it may mask the adrenergic symptoms of hypoglycemia. Timolol, nadolol, atenolol, and metoprolol probably have approximately the same benefit in migraine as propranolol. The mechanism of action is not known. The only pharmacological trait that separates β-adrenergic blocking agents effective in migraine from those that are not is a lack of sympathomimetic activity. Calcium channel blockers. Although the relevant mechanism by which calcium channel antagonists affect migraine is not known, their use in migraine was originally based on their ability to prevent vasoconstriction and on their other actions, including prevention of platelet aggregation and alterations in release and reuptake of serotonin. Several clinical trials have indicated some benefit for verapamil and flunarizine in preventing recurrent migraine. Little evidence exists to support the use of nimodipine. Verapamil in doses of 80–160 mg three times a day reduces the incidence of migraine with aura, but it is not as useful in migraine without aura. Experience with diltiazem is too limited to permit an assessment of its value at this time. Antidepressants. Amitriptyline and other tricyclic antidepressants can be helpful in migraine prophylaxis (Silberstein et al., 2012). The benefit seems to be independent of their antidepressant action, which typically requires doses higher than that used for migraine. Used in doses of 10–150 mg at night, amitriptyline, nortriptyline, imipramine, or desipramine may all provide some reduction in attacks of migraine, although evidence of efficacy in clinical trials is available only for amitriptyline. Protriptyline is an alternative without sedating properties, although there is no support in the literature for its use in chronic migraine. Side effects can be rather troublesome. Morning drowsiness, dryness of mouth, weight gain, tachycardia, and constipation are common. The anticholinergic side effects may decrease with time. If tolerated, give the tricyclic agents a trial of at least 3 months after reaching a therapeutic dose. The optimal dose for migraine prophylaxis is determined by titration to the effective or maximum tolerated dose within the therapeutic range (e.g. usually 50–150 mg for amitriptyline and nortriptyline).

Some Commonly Used Migraine Preventive Medications

Drug

Initial Dose (mg)

Typical Daily Dose Range

Common Adverse Effects

Serious Adverse Effects

Amitriptyline Nortriptyline Protriptyline Topiramate

10–25 10–25 5–10 15–25

25–150 25–150 10–30 75–200

Divalproex sodium Gabapentin Propranolol Atenolol Verapamil

250–500

750–1500

Weight gain, constipation, sedation Weight gain, constipation, sedation Constipation, sedation Paresthesias, fatigue, weight loss, cognitive impairment Alopecia, weight gain, tremor, nausea

Cardiac dysrhythmias Cardiac dysrhythmias Cardiac dysrhythmias Glaucoma, hyperthermia, metabolic acidosis, nephrolithiasis Pancreatitis, liver failure, thrombocytopenia

300 40–60 25 80–160

900–2400 40–240 50–100 160–480

Dizziness, fatigue, edema, sedation Depression, fatigue Depression, fatigue Edema, constipation

Bradyarrhythmia Bradyarrhythmia Hypotension, dysrhythmias

Adapted from Garza, I., Swanson, J.W., 2006. Prophylaxis of migraine. Neuropsychiatr. Dis. Treat. 2 (3), 281–291.

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Selective serotonin reuptake inhibitors have not consistently proven to be effective for migraine prophylaxis and in some cases may elicit or aggravate headaches. Given the frequent comorbidity of generalized anxiety disorder and panic disorder, a serotonin-norepinephrine reuptake inhibitor such as venlafaxine may be considered if a single agent is desired. Venlafaxine is probably used less commonly than the tricyclic antidepressants discussed above. Nonetheless, venlafaxine was found to be effective in a placebo-controlled trial and remains an option which may prevent migraine headaches in some. Among patients with comorbid generalized anxiety disorder, venlafaxine may be an appropriate weight-neutral treatment option to facilitate dual treatment. There are uncontrolled studies to support the use of the monoamine oxidase inhibitor (MAOI) phenelzine for migraine prophylaxis. Unfortunately, the dietary restrictions that must be carefully followed if a hypertensive crisis is to be avoided limit the widespread use of these inhibitors for prevention of migraine. Dangerous drug interactions can occur with preparations such as sympathomimetic agents, central anticholinergics, tricyclic antidepressants, and opioids, especially meperidine. Side effects of MAOIs include hypotension as well as hypertension, agitation, hallucinations, retention of urine, and inhibition of ejaculation. Anticonvulsants. Antiepileptic medications are in general a highly efficacious class of prophylactic treatment. Their mechanisms of action in migraine prophylaxis are unknown. In the early 1990s, several blinded placebo-controlled studies showed a beneficial effect of valproate in the prophylactic treatment of migraine; 50% of patients showed a response with a 50% or better reduction in migraine incidence. Valproic acid, given in the form of divalproex sodium, is generally effective (Silberstein et al., 2012) at a range of 500–1750 mg/day, taken in divided doses. Side effects include sedation, dizziness, increased appetite, increased bleeding time, increased fragility of hair, and an asymptomatic increase in liver function test values. Valproate is contraindicated in women who are at risk for becoming pregnant, because it is associated with an increased risk for neural tube defects. While only limited evidence is available to support its use, gabapentin does appear to be effective in the reduction of migraine frequency in clinical practice. It also has beneficial effects in somatic pain and may be a good choice if a patient has neck pain, back pain, or painful peripheral neuropathy as well as migraine. It appears relatively well tolerated, although dizziness and sedation may limit its use in some patients. The usual therapeutic dose range for gabapentin is 900–2400 mg/day. Topiramate’s efficacy for migraine was demonstrated in pivotal large randomized trials (Brandes et al., 2004). Topiramate has effects not only on γ-aminobutyric acid (GABA) but also on non-N-methyl-d-aspartate glutamate and carbonic anhydrase activity. It may have prominent sedating and cognitive side effects, making a slow gradual titration of the drug (15–25 mg/wk initially) to the therapeutic range of 75–200 mg/day the most successful strategy. Too rapid a titration schedule increases the risk of precipitating depression, especially if there is a personal or family history (Mula et al., 2009). Other side effects include paresthesia and weight loss, the latter making topiramate a particularly attractive choice for many patients. It is also associated with a mildly increased risk for calcium phosphate kidney stones. Zonisamide may be a good alternative in topiramate-intolerant patients who had previously experienced a good response (Mohammadianinejad et al., 2011). Other prophylactic agents. Cyproheptadine is a peripheral serotonin antagonist, typically used in pediatric patients. For younger patients unable to swallow pills, cyproheptadine is available in a syrup formulation. At all ages, it causes drowsiness and may cause significant weight gain. Methysergide, a peripheral serotonin antagonist and

central serotonin agonist, is no longer available in the United States and Canada. Historically, it was a very useful agent despite its potential for producing serious complications. Two small clinical trials have demonstrated efficacy of an extract of butterbur root in migraine prophylaxis, at a total daily dose of 150 mg daily (in two or three divided doses). The treatment is well tolerated, but gastrointestinal symptoms may occur. Recently, the safety of butterbur root has come into question due to potential for hepatotoxicity and carcinogenesis. Riboflavin administered orally in a dose of 400 mg/day has been shown by Schoenen to be effective in migraine prophylaxis in a prospective randomized controlled study that enrolled a relatively small number of subjects. Its effect on the frequency of attacks was not statistically significant until the third month of the trial. There are minimal side effects associated with this agent. Evidence is mixed regarding the efficacy of magnesium in migraine prophylaxis. Oral magnesium supplementation with 600 mg of a chelated or slow-release preparation is the recommended dosage. Magnesium-induced diarrhea and gastric irritation are the most common side effects. Aspirin, 325 mg, taken every other day for the prevention of cardiovascular disease, may slightly reduce the frequency of migraine. NSAIDs are being increasingly recognized as having benefit in migraine prophylaxis and may be associated with reduced risk of chronic migraine development in individuals with less than 10 headache days per month based on epidemiological studies (Lipton et al., 2013). OnabotulinumtoxinA injection in the treatment of chronic migraine is now supported by two large multicenter placebo-controlled randomized clinical trials and is currently the only FDA-approved treatment specifically for chronic migraine (Dodick et al., 2010) (see chronic migraine discussion). OnabotulinumtoxinA is established as ineffective and should not be offered for episodic migraine (Simpson et al., 2016). Candesartan (angiotensin II receptor blocker), at a dose up to 16 mg daily, and lisinopril (angiotensin converting enzyme inhibitor), at a dose from 10 to 20 mg daily, are antihypertensives that are probably used less often than other blood-pressure medications discussed here previously. Nonetheless, both have been found to be effective as migraine preventives in randomized controlled trials and remain an option when other more commonly used preventives fail or are not tolerated.

Neurostimulation In March 2014, a transcutaneous supraorbital nerve stimulator was approved by the FDA for migraine prevention following a small clinical trial showing modest benefit among patients with episodic migraine (Schoenen et al., 2013b). The device is considered to be safe; however, efficacy has not been independently confirmed by other investigators. Transcranial magnetic stimulation (TMS), a noninvasive technique utilizing a magnetic pulse hypothesized to disrupt cortical spreading depression, has now been approved by the FDA for the symptomatic treatment of migraine with aura. Single-pulse TMS (sTMS) was studied in a randomized, double-blinded, sham-controlled study, where greater pain-free responses were observed at 2 hours, with a sustained effect noted at 24 and 48 hours after treatment of migraine with aura (Lipton et al., 2010). In a prospective, open-label study of 263 patients with migraine with or without aura, scheduled twice-daily treatment with sTMS for 3 months, 46% of the patients reduced their headache frequency by half or more, and no serious adverse effects were observed (Starling et al., 2018). A noninvasive vagal nerve stimulator was evaluated for acute treatment of migraine in a double-blind, randomized, sham-controlled trial (Tassorelli et al., 2018). When attacks were initially treated within 20

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CHAPTER 102 Headache and Other Craniofacial Pain minutes, superior efficacy for pain freedom was observed at early (30and 60-minute) time points, but not at a later (2-hour) time point. No serious adverse events were observed.

Calcitonin Gene-Related Peptide Targeted Therapies There has been a long-standing literature documenting a fundamental role for CGRP in the pathophysiology of migraine (Edvinsson, 2017). Along these lines, elevated levels of CGRP can be measured in the internal jugular vein during an acute attack of migraine, which then normalize with treatment with sumatriptan. Further, experimental infusion of CGRP triggers migraine in patients with migraine but not controls. The development of oral CGRP antagonists (“-gepants”) have largely been hampered by hepatotoxicity in clinical trials; however, at least two agents (rimegepant and ubrogepant) have demonstrated efficacy and safety in phase III clinical trials for acute treatment of migraine. Four different monoclonal antibodies have demonstrated safety and efficacy for preventive treatment of migraine in phase III trials. Prospective data indicate that these medications remain effective even among patients who have failed up to four prior preventive trials. Injection site discomfort is the most common side effect, with small numbers of patients also reporting constipation. Three of these monoclonal antibodies have been licensed in the United States: erenumab which targets the CGRP receptor, and fremanezumab and galcanezumab, both of which target CGRP. The AHS has released a consensus statement offering guidance as to how to incorporate CGRP-based immunotherapies into clinical practice (American Headache Society, 2019) based on number of headache days per month and headache-related disability, as measured by the Migraine Disability Assessment Scale or the Headache Impact Test. For patients reporting 4–7 monthly headache days and at least moderate disability despite at least two 6-week trials of AAN level A or B preventive therapies, CGRP-based immunotherapy would be indicated. For patients reporting 8–14 monthly headache days, a CGRP-based immunotherapy is indicated at any disability level if at least two 6-week trials of preventive therapies have not been successful. Finally, CGRP-based immunotherapies are indicated for patients with chronic migraine if they have not responded to either two 6-week oral preventive trials or two quarterly injection cycles of onabotulinumtoxinA. Despite general enthusiasm for the availability of a novel class of pharmacotherapy with a benign side-effect profile, significant pre-clinical concerns warrant caution pending longer term post-marketing experience. Specifically, CGRP is known to exert several protective physiological roles including vasodilation, raising concerns that worse outcomes could be observed if a patient exposed to treatment were to experience a vascular event (Deen et al., 2017). Nonetheless, open-label experience now reported out to 3 years fortunately has not documented such adverse outcomes.

Hormones and Migraine Migraine occurs equally in both sexes before puberty, but it becomes three times more common in women after menarche. Approximately 25% of women have migraine during their reproductive years. The changing hormonal environment throughout a woman’s life cycle, including menarche, menstruation, oral contraceptive use, pregnancy, menopause, and hormone replacement therapy (HRT), can have a profound effect on the course of migraine. Menstrual migraine. Migraine attacks are generally associated with menses in one of two ways. The attacks may occur exclusively during menstruation and at no other time during the cycle. This association is referred to as pure menstrual migraine (PMM), and it has

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been proposed that PMM be defined as attacks that occur between days −2 and +3 of the menstrual cycle. The prevalence of PMM according to this definition is about 7%. More commonly, migraine attacks occur throughout the cycle but increase in frequency or intensity at the time of menstruation (menstrually related migraine). This association occurs in up to 60% of female migraineurs. Menstrual migraines have a tendency to be more severe, disabling, and treatment-refractory. Aura is uncommon. Finally, headache may be a symptom of the premenstrual syndrome, where depression, irritability, fatigue, appetite changes, bloating, backache, breast tenderness, and nausea characterize the disorder. These different relationships between migraine and the menstrual cycle can be determined by reviewing headache diaries, and their distinction is important because the pathophysiology may differ, as would the therapeutic approach. Numerous mechanisms have been proposed to explain the pathogenesis of menstrual migraine. There is abundant clinical and experimental evidence to support the theory that estrogen withdrawal before menstruation is a trigger for migraine in some women. Estrogen withdrawal may modulate hypothalamic β-endorphin, dopamine, β-adrenergic, and serotonin receptors. This complex relationship causes significant downstream effects such as a reduction in central opioid tone, dopamine receptor hypersensitivity, increased trigeminal mechanoreceptor receptor fields, and increased cerebrovascular reactivity to serotonin. These changes, which occur during the luteal phase of the cycle, may be germane to the pathogenesis of menstrual migraine. Several lines of investigation have implicated both prostaglandins and melatonin in the pathogenesis of menstrual migraine. Prostaglandins and melatonin are important mediators of nociception and analgesia, respectively, in the CNS. The concentrations of prostaglandin F2 and nocturnal melatonin secretion increase and decrease, respectively, during menstruation in female migraineurs. These observations are the basis for the clinical use of NSAIDs and melatonin for menstrual migraine prophylaxis.

Management of Menstrual Migraine To establish a direct link between menstruation and headache attacks, ask the patient to keep a diary of migraine attacks and menstrual periods for at least 3 consecutive months. The nature of this relationship determines subsequent therapy. For example, for patients who have both menstrual and nonmenstrual migraine, a standard prophylactic medication might be used throughout the cycle rather than the perimenstrual use of a prophylactic agent. Clearly outline the goals of therapy in addition to the dosages, benefits, and side-effect profile of each recommended medication. Ideally, the headache diary can help identify other nonhormonal triggers. Biofeedback and relaxation therapy can be helpful in selected patients and should be used whenever possible. Acute menstrual migraine therapy. The goal of acute menstrual migraine therapy is to decrease the severity and duration of pain as well as the associated symptoms of an individual migraine attack, including nausea, vomiting, photophobia, and phonophobia. Some women may control attacks of menstrual migraine quite adequately with abortive therapy only (see Migraine/Symptomatic Treatment section, previously). The acute management of menstrual migraine does not differ from the treatment of migraine unassociated with menstruation (see Migraine/Symptomatic Treatment section, discussed previously). Prophylactic menstrual migraine therapy. Prophylaxis may either be perimenstrual (cyclic) (Box 102.3) or continuous (noncyclic, see Migraine/Prophylactic Treatment section, discussed previously). Many of the regimens suggested for perimenstrual migraine prophylaxis depend on regular menstruation and the ability to predict headache

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PART III Neurological Diseases and Their Treatment

Cyclic (Perimenstrual) Prophylaxis for Menstrual Migraine

BOX 102.3

Nonsteroidal anti-inflammatory drugs (days −3 through +3): Naproxen sodium, 550 mg bid Mefenamic acid, 250 mg tid Ketoprofen, 75 mg tid Ergots (days −3 through +3): Ergotamine tartrate + caffeine (Wigraine), 1 mg qhs or bid Dihydroergotamine, 0.5–1 mg (subcutaneous, intramuscular, or intranasal) bid Triptans: Naratriptan, 1 mg bid for 5 days Frovatriptan, 2.5 bid for 6 days Zolmitriptan, 2.5 mg bid or tid for 7 days bid, Twice daily; qhs, every day at bedtime; tid, three times daily.

onset in relationship to menses. Perimenstrual prophylaxis commences a few days before the period is expected and continues until the end of menstruation. In women whose cycles are difficult to predict, continuous prophylaxis with standard migraine prophylactic agents is called for (see Migraine/Prophylactic Treatment section, discussed previously). NSAIDs are considered first-line agents for perimenstrual prophylactic therapy in patients with either menstrual-associated migraine, or PMM, when the timing of menstruation is predictable. Different classes of NSAIDs should be tried because response may vary in a given individual. Ergot derivatives can also be effective when used as perimenstrual prophylactic drugs around the time of menstruation. Risks for rebound headaches are minimal, given the limited duration of treatment when drugs are used perimenstrually. Frovatriptan, naratriptan, and zolmitriptan have been found to be effective for perimenstrual prophylaxis and are included in the AAN and AHS guidelines on migraine prophylaxis (Silberstein et al., 2012). It is worth noting that severe menstrually related migraine may respond better to short-term or perimenstrual prophylaxis while on a chronic (continuous, noncyclic) preventive agent. Other treatments. For those with PMM, attacks are also preventable by stabilizing estrogen levels during the late luteal phase of the cycle. Estrogen levels can be stabilized by maintaining high levels with estrogen supplements. These should be directed by the patient’s gynecologist. The use of magnesium for acute and prophylactic treatment of migraine and menstrual migraine may be considered. Women with menstrual migraine have low levels of systemic magnesium, and MRS studies have demonstrated reduced levels of intracellular magnesium in the cerebral cortex of migraineurs. Low levels of intracellular magnesium may lead to neuronal hyperexcitability and spontaneous depolarization, which may be the central process initiating a migraine attack. This has led some investigators to study the effect of magnesium on menstrual migraine management. Some physicians still advocate the use of hysterectomy and oophorectomy in women with intractable PMS and menstrual migraine whose headaches respond to medical ovariectomy. No long-term follow-up or controlled studies exist that conclusively substantiate this position. Because no study has been placebo controlled, the positive results seen in some studies may reflect the daily postoperative use of estrogen. Although two-thirds of women who have physiological menopause experience migraine relief, the opposite effect may occur with surgical menopause with bilateral oophorectomy. In a retrospective study of 1300 women, Granella and colleagues also demonstrated

the unfavorable effects of surgical menopause on migraine. Therefore, until convincing evidence demonstrates otherwise, hysterectomy with or without oophorectomy is not currently a recommendation for women with menstrual migraine.

Oral Contraception in Female Migraineurs Migraine prevalence is highest in women during their reproductive years, the very population who use oral contraceptive therapy. Oral contraceptives have a variable effect on migraine. Migraine may begin de novo after a woman starts taking oral contraceptives, pre-existing migraine may worsen in severity or frequency, or the characteristics of the migraine attack may change (e.g., development of aura symptoms in a woman who for years had migraine without aura). Migraine attacks may also lessen after starting an oral contraceptive, particularly in women whose migraine attacks had a very close relationship to menstruation. In the majority of women, however, the pattern of migraine does not change appreciably after they start taking an oral contraceptive, particularly with the lower doses of estrogen and progestin now found in most oral contraceptives. The concern about the use of synthetic estrogen in women with migraine pertains to the increased risk for ischemic stroke in this population, relative to age-matched women without migraine. There is now convincing evidence that female migraineurs have a small, but measurably increased risk of experiencing ischemic stroke. A 1995 case-control study found migraine to be strongly associated with the risk for ischemic stroke in young women (odds ratio [OR], 3.5), and this association was independent of other vascular risk factors. The risk for ischemic stroke was particularly increased in women with migraine who were using oral contraceptives (OR, 13.9), were heavy smokers (OR, 10.2), or who had migraine with aura (OR, 6.2). The estimated incidence of ischemic stroke in young women with migraine with aura who use oral contraceptives is 28 per 100,000 women aged 25–34, and 78 per 100,000 aged 35–44. This is in contrast to the incidence of ischemic stroke of approximately 4 and 11 per 100,000 women in the general population in the same respective age groups. Although the relative risk for ischemic stroke is increased in this group, it is important to bear in mind that the absolute risks are still small. Further, there is no convincing evidence that exposure to very low dose estrogen (50% reduction in headache days), the medication is continued until there has been clinical stabilization for at least 6–12 months. It must be remembered that the full benefit of a preventive medication may take up to 6 months to be realized. An attempt to taper and discontinue the preventive medication is reasonable, but only after consultation with the patient and after a reasonable period of stability (>6–12 months). Patients with chronic migraine should limit acute treatment use to prevent development of medication overuse headache (see Medication Overuse Headache section, previously).

Cluster Headache Among the many painful conditions that affect the head and face, cluster headache is without doubt the most painful recurrent headache, and the one that produces the most stereotyped attacks. In episodic cluster headache, attacks of pain occur in periods lasting 7 days to 1 year, separated by pain-free periods lasting 3 months or longer. In chronic cluster headache, attacks of pain occur for more than 1 year without remission or with remissions lasting less than 3 months (IHS, 2018). This chronic form of the disease may develop de novo or may evolve from episodic cluster headache. Approximately 90% of patients have episodic cluster headache, and 10% have the chronic form.

Epidemiology Compared with tension headache and migraine, the syndrome of cluster headaches is considerably less common. In many headache clinic populations, migraine is 10–50 times more common than cluster headache. The prevalence of cluster headache is about 1 person per 500. It occurs approximately three times more often in men than in women but is clinically identical in both genders. Although not universally observed, there is a tendency for cluster headache symptoms to remit with age (May, 2005). Unlike migraine, cluster headache has not been considered until recently to be an inherited condition. Several twin studies have demonstrated 100% concordance in monozygotic twins. Two genetic epidemiological surveys suggest that first-degree relatives may have up to an 18-times higher risk and second-degree relatives a 1- to 3-times higher risk of cluster headache than the general population. The increased familial risk of cluster headaches suggests a genetic underpinning. Inheritance is likely to be autosomal dominant with variable penetrance; nonetheless, in some families it may be autosomal recessive or multifactorial (Russell, 2004).

Clinical Features Onset typically begins in the third decade of life, although it has been described as early as 1 year of age and as late as the seventh decade. Periodicity is a cardinal feature of cluster headache. In most patients, the first cluster of attacks, the cluster period, persists on average for

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CHAPTER 102 Headache and Other Craniofacial Pain 6–12 weeks and is followed by a remission lasting for months or even years. The duration of the cluster period is often strikingly consistent for a given patient. A common pattern is one or two cluster periods per year. With time, however, the clusters may become seasonal and then occur more often and last longer. During a cluster, patients typically experience from 1 to 3 or more attacks in 24 hours. The attacks commonly occur at similar times throughout the 24 hours for several weeks to months. Onset during the night, or 1–2 hours after falling asleep, is common. In some patients, these may occur at the onset of rapid eye movement (REM) sleep. At times, several attacks per night can result in sleep deprivation in patients with chronic cluster headache, particularly when they avoid sleep for fear of inducing a further attack. With increasing age, the distinct clustering pattern may be less recognizable. The attacks of pain are similar among individuals. The pain is strictly unilateral and almost always remains on the same side of the head from cluster to cluster. Rarely it may switch to the opposite side in a subsequent cluster or even (less frequently) during a single attack (Capobianco and Dodick, 2006). The pain is generally felt in the retro-orbital and temporal regions (upper syndrome) but may be maximal in the cheek or jaw (lower syndrome). It is usually described as steady or boring and of terrible intensity (so-called suicide headache). Graphic descriptions of feeling the eye being pushed out or an auger or hot poker going through the eye are common. Onset is usually abrupt or preceded by a brief sensation of pressure in the soon-to-be-painful area. An occasional patient may describe tension and discomfort in the limbs and neck ipsilateral to the pain, either during the attack or just preceding it. Infrequently, aura symptoms (as seen in migraine) may precede cluster attacks. The pain intensifies very rapidly, peaking in 5–10 minutes and usually persisting for 45 minutes to 2 hours. Toward the end of this time, brief periods of relief may be followed by several transient peaks of pain before the attack subsides over a few minutes. Occasionally, attacks last twice as long or, less commonly, attacks may seem to merge together, producing 12 or more hours of pain. After the attack, the patient is pain free but exhausted; however, the respite may be transient because another attack may occur shortly. During the pain, patients almost invariably avoid the recumbent position because doing so increases pain intensity. Unlike patients with migraine, they are restless and prefer to pace or sit during an attack. Some remain outdoors even in freezing weather for the duration of the attack. Interestingly, some may find relief or even abort an attack with physical exertion such as push-ups. Otherwise rational persons may strike their heads against a wall or hurt themselves in some other way as a distraction from the intense head pain. Most patients prefer to be alone during the attack. Some apply ice to the painful region, others prefer hot applications; almost all press on the scalp or the eye to try to obtain relief. During the pain, some patients consider suicide; a few attempt it. During the pain of cluster headache, the nostril on the side of the pain is generally blocked; this blockage in turn can be followed by ipsilateral lacrimation. The conjunctiva may be injected ipsilaterally, and the superficial temporal artery may be visibly distended. Profuse sweating and facial flushing on the side of the headache have been described but are rare. Nasal drainage usually signals the end of the attack. Ptosis and miosis on the side of the pain may occur. This Horner syndrome may persist between attacks and is believed to be due to compression of the sympathetic plexus secondary to vasodilatation or other changes in the region of the carotid siphon. Migrainous symptoms such as nausea, photophobia, phonophobia, and/or osmophobia commonly accompany cluster headache (Bahra et al., 2002). Facial swelling, most often periorbital, may develop with repeated attacks. Rarely, transient

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localized swelling of the palate ipsilateral to the pain can be observed. Cluster headache patients tend to have coarse facial skin, deep nasolabial folds, and an increased incidence of hazel eye color. Many of the patients are heavy cigarette smokers and tend to use more alcohol than age- and sex-matched control subjects. Most patients, however, abstain from alcohol during a cluster period, since it commonly triggers attacks.

Pathophysiology The pathogenesis of cluster headache is not entirely understood. While the pain is likely mediated by activation of the trigeminal nerve pathways, the autonomic symptoms are due to parasympathetic outflow and sympathetic dysfunction. The periodicity suggests a defect in CNS cycling mechanisms that is likely related to hypothalamic dysfunction. The most direct evidence in support of a role of the hypothalamus in cluster headache comes from neuroimaging. PET imaging studies have shown activation in the ipsilateral ventral diencephalon during nitroglycerin-induced cluster attacks. In addition, a morphometric study of MRI scanning technology has shown an increase in volume in the diencephalon. Asymmetric facilitation of trigeminal nociceptive processing predominantly at a brainstem level has been detected in patients with cluster headache (Holle et al., 2012). Although vasodilatation has been generally believed to be responsible for the pain, PET studies have shown that carotid artery dilation is not specific for cluster headache but is seen with other types of ophthalmic division pain; it appears to be an epiphenomenon of a primary neural process. In 1993, Moskowitz emphasized the role of the trigeminovascular connections and substance P in the pathogenesis of vascular head pain. Further evidence suggested activation of the trigeminovascular system as manifested by increased levels of CGRP in blood sampled from the external jugular vein ipsilateral to an acute spontaneous attack of cluster headache. Vasoactive intestinal polypeptide levels were similarly elevated in the cranial venous blood during a cluster attack, demonstrating activation of the cranial parasympathetic nervous system. Parasympathetic activation is believed to be responsible for the ipsilateral conjunctival injection, lacrimation, nasal congestion, rhinorrhea, and/or eyelid edema. Trigeminal-parasympathetic overactivity may result in perivascular edema compromising the carotid canal, leading to neurapraxic injury of postganglionic sympathetic fibers and hence a Horner syndrome manifested in ptosis and miosis (May, 2005). The fact that low-frequency sphenopalatine ganglion (SPG) stimulation can provoke cluster-like headaches with autonomic features suggests efferent parasympathetic outflow from this ganglion may give rise to autonomic symptoms and activate the trigeminovascular sensory afferents which may initiate pain (Schytz et al., 2013).

Investigations In most patients, the diagnosis is certain on clinical grounds alone. However, imaging studies are recommended for all patients at the time of diagnosis, particularly for those presenting with an atypical episodic cluster (“cluster-like”) headache or for patients with headache in the chronic phase. “Cluster-like” headaches can be associated with underlying intracranial or neck structural lesions such as neoplasms, paranasal sinus disease, vascular malformations, and cervicocephalic arterial aneurysms or dissections (Capobianco and Dodick, 2006). Therefore, as part of the evaluation, a contrast-enhanced brain MRI scan is recommended to help reassure the patient, their relatives, and physicians that the extremely painful attacks are not due to some major abnormality. Clinical judgment guides the necessity for further testing.

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PART III Neurological Diseases and Their Treatment

Differential Diagnosis The diagnosis of cluster headache is essentially clinical. It is helpful to have confirmation from the spouse or relatives of the periodicity, rapidity of onset and resolution, and presence of conjunctival injection, rhinorrhea, ptosis, and altered behavior during the attack. Despite the stereotyped nature of the attacks from episode to episode and from patient to patient, the diagnosis is often missed for several years. Conditions that cause episodic unilateral head and facial pain should be considered, but they are easy to exclude. Trigeminal neuralgia, sinusitis, dental disease, and glaucoma may superficially mimic the pain of cluster headache, but, in each, the temporal profile, lack of associated autonomic features, and past history allow easy differentiation. Similarly, migraine, temporal arteritis, and the headache of intracranial space-occupying lesions should not be difficult to differentiate from cluster headache. Orbital, retro-orbital, and frontal pain associated with Horner syndrome can result from ipsilateral dissection of the carotid artery; unlike the pain of cluster headache, however, it is not episodic and does not produce the restlessness so characteristic of this condition. The pain associated with Tolosa-Hunt syndrome and Raeder paratrigeminal syndrome is accompanied by oculomotor or trigeminal nerve dysfunction, a feature that should easily prevent confusion with cluster headache. Similarly, pain from compression of the third cranial nerve by an aneurysm should be easy to distinguish from cluster headache pain, especially when partial or complete third cranial nerve palsy is detected. Cluster headache is a member of the primary headache syndromes collectively referred to as the trigeminal-autonomic cephalalgias (TACs); the other TACs have to be differentiated from cluster headache, since their management is usually different. These are discussed elsewhere in this chapter.

Treatment and Management The patient should be reassured that the syndrome, even though unbearably painful, is benign and not life threatening. Pain reduction but not cure should be promised. The frequency, severity, and brevity of individual attacks of cluster headache and their lack of response to many symptomatic measures necessitate the use of a prophylactic treatment regimen for most patients. The treatment plan is determined by several factors, including whether the phase is episodic or chronic and whether other disease states such as hypertension and coronary or peripheral vascular insufficiency are present.

Pharmacological management

Acute (symptomatic) therapy. Given the rapid onset and short time to peak intensity of the pain of cluster attacks, fastacting symptomatic treatment is imperative. Oxygen, subcutaneous sumatriptan, and subcutaneous or intramuscular DHE provide the most rapid, effective, and consistent relief for cluster headache attacks. Oxygen inhalation is one of the most effective symptomatic treatments for cluster headache. Its advantages are that it has no established adverse effects, it can be administered several times daily, it can be combined with other treatments, and it is inexpensive. Inhaled oxygen at 100% for 15–20 minutes via a nonrebreathing face mask can be dramatically effective for aborting a cluster attack. Rates of oxygen delivered at 12 L/min have been demonstrated to be effective (Cohen et al., 2009). Flow rates of 15 L/min may be effective when lower rates are not (Rozen, 2009). The best position for oxygen inhalation is sitting on the edge of a chair or bed and leaning forward with arms on knees. The mechanism of action of oxygen remains to be fully elucidated; recent data suggest

that the beneficial response is mediated through its effects on the parasympathetic outflow via the facial/greater petrosal nerve, with no direct effect on trigeminal afferents (Akerman et al., 2009). Although portable regulators are available, the major drawbacks to oxygen use are the inconvenience, lack of accessibility, and need to have a regulator and canister available at all times. Unfortunately, in some cases, oxygen merely delays an attack rather than aborting it (Capobianco and Dodick, 2006). Administration of sumatriptan by subcutaneous injection in a dose of 4–6 mg is an effective means of aborting an individual cluster attack. Sumatriptan nasal spray is less effective than the subcutaneous formulation. DHE is available in injectable and intranasal formulations. DHE-45 administered IV provides prompt and effective relief of a cluster attack. The intramuscular and subcutaneous routes of administration provide slower relief. The potential role of intranasal DHE (2 mg) has not been validated in a controlled fashion. Other potential symptomatic options include zolmitriptan nasal spray, octreotide, and intranasal lidocaine administered by dripping 4% viscous lidocaine into the nostril ipsilateral to the pain. Preventive pharmacotherapy. Use of an effective preventive regimen cannot be overemphasized. The goals of preventive therapy are to produce a rapid suppression of attacks and maintain remission over the expected duration of the cluster period. Preventive therapy in cluster headache can be divided into transitional and maintenance prophylaxis. Transitional p rophylaxis. Transitional prophylaxis involves the short-term use of corticosteroids, occipital nerve blocks, ergotamine, or DHE. This typically induces a rapid suppression of attacks while one of the maintenance agents can take effect. During the initial cluster or when the patient’s past history suggests that a cluster will be of limited duration, relief can usually be obtained by administering a short course of corticosteroids. Several regimens are effective, such as 60 mg of prednisone as a single daily dose for 3–4 days, followed by a 10-mg reduction after every third or fourth day, to thereby taper the dose to zero over 18 or 24 days. Alternatively, an intramuscular injection of triamcinolone (80 mg) or methylprednisolone (80–120 mg) can be used to give a tapering corticosteroid blood level. Whichever treatment regimen is used, the patient usually obtains relief from the headaches until the lower doses or blood levels of corticosteroids are approached. The course can be repeated several times, but thereafter the risk for side effects suggests that an alternative prophylactic regimen should be used if the cluster has not run its course. Ergotamine tartrate can be given orally or by rectal suppository on retiring to prevent nocturnal attacks of headache. This approach may only postpone the attack until morning, when it may be more troublesome if it occurs when the patient is at work. Prophylactic use of ergotamine tartrate can nevertheless be valuable, but great care must be taken to regulate the dose if chronic ergotism is to be avoided. Most patients with cluster headache can be given 2 mg of ergotamine tartrate daily for several days without adverse effects; however, caution must be used with ergotamine, triptans, and analgesics to avoid the development of MOH (Paemeleire et al., 2006). DHE is a well-tolerated ergot derivative that can be given in a dose of 0.5–1 mg every 6–8 hours in an attempt to prevent headaches, but this dose should be continued for only a few days to avoid ergotism. In addition, an occipital nerve block ipsilateral to the cluster headache may be useful as a transitional measure in some patients when the use of other medications may be contraindicated or poorly tolerated.

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CHAPTER 102 Headache and Other Craniofacial Pain Repeating this every 3 months may benefit some with chronic cluster headache (Lambru et al., 2014a). Maintenance prophylaxis. Maintenance prophylaxis refers to the use of preventive medications throughout the anticipated duration of the cluster period. The preventive medication is initiated at the onset of the cluster period, typically in conjunction with corticosteroids, and is continued after the initial suppressive medication is discontinued. The calcium channel blockers (Leone et al., 2009), particularly verapamil, are considered first-line preventive therapy for both episodic and chronic cluster headache. They are generally well tolerated and can be used safely in conjunction with ergotamine, sumatriptan, corticosteroids, and other preventive agents. The initial starting dose of verapamil is 80 mg three times a day after a normal ECG has been demonstrated. The authors have encountered several patients who appear to have an improved response with the nonsustained release formulation. The daily dose can be increased in 40- to 80-mg increments every 7–14 days until the attacks disappear, adverse effects occur, or the maximum daily dose of 720 mg is achieved (Leone et al., 2009). Doses as high as 960 mg daily may be required (Goadsby, 2012). These doses are considerably higher than those used for hypertension and heart disease (Rozen, 2009). If a patient requires more than 240 mg/day, an ECG is recommended before each dose increment, 2 weeks after the last adjustment, and periodically thereafter if verapamil is used long term (Cohen et al., 2007). The most common side effect of verapamil is constipation, but lightheadedness, hypotension, fatigue, peripheral edema, and bradycardia can also occur. Methysergide can be effective for reducing or preventing cluster headache in about 60% of patients, but it is no longer available in the United States or Canada. For patients who have chronic cluster headache with attacks that occur daily for years, relief may be obtained with lithium. Lithium carbonate, 300 mg three times a day, can be given initially and the dose adjusted at 2 weeks to obtain a serum lithium level of about 1 mEq/L. Side effects at this level include a mild tremor of the limbs, gastrointestinal distress, and increased thirst. The therapeutic range is very narrow, and blood levels of more than 1.5 mEq/L are to be avoided. Nephrotoxicity, goiter formation, and a permanent diabetes insipidus-like state have been reported after lithium treatment. In chronic cluster headache, lithium may have a beneficial effect within 1 week, but the response is typically delayed for several weeks. Although attacks may recur after some months, a renewed response to lithium may occur if the drug is withdrawn and then reintroduced after a few weeks. In patients whose headaches respond to lithium, use of the drug should be discontinued every few months to determine whether the cluster headaches have subsided. While lithium is being given, it is necessary to monitor the blood level at regular intervals to avoid the development of serious side effects. Thiazide diuretics should not be used concurrently because they can cause a rapid elevation of blood levels of lithium. Despite the available treatments, management of patients with chronic cluster headache can be extremely difficult because many of their headaches do not respond or respond only briefly to the treatment regimens already described. In such patients, a combination of several medications may give relief. On the basis of clinical experience, the combination of verapamil and topiramate or verapamil and lithium can prove effective. For particularly resistant headaches, triple therapy may be necessary, consisting of verapamil with either topiramate or valproate plus lithium. The authors have had some success with onabotulinumtoxinA injections for chronic cluster headache, although there are no controlled studies available for its use in cluster

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headache. Corticosteroids can be useful in chronic cluster headache to provide brief remissions for fixed periods. Nonetheless, long-term use of corticosteroids in patients with chronic cluster headache must be resisted. Given the role that CGRP plays in cluster headache, the monoclonal antibodies targeting CGRP or its receptor could prove to be viable options in the prophylaxis of headache. Only galcanezumab has been studied in cluster headache, but as of this publication has not been FDA-approved for cluster headache. In patients for whom conventional first-line therapy is ineffective, poorly tolerated, or contraindicated, one may consider adjunctive therapy with a number of potential agents including melatonin, baclofen, and intranasal civamide (Francis et al., 2010; May et al., 2006). Surgical treatment. Surgery is a last resort for medicationresistant chronic cluster headache, an option to be considered when all pharmacological treatment options have been thoroughly exhausted (Leone et al., 2009). Ablative procedures reported as potentially successful include radiofrequency thermocoagulation of the gasserian ganglion, trigeminal sensory rhizotomy, microvascular decompression of the trigeminal nerve, and sphenopalatine ganglion radiofrequency ablation (Leone et al., 2009; Narouze et al., 2009). Unfortunately, adverse events of these procedures can be severe and include corneal anesthesia, keratitis, and anesthesia dolorosa. Furthermore, the benefit may be less than robust and short-lived. These procedures have therefore been for the most part abandoned and are now used only rarely. Neurostimulation procedures involving central or peripheral nervous system targets have been employed to treat refractory chronic cluster headache (Leone et al., 2009). At present, these are preferred over the previously discussed interventions but should only be considered in patients with medically intractable CH in tertiary headache centers, and the least invasive options should be considered first (Martelletti et al., 2013). In 2003, Franzini and colleagues reported a complete response in five patients with medically refractory chronic cluster headache after stereotactic implantation of a stimulating electrode into the periventricular hypothalamus. The rationale for this procedure is based on the activation of the periventricular hypothalamus seen on PET scanning of patients during attacks of cluster headache. Sixteen patients with intractable chronic cluster headache were successfully treated by hypothalamic stimulation, with no significant adverse events in this series (Leone et al., 2005). At a mean follow-up of 23 months, 13 of the 16 patients were persistently pain free or almost pain free, while the rest were improved (Leone et al., 2006). Similar results from approximately 60 treated patients have been reported thus far. Hypothalamic deep brain stimulation may therefore be an efficacious procedure to relieve intractable chronic cluster headache. There have been, however, several intracranial hemorrhages reported with this procedure, including one death from such a hemorrhage. Less-invasive interventions are therefore favored prior to considering deep brain stimulation. Peripheral stimulation of the occipital nerve has been employed in several open-label trials of patients with medically intractable cluster headache. One used bilateral stimulators in eight patients (Burns et al., 2007), and the other used unilateral stimulation (side ipsilateral to headaches) in eight patients (Magis et al., 2007). Substantial improvement occurred in a majority of individuals in each study, which was durable for a mean follow-up of 20 months and 15 months, respectively. The favorable outcome of 14 patients with medically intractable chronic cluster headache implanted with bilateral electrodes in the suboccipital region was published (Burns et al., 2009). Others have

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PART III Neurological Diseases and Their Treatment

Paroxysmal hemicrania (PH), short-lasting unilateral neuralgiform headache attacks (SUNCT/SUNA), and hemicrania continua (HC) are all classified along with cluster headache as trigeminal autonomic cephalalgias by the Headache Classification Committee (IHS, 2018). PH and SUNCT/SUNA are distinguished from cluster headache by having shorter attack durations and higher attack frequencies. PH and HC (the most prolonged TAC), respond completely to preventive treatment with indomethacin, which is not the circumstance in cluster headache or SUNCT/SUNA. Although rare, the occurrence of concomitant different TACs may manifest in single individuals (Totzeck et al., 2014).

and consider an alternative diagnosis. If there is an absolute response to the indomethacin trial, however, indomethacin is continued as long as it is tolerated. The headache usually resolves within 1–2 days of initiating the effective dose. Dose adjustments are often needed to address clinical fluctuations. Skipping or delaying doses may result in recurrence of the headache. Efforts should be placed for patients to find the lowest dose possible that controls the pain. We typically place patients on gastric mucosa protective agents while they take daily indomethacin. In patients with episodic PH, the indomethacin can be continued for roughly 2 weeks beyond the typical headache bout duration, and then a trial of tapering can be undertaken. Some patients are able to discontinue indomethacin without recurrence (presumably representing a transition from chronic to episodic PH), so treatment should be tapered periodically to ensure that patients are still symptomatic. During this taper, we usually decrease the indomethacin dose by 25 mg every 3 days until either the headache recurs or the patient gets completely off indomethacin. Despite the differences in typical attack frequency and duration between cluster headache and PH, in some circumstances cluster headache and PH can be clinically indistinguishable. Thus, any patient presenting with what appears to be cluster headache but is refractory to usual cluster headache treatments should have an indomethacin trial. The therapeutic response to indomethacin is the most reliable differential diagnostic criterion for cluster headache and PH. Other treatments reported to be effective in PH include celecoxib, rofecoxib, botulinum toxin A, verapamil, nicardipine, flunarizine, ibuprofen, ketoprofen, aspirin, piroxicam, naproxen, diclofenac, phenylbutazone, acetazolamide, topiramate, prednisone, lithium, ergotamine, sumatriptan, oxygen, greater occipital nerve block, occipital nerve stimulation, and hypothalamic stimulation (Boes and Swanson, 2006; Goadsby et al., 2010).

Paroxysmal Hemicrania

Short-Lasting Unilateral Neuralgiform Headache Attacks

Paroxysmal hemicrania has a typical onset in the third decade of life. The female-to-male ratio is approximately 1:1, which contrasts with cluster headache, for which there is an overwhelming male predominance (Cittadini et al., 2008). Chronic PH and episodic PH differ in their temporal profile. In chronic PH, attacks occur for more than a year without remission or with remission periods lasting less than 3 months. Episodic PH is characterized by bouts of attacks occurring in periods lasting from 7 days to 1 year and separated by pain-free remission periods lasting at least 3 months (IHS, 2018). The headache bouts can range from 4 to 24 weeks, and remission periods can last 12–376 weeks. While active, both disorders are associated with daily attacks of severe short-lived unilateral pain, which is often maximally felt in the orbital/retro-orbital or temporal region, although extra-trigeminal pain in the occiput can occur. The mean attack frequency in one study was 11 in 24 hours, with a median of 9 attacks in 24 hours and a range from 2 to 50 attacks per day (Cittadini et al., 2008). The mean length of attacks was 17 minutes, with a median of 19 minutes and a range from 10 seconds to 4 hours. Similar to cluster headache, each paroxysm is accompanied by at least one robust ipsilateral autonomic feature, which may include lacrimation, miosis, ptosis, eyelid edema, conjunctival injection, nasal congestion, rhinorrhea, or forehead/facial sweating. Numerous cases of secondary PH have been reported and underline the importance of MRI of the brain in every case. PH typically responds completely to indomethacin. The dose required ranges from 25 to 300 mg/day. Most patients require around 150 mg/day. In a patient with suspected PH, the usual indomethacin trial includes indomethacin 25 mg 3 times a day for 3 days, then 50 mg 3 times a day for 3 days, and then finally 75 mg 3 times a day for 3 days. If at the end of this trial there is minimal or no response, discontinue indomethacin

Short-lasting unilateral neuralgiform headache attacks are attacks of moderate or severe, strictly unilateral head pain lasting seconds to minutes, occurring at least once a day and usually associated with prominent lacrimation and redness of the ipsilateral eye. This disorder has two clinical phenotypes. When the attacks are associated with both conjunctival injection and lacrimation (tearing) it is referred to as SUNCT (short-lasting unilateral neuralgiform headache with conjunctival injection and tearing). When only one or neither of conjunctival injection or lacrimation is present it is diagnosed as SUNA (short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms) (IHS, 2018). SUNCT and SUNA are rare disorders and their treatment is entirely prophylactic, in general using the same medications. Knowledge of SUNCT is more ample when compared to SUNA, as the latter has been described more recently. SUNCT’s painful paroxysms are usually felt in or around the eye and can sometimes be triggered by cutaneous stimuli. Single stabs last on average 58 seconds, groups of stabs usually last 396 seconds, and a sawtooth attack (many stabs between which the pain does not totally resolve) typically lasts 1160 seconds (Cohen et al., 2006). Attacks may occur 2–600 times a day, with a mean of 59 attacks per day. The associated ipsilateral conjunctival injection and lacrimation are very prominent. Unlike trigeminal neuralgia, most of the pain in SUNCT is in a V1 distribution, and tears often run down the face. Only 4% of patients with trigeminal neuralgia have pain in the ophthalmic division alone (Boes and Swanson, 2006). Unlike trigeminal neuralgia, 95% of SUNCT patients have no refractory period. The brevity and high frequency of attacks in SUNCT should make the distinction from cluster headache quite clear. Numerous cases of secondary SUNCT have been

reported similar outcomes (Leone et al., 2017; Miller et al., 2017). This approach deserves additional study via prospective randomized controlled trials to further determine its role in cluster headache management. Factors predictive of a beneficial response to occipital nerve stimulation have failed to be elucidated; pain relief after greater occipital nerve block does not predict efficacy (Leone et al., 2009). Schytz has shown that high-frequency stimulation of the SPG can abort cluster headaches (Schytz et al., 2013). Of very recent interest are the encouraging results from a randomized, sham-controlled study stimulating the SPG in medically refractory chronic cluster headache. Throughout a period up to 8 weeks, 19 of 28 (68%) patients had a clinically significant improvement: seven (25%) achieved pain relief in ≥50% of treated attacks, 10 (36%) a ≥50% reduction in attack frequency, and two (7%), both. Results suggest a potential dual benefit (acute pain relief and attack prevention) (Schoenen et al., 2013a). Other studies are necessary to confirm these findings.

Other Trigeminal Autonomic Cephalalgias

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CHAPTER 102 Headache and Other Craniofacial Pain reported and underline the importance of MRI of the brain in every case. Lamotrigine has been effective in several patients when given in an open fashion. Topiramate, carbamazepine, and gabapentin are all reasonable alternatives to consider. Other options with uncontrolled evidence include oxcarbazepine, verapamil, clomiphene, zonisamide, onabotulinumtoxinA, corticosteroids, and IV lidocaine. Indomethacin has no effect. The role of neurosurgical intervention directed at the trigeminal nerve in the treatment of SUNCT is unclear, and it should only be considered as a last resort. Other treatments reported to be effective in SUNCT include occipital nerve block, opioid blockade of the superior cervical ganglion, hypothalamic stimulation, and surgical removal of a pituitary microadenoma. Both SUNCT and SUNA have been reported to respond to trigeminal nerve microvascular decompression (Williams et al., 2010). Out of 16 patients, 75% have become pain free for up to 32 months (Favoni et al., 2013). Of more recent interest in medically refractory SUNCT and SUNA is the possible role of bilateral occipital nerve stimulation (ONS). Out of nine patients in a recent study, all but one obtained substantial relief. Because ONS is not cranially invasive or neurally destructive, it might be considered the surgical treatment of choice for medically intractable SUNCT and SUNA (Lambru et al., 2014b). The precise role these two interventions may have in the management of medically refractory SUNCT/SUNA remains to be determined.

Hemicrania Continua As the name implies, hemicrania continua is characterized by a continuous unilateral headache of moderate intensity that may involve the entire hemicranium or simply be confined to a focal area. The femaleto-male ratio is approximately 2:1, and the average age of onset is 28 years (range, 5–67 years). Although invariably continuous, this disorder may sometimes resemble a prolonged unilateral migraine attack lasting several days to weeks, with headache-free remissions. The continuous headache is typically punctuated by painful unilateral exacerbations lasting 20 minutes to several days. These periods of increasing pain intensity are accompanied by one or more autonomic features that are usually subtler than those seen in PH or cluster headache and about two-thirds report a sense of restlessness or agitation (Cittadini and Goadsby, 2010). Primary stabbing headache (“icepick headache”) is often a feature of this disorder, usually on the ipsilateral side and usually during a period of exacerbation. About a third report an ipsilateral eye itch and most have migrainous features including photoand phonophobia (unilateral in half of patients) and motion sensitivity (Cittadini and Goadsby, 2010). Because of its daily persistence, hemicrania continua may be seen in the context of medication overuse, which may alter the clinical features. Therefore, a higher index of suspicion may be required in these cases. It is reasonable to consider a trial of indomethacin in any patient with a chronic unilateral daily headache that does not respond to other conventional medications, especially if autonomic features are present. Several cases of secondary hemicrania continua have been reported, highlighting the importance of brain MRI in the evaluation of these patients. Hemicrania continua patients respond completely to prophylactic indomethacin. The indomethacin regimen is similar to that described for PH. Unfortunately, about a fourth of patients do not tolerate indomethacin, mainly from gastrointestinal side effects. Without indomethacin, treatment can be challenging. Cases of hemicrania continua have been reported that have not recurred after stopping indomethacin. It is therefore reasonable to periodically withdraw treatment (Boes and Swanson, 2006). Complete response to rofecoxib, celecoxib, aspirin, naproxen, ibuprofen, diclofenac, and piroxicam in hemicrania continua has been reported. Dihydroergotamine, methysergide, corticosteroids,

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acemethacin, acetaminophen with caffeine, lamotrigine, gabapentin, topiramate, melatonin, valproic acid, verapamil, onabotulinumtoxinA, and lithium have been reported to be effective in some cases. Other treatments include occipital or supraorbital nerve blocks and occipital nerve stimulation.

Other Primary Headaches Tension-Type Headache

Almost everyone has a headache at some time when stressed, overworked, anxious, or subject to prolonged muscular strain. Such headaches rapidly subside with relaxation, sleep, or ingestion of simple analgesics. Tension-type headaches have historically been ascribed to persistent contraction of scalp, neck, and jaw musculature. However, the concept of muscle contraction causing headache has been questioned. Electromyographic (EMG) studies and other observations have led some to believe tension-type headache and migraine may be extreme ends of a spectrum. In the past, the term “tension” had been tacitly taken to mean either emotional or muscle tension, thus implying both pathogenesis and pain mechanism. The current classification places the word “type” after “tension,” and the term tension-type headache is now used to bring attention to the fact that actual muscle tension may not be a key factor in the pathophysiology. The prevalence of tension-type headache ranges in the general population from 30% to 78% (IHS, 2018). In the United States, an epidemiological study showed a higher prevalence in Caucasian women and in patients aged 30–39 (Schwartz et al., 1998). Tension-type headaches can begin at any age, are generally bilateral, and are often described as a sense of pressure or wearing a tight band around the head. The pain is of mild to moderate intensity, tends to not be aggravated by routine physical activity, and may wax and wane throughout the day or may be present and steady for days, weeks, or even years at a time. Tension headaches have no associated nausea or vomiting and are much less commonly associated with light and sound sensitivity than migraine. The pathophysiology of tension-type headache is incompletely understood. That emotional tension leads to muscle tension and hence to headache is too simplistic. A far more complex central mechanism is likely responsible for the pain, likely involving interaction between peripheral myofascial input and sensitization of second-order nociceptive neurons in the trigeminal nucleus and spinal dorsal horn (Fumal and Schoenen, 2008). A lower-pressure pain tolerance threshold has been shown in the fingers of patients with chronic tension-type headache compared to healthy controls, suggesting the presence of allodynia and hyperalgesia in patients with this disorder. Physical examination in acute tension-type headache is generally unrevealing. Chronic tension-type headache may be associated with craniocervical musculature tenderness. In elderly patients, the ESR should be determined to help exclude giant-cell arteritis. If the headache is new or progressively worsening, a CT or MRI of the brain can help rule out serious structural intracranial diseases mimicking tension-type headache. Cervical spine imaging may be needed to rule out secondary causes of sustained contraction of the cervical and scalp muscles. Patients with obstructive sleep apnea (OSA) have a higher likelihood of developing tension-type headache than patients without it. (Chiu et al., 2015). We routinely screen for OSA in patients with frequent or chronic tension-type headache. For occasional mild tension-type headache, treatment with aspirin, acetaminophen, or NSAIDs may be sufficient. More severe headaches usually require a prescription analgesic, but no specific

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1776

PART III Neurological Diseases and Their Treatment

preparation has been shown to be better than another. The combination of acetaminophen with isometheptene and dichloralphenazone may be useful for moderately severe headaches. The frequent use of combination analgesics with codeine, propoxyphene, or butalbital with or without caffeine should be avoided to prevent nedication overuse headache. The most effective prophylactic drug is possibly amitriptyline. Controlled trials have shown more than 50% improvement in over 65% of patients. The usual dose is 50–150 mg/day. The drug is better tolerated if given as a single bedtime dose. Other tricyclic antidepressants, gabapentin, mirtazapine, sodium valproate, or topiramate may be used as prophylactics if amitriptyline is not tolerated or contraindicated. Techniques to promote relaxation of the scalp and neck muscles (e.g., biofeedback, neck massage) can help in the short term, but their long-term benefit has not been established (Fumal and Schoenen, 2008). In contradistinction to the infrequent variety, chronic tension-type headache (more than 15 headache days a month) can persist for years and can be difficult to manage.

Primary Cough Headache Cough headache is a headache of sudden onset that is precipitated by a brief, nonsustained Valsalva maneuver such as coughing, laughing, sneezing, or bending over. The pain is typically bilateral, explosive, and lasts seconds to minutes (Chen et al., 2009; Pascual, 2009). As a rule, the patient is free from pain between attacks. The mean age at onset of primary cough headache is around 60 years. The proportion of patients who have an underlying structural cause has varied between 11% and 59% in studies done in the MRI era. Chiari type I malformation is the most common structural abnormality found on imaging, but other entities have been described, such as headache secondary to spontaneous spine CSF leak, middle cranial or posterior fossa brain tumors, brain metastases, pituitary tumors, posterior fossa arachnoid cysts, basilar impression, sphenoid sinusitis, subdural hematoma, RCVS, and possibly unruptured intracranial aneurysm and carotid stenosis (Chen et al., 2009; Evans and Boes, 2005; Kato et al., 2018; Pascual et al., 2008). As a spontaneous spine CSF leak can present as cough headache without an orthostatic component, all patients presenting with cough headache should get an MRI with gadolinium to look for pachymeningeal enhancement (Evans and Boes, 2005). In a large series of spontaneous spinal CSF leaks secondary to CSF-venous fistulas headache occurred in isolation to Valsalva maneuvers in 12% of patients; a finding that warrants considering this entity early in the differential diagnosis of Valsalva-induced (“cough”) headache (Duvall et al., 2019). Whether an unruptured intracranial aneurysm can present with cough headache is unclear but given this possibility as well as the possibility of reversible cerebral vasoconstriction, it would be reasonable to obtain an MRA of the intracranial circulation in most cases. Typically cervical vessels do not need to be imaged unless symptoms of cerebral ischemia are present. The treatment of choice is indomethacin, administered in a regimen similar to that described for PH. The response to indomethacin does not confirm a benign etiology. Other reports suggest that primary cough headache may respond to topiramate, acetazolamide, methysergide, or LP (Chen et al., 2009; Medrano et al., 2005). Any chest disease that may be causing the cough should be identified and treated.

Primary Exercise Headache Primary exercise headache (previously called primary exertional headache) is a bilateral throbbing headache that is precipitated by prolonged physical exercise. The ICHD-3 differentiates the exercise with this type of headache as more sustained strenuous effort rather than a short burst

of effort (like a Valsalva maneuver) that may trigger primary cough headache, though the two headaches may occasionally co-occur in the same patient (IHS, 2018; Sjaastad and Bakketeig, 2002). The headache is not explosive in onset but rather builds in intensity and lasts between 5 minutes and 48 hours. The headache can be prevented by avoiding excessive exertion, particularly in hot weather or at high altitude. In one prospective study, the average age at onset for primary exertional headache was 40 years, whereas the average age at onset for primary cough headache was 60 years (Pascual et al., 2008). Similar to cough headache, this disorder can be benign or symptomatic of an underlying cause. In one series, 12 of 28 patients with exertional headache were found to have underlying causes (Pascual et al., 1996). These patients, however, were older (mean age 42 vs. 24 years), developed acute severe bilateral headaches lasting 1 day to 1 month, and developed accompanying symptoms of vomiting, diplopia, or neck rigidity. Potential causes of secondary exertional headache include subarachnoid hemorrhage, cerebral metastases, intracranial hypertension, pansinusitis, and pheochromocytoma. Exercise-induced cardiac ischemic pain can refer to the head and neck and is referred to as cardiac cephalalgia. A patient with risk factors for coronary artery disease presenting with an exertional headache should get an exercise stress test or comparable investigation. Preventive treatment with a beta-blocker or indomethacin on a daily basis is effective in some primary exertional headache patients. Other migraine preventives may show benefit. Ergotamine or indomethacin preemptively before exercise may be effective. A prescribed warm-up period can sometimes prevent exertional headache (Pascual, 2009).

Primary Headache Associated With Sexual Activity Headaches precipitated by sexual activity can occur as a dull bilateral ache which gradually increases with sexual excitement (previously called preorgasmic headache) or an abrupt explosive headache at orgasm (previously called orgasmic headache), with some patients experiencing both (IHS, 2018). The pain is usually bilateral with a median duration of 30 minutes (severe pain may last 1 minute to 24 hours). The mean age at onset ranges from the second to the fourth decade, and there is a clear male predominance (Cutrer and DeLange, 2014). Three-quarters of patients have their headaches in bouts. Symptomatic headaches precipitated by sexual activity share a similar differential to secondary causes of exercise-induced headaches. With orgasmic headache in particular, it is mandatory to exclude such conditions as subarachnoid hemorrhage, arterial dissection, pheochromocytoma, and RCVS. In patients with risk factors for coronary artery disease, the possibility of cardiac cephalalgia should also be investigated. Approximately 50% of patients can ease the headache by taking a more passive role during sexual activity. Indomethacin (25–50 mg) given 30–60 minutes prior to sexual activity may prevent the headache. For those intolerant of or unresponsive to indomethacin, an oral triptan can be tried 30–45 minutes before sexual activity (Frese et al., 2006). For patients with frequent attacks, daily propranolol, metoprolol, or diltiazem may be effective.

Primary Thunderclap Headache A “thunderclap headache” is a severe headache that reaches maximal intensity in less than 1 minute (IHS, 2018). It is the rapidity with which the headache reaches maximum intensity that differentiates a thunderclap headache from other severe headache types. As discussed previously, there are numerous potential causes of a thunderclap headache, including but not limited to subarachnoid hemorrhage, spontaneous spine CSF leak, RCVS, cervical artery dissection, cerebral venous sinus thrombosis, pheochromocytoma, and hypertensive crisis

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CHAPTER 102 Headache and Other Craniofacial Pain (see Subarachnoid Hemorrhage and Thunderclap Headache section). When no underlying cause for the thunderclap headache is identified following a comprehensive evaluation, a diagnosis of “primary thunderclap headache” is given. It is not clear if primary thunderclap headaches are a true entity or if they represent missed diagnoses of underlying causes for the thunderclap headache such as mild forms of the RCVS or RCVS with delayed angiographic appearance of vasoconstriction.

Cold-Stimulus Headache Cold-stimulus headache is a generalized headache that follows exposure to a cold stimulus that is either applied externally, ingested, or inhaled. For example, this might include exposure to cold weather, diving into cold water, or passing a solid or liquid cold material over the palate or posterior pharynx (previously known as ice cream headache) (IHS, 2018). A lifetime prevalence of 15% was found in a cross-sectional epidemiological survey of a 25- to 64-year-old general population (Rasmussen and Olesen, 1992). Whether this disorder is more common in migraineurs is a matter of debate. The pathophysiology is not completely understood. Clinically, after exposure to the cold stimulus, the pain begins within seconds, peaks over 20–60 seconds, and then subsides within 10 minutes after removal of the stimulus (or up to 30 minutes after removal of an external cold stimulus). The headache location is most commonly midfrontal, followed by bitemporal or occipital. In patients with migraine, the pain might be referred to the usual site of their migraine headaches. Cold-stimulus headache is best prevented by avoiding the known stimulus. Cheshire and colleague suggest divers can prevent the headaches by using a Neoprene hood when exposed to very cold waters (Cheshire and Ott, 2001).

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rounded or elliptical area of the head, typically 1–6 cm in diameter. Pain is commonly described as pressure or stabbing, and is frequently accompanied by hypesthesia, dysesthesia, paresthesia, allodynia, and/ or tenderness (IHS, 2018). A minority of patients may develop trophic changes such as hair loss or a patch of skin depression. Hair heterochromia has been described in one patient (Dabscheck and Andrews, 2010). Similar headaches have been related to structural lesions such as meningiomas, arachnoid cysts, and fibrous dysplasia of the skull. It is therefore important to perform imaging with an MRI to rule out underlying structural etiologies. Local subcutaneous anesthetic injections are generally not felt to be helpful. Small series suggest that gabapentin (300–1800 mg daily), tricyclic antidepressants, and onabotulinumtoxinA may be useful (Cuadrado et al., 2018; Guerrero et al., 2012). Twenty-five units of onabotulinumtoxinA divided among 10 injection sites in and around the circumscribed affected areas of pain has been reported to help some (Mathew et al., 2008a), the procedure is repeated approximately every 3 months if a favorable response is obtained. While one series also suggests local arterectomy may help in a select subset of patients (Guyuron et al., 2018), this is not a treatment we recommend performing routinely at present.

Hypnic Headache

External-pressure headache refers to headache which arises from compression or traction on the scalp, without actual tissue damage. The headache should exclusively come on within an hour of stimulus exposure and remit within an hour of removal. Reported examples include headache from helmet wearing, swimming goggles, and traction from a ponytail.

Hypnic headache is a primary headache disorder wherein the attacks of headache occur exclusively during sleep, often between 2 a.m. and 4 a.m. (Holle et al., 2013). The mean age of onset is 63 years. The pain is usually mild to moderate, but 20% of patients report severe pain. The pain is bilateral in about two-thirds of cases. The attack usually lasts from 15–180 minutes, but longer durations have been described. In contrast to cluster headache, hypnic headache usually has no autonomic features. Caffeine before bedtime (one strong cup of regular coffee or an espresso if available) is often helpful in preventing that night’s hypnic headache. Lithium, melatonin, and indomethacin can also be helpful in preventing hypnic headache. Patients responsive to gabapentin, pregabalin, verapamil, acetazolamide, onabotulinumtoxinA, topiramate, and hypnotics have also been reported (Garza and Swanson, 2007).

Primary Stabbing Headache

New Daily Persistent Headache

Patients with primary stabbing headache describe brief, extremely sharp jabs of pain that occur without warning and can be felt anywhere in the head, including the orbit. These recur with irregular frequency, one or many times per day. The pains are described as being like a spike driven into the skull: hence, the previous term icepick headache. Similar pains have been described under different terms by other investigators (e.g., jabs and jolts, ophthalmodynia periodica). There are no associated cranial autonomic features and no trigeminal distribution trigger points (Pascual, 2009). Stabbing pains more commonly occur in patients subject to migraine, cluster headache, or hemicrania continua. Icepicklike head pain has also been described in patients with giant-cell arteritis. Because of the brevity of the pain, the sporadic nature of attacks, and the common occurrence of spontaneous remissions, treatment is not usually required and reassurance generally suffices. However, in patients with “icepick status,” in whom stabs of pain occur often, the treatment of choice is indomethacin, administered in a regimen similar to that described for PH. Cyclooxygenase-2 (COX-2) inhibitors, gabapentin, and melatonin (3–12 mg orally at night) have also been reported to be useful (Ferrante et al., 2010; Franca et al., 2004).

New daily persistent headache (NDPH) is a daily headache that is unremitting from onset or very soon after onset (within 24 hours at most) (IHS, 2018). The vast majority of patients can pinpoint the exact date their headache started. Infection, flu-like illness, surgery, and stressful life events may precede NDPH. How these may result in NDPH is unclear and more than half of patients do not recognize a triggering or precipitating event (Rozen, 2016). Clinically, NDPH may have features suggestive of either migraine or tension-type headache. Secondary headache disorders, particularly spontaneous spine CSF leaks and cerebral venous sinus thrombosis, need to be ruled out. In general, if no secondary headache cause is found, it is recommended to classify the dominant headache phenotype, whether it is migraine or tension-type headache, and treat with preventives accordingly. Even with aggressive treatment, however, unfortunately many patients do not improve and become treatment refractory (Garza and Schwedt, 2010).

External-Pressure Headache

Nummular Headache Nummular headache, previously called coin-shaped headache, describes a focal head pain felt in one small, fixed, well-defined

OTHER HEADACHES AND FACIAL PAINS Neck-Tongue Syndrome Neck-tongue syndrome describes paroxysmal sharp pain in the neck, occiput, or both, associated with ipsilateral sensory changes in the tongue, precipitated by neck movement. The pain lasts seconds to minutes and may be associated with sensory changes over the neck and

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occipital region. Though this syndrome may occur from early childhood to adulthood, the majority of reported cases in the literature have had an onset of symptoms before age 21 (Gelfand et al., 2018). The exact mechanism remains speculative. Proprioceptive fibers from the tongue travel in the lingual nerve, anastomose with the hypoglossal nerve within the tongue, then travel via the ansa cervicalis to the ventral ramus of the C2 nerve root. Evidence supports that subluxation of the atlantoaxial joint, among other conditions, may compromise the second cervical dorsal root during sudden neck rotation, resulting in numbness, paresthesia, or a sense of involuntary movement in the ipsilateral tongue (Orrell and Marsden, 1994). In general, the condition is benign. In the absence of any structural abnormality, management is conservative and may include antiinflammatory agents, temporary immobilization of the neck in a cervical collar, and possibly physical therapy exercises (Niethamer and Myers, 2016).

Painful Posttraumatic Trigeminal Neuropathy Painful posttraumatic trigeminal neuropathy, previously called anesthesia dolorosa, consists of persistent painful anesthesia or hypesthesia in the distribution of the trigeminal nerve or one of its divisions following traumatic injury. Often related to surgical trauma of the trigeminal nerve or ganglion, it most frequently occurs as a complication of rhizotomy or thermocoagulation done to treat trigeminal neuralgia. In different series of patients treated for trigeminal neuralgia, anesthesia dolorosa has developed in anywhere from 0% to 3%, depending on the specific procedure performed (Barker et al., 1996; Maarbjerg et al., 2017). This painful numbness can be even more unbearable than the pain from trigeminal neuralgia itself, warranting careful decision making when considering surgical treatment for this condition.

Persistent Idiopathic Facial Pain

Painful Trigeminal Neuropathy Painful trigeminal neuropathy describes head and/or facial pain in the distribution of one or more branches of the trigeminal nerve and is associated with nerve damage. In contrast to the paroxysmal lancinating pain of trigeminal neuralgia, painful trigeminal neuropathy tends to be a more persistent pain of highly variable character and intensity, often associated with numbness, dysesthesia, or paresthesia. There is a broad differential for neuropathy of the trigeminal nerve, including trauma, demyelination, infection, inflammation, and neoplasm (Smith and Cutrer, 2011). Unexplained neuropathy, especially with progressive worsening, warrants further investigation with MR imaging, with special attention to the course of the trigeminal nerve. Isolated involvement of the mental nerve, with resultant chin numbness (i.e., numb chin syndrome), is a red flag for a potential metastatic lesion, and may require more detailed imaging of the mandible (Smith et al., 2015).

Painful Trigeminal Neuropathy Attributed to Herpes Zoster Painful trigeminal neuropathy may occur acutely during herpes zoster infection, and in some patients may persist for longer than 3 months (referred to as postherpetic neuralgia, though technically a neuropathy/neuronopathy). Pain may be burning, stabbing, itching, or aching, often with sensory abnormalities and allodynia. The diagnosis is suggested if there is a history of a vesicular rash in the distribution of pain (or pale purple scars present as sequelae of herpetic eruption). In rare cases where there is no rash present, the diagnosis can be confirmed by varicella zoster viral DNA in the CSF (IHS, 2018). Pain during the acute phase of herpes zoster trigeminal neuropathy is severe and may require opioid analgesics. Antiviral drugs and prednisone can decrease the pain during this stage. Once developed, postherpetic neuralgia may persist indefinitely, although with time it may become less severe. Many elderly patients with this distressing pain become depressed, lose weight, and become withdrawn. Treatment of established postherpetic neuralgia is difficult and in many instances ineffective. Tricyclic antidepressants, gabapentin, pregabalin, opioids, and lidocaine patches may all be helpful in select patients (Dubinsky et al., 2004).The use of topical capsaicin is not practical in this disorder. Procedures to denervate the affected area of skin, trigeminal destructive procedures, and trigeminal tractotomy have been used for control of pain, but they are rarely used at present. When the herpes zoster infection affects the ophthalmic division of the trigeminal nerve (i.e., herpes zoster ophthalmicus), it can affect the eye and vision, sometimes leading to a keratitis that can permanently scar the cornea. For this reason, aggressive management with systemic antivirals is recommended (Schuster et al., 2016).

Previously known as atypical face pain, persistent idiopathic facial pain (PIFP) is essentially a facial pain of unknown cause with no associated neurological deficit. The diagnosis of PIFP should be considered only when all facial pains due to disturbances of anatomy and pathophysiology have been excluded, including trigeminal neuropathy. Exhaustive radiographic and other imaging techniques may be necessary to exclude conditions such as nasopharyngeal and sinus neoplasms, bony abnormalities of the base of the skull, and dental conditions such as cryptic mandibular and maxillary abscesses. Evaluation may also require a chest roentgenogram or chest CT scan if referred pain from lung cancer is suggested by the history (smoker) or examination (digital clubbing). Patients in whom PIFP is eventually diagnosed are usually middle-aged and predominantly female. A subset of patients may develop PIFP after insignificant trauma to the face, teeth, or gums, suggesting that PIFP and traumatic trigeminal neuropathy may represent extremes on a continuum of injury-induced neuropathic pain (Benoliel and Gaul, 2017). Pain is commonly felt in the nasolabial fold or on one side of the chin but can spread to wider areas of the face and neck. Patients complain of deep, poorly localized pain. Generally unilateral, but occasionally bilateral, the pain may be described in graphic terms such as tearing, ripping, or crushing, or often as aching and boring. The pain is usually present all day and every day, and gradually worsens with time. It is not influenced by factors such as alcohol consumption, heat, or cold or by factors that trigger trigeminal neuralgia. Local anesthetic blocks of the trigeminal nerve do not relieve the pain. Many patients have already undergone extensive dental, nasal, or sinus operations to no avail. Pain may be associated with other comorbid pain conditions such as chronic widespread pain and irritable bowel syndrome (IHS, 2018). When no symptomatic etiology is identified, tricyclic antidepressants such as amitriptyline are considered first line. Medications used to treat central neuropathic pain, such as gabapentin, pregabalin, or duloxetine, may also be tried.

Cranial and Facial Neuralgias Trigeminal Neuralgia

Clinical symptoms. Trigeminal neuralgia describes paroxysmal pain felt within the distribution of one or more divisions of the trigeminal nerve. The pain is often triggered by a sensory stimulus to the skin, mucosa, or teeth within the area innervated by the ipsilateral trigeminal nerve. The trigger zone most commonly occurs near the nasolabial fold and may be remote from the site of pain. Chewing, teeth brushing, talking, and even cool breeze striking the face are commonly reported triggers. The pain is described as electric shock-like, shooting,

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CHAPTER 102 Headache and Other Craniofacial Pain or lancinating. Each attack lasts only seconds, but the pain may be repetitive at short intervals, so that the individual attacks blur into one another. After many attacks within a few hours, the patient may describe a residual lingering facial pain. Attacks of trigeminal neuralgia are most common in the second and third divisions of the nerve. Pain confined to the ophthalmic division is extremely rare. Attacks of pain during sleep are uncommon but do occur. Frequent attacks may be associated with weight loss, dehydration, or depression. In the current ICHD-3 classification, classical trigeminal neuralgia refers to trigeminal neuralgia with evidence of vascular compression of the trigeminal nerve (by MRI or surgery), with associated nerve root atrophy or displacement. Secondary trigeminal neuralgia is due to an underlying disease such as multiple sclerosis or a space-occupying lesion, and may present as both paroxysmal pain and a concomitant continuous or near-continuous pain. If evaluation shows no underlying etiology and no clear morphological change (atrophy or displacement) in the nerve root related to blood vessel contact, the term idiopathic trigeminal neuralgia is preferred (IHS, 2018). Physical findings. In classical trigeminal neuralgia, there is no sensory impairment, and the motor division of the nerve is intact. The presence of physical signs such as sensory loss or masticatory muscle weakness suggests a secondary cause for trigeminal neuralgia, though a more accurate description in this case would be trigeminal neuropathy. This could be secondary to a lesion or mass affecting the gasserian ganglion, main sensory root, or root entry zone in the pons. Laboratory and radiological findings. Idiopathic trigeminal neuralgia has no accompanying laboratory or radiographic abnormalities. EMG and nerve stimulation (such as blink reflex studies) are normal. Imaging with MRI is done primarily to look for structural lesions such as a pontine lacunar infarct, demyelinating plaque, meningioma or schwannoma of the posterior fossa, or malignant infiltration of the skull base. High-resolution MRI and MRA may be able to identify vascular compression in select cases. Pathogenesis and etiology. Classical trigeminal neuralgia cases are felt to be related to neurovascular compression of the trigeminal nerve by neighboring vessels, including the superior cerebellar artery, anterior and posterior inferior cerebellar arteries, and superior petrosal vein. Vascular compression is believed to increase with age and contribute to focal demyelination of primary trigeminal afferents near where the trigeminal nerve enters the pons (i.e., nerve root entry zone). In pathology studies, vacuolated neurons, segmental demyelination, vascular changes, and other abnormalities were more common in gasserian ganglia from patients with a history of trigeminal neuralgia than in control specimens. This focal demyelination of axons in the main sensory root is hypothesized to contribute to focal hyperexcitability, leading to ectopic and repetitive neuronal discharges. In secondary trigeminal neuralgia, structural lesions may contribute to pain through a similar pathophysiological mechanism (Maarbjerg et al., 2017). Epidemiology. Trigeminal neuralgia begins after the age of 40 years in 90% of patients. It is slightly more common in women. The incidence progressively increases with increasing age (Manzoni and Torelli, 2005). Rare familial cases have been described, suggesting that genetics may play a role in some families. Course and prognosis. Trigeminal neuralgia frequently has an exacerbating and remitting course over many years. During exacerbations, the painful attacks may occur many times a day for weeks or months at a time. A spontaneous remission may occur at any time and last for months or years. The reasons for these fluctuations are unknown. Treatment and management. Treatment of trigeminal neuralgia due to a focal lesion compressing the sensory root of the trigeminal

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nerve is surgical exploration and decompression of the nerve. Management of classical trigeminal neuralgia can be either medical or surgical. Sodium channel blockers, such as carbamazepine or oxcarbazepine, are considered the drugs of choice for treatment of trigeminal neuralgia, with a highly favorable response in a majority of patients. Administration of carbamazepine must be initiated with small doses of 50–100 mg and increased slowly as tolerated. Vertigo, drowsiness, and ataxia are common side effects if the preparation is introduced too quickly, especially in elderly patients. Therapeutic doses generally range from 600 to 1200 mg/day in divided dosing. The appropriate dose is the lowest dose needed to control the pain. Once the pain is controlled completely, the dose can be tapered every few weeks to determine whether a remission has developed. Oxcarbazepine may be better tolerated, but may be associated with sometimes prominent hyponatremia. When starting these medicines, regular blood counts (monitoring for agranulocytosis), liver function tests, and serum sodium should be performed for the first few months and once a year thereafter. Second-line options for the management of trigeminal neuralgia include gabapentin, pregabalin, phenytoin, and baclofen. Other drugs that have been used include lamotrigine, valproate, clonazepam, and topiramate (Cheshire, 2007; Maarbjerg et al., 2017). Second-line drugs should be considered for trial, alone or in combination, when sodium channel blockers are either unhelpful or not tolerated. Given the beneficial effects of gabapentin in other neuropathic conditions and its benign side-effect profile, an initial trial with this drug may be an alternative option to carbamazepine/oxcarbazepine. On occasion, one may encounter a patient in the midst of a severe attack. A useful technique in this situation is the administration of IV fosphenytoin at a dose of 15–20 mg phenytoin sodium equivalents (PE)/kg. Anesthetizing the ipsilateral conjunctival sac with the local ophthalmic anesthetic proparacaine has also proved effective in providing relief from pain for several hours to days. A patient who is refractory to medical therapy may be a candidate for a surgical procedure. The most commonly performed surgical procedures include percutaneous procedures on the trigeminal nerve or gasserian ganglion (rhizotomy), Gamma Knife radiosurgery, and microvascular decompression. Picking the best surgical option often involves a discussion with the patient about the potential risks of the procedure based on their age and comorbidities, as well as the risk of pain recurrence. The simplest nonmedical therapy is an alcohol block of the peripheral branch of the division of the trigeminal nerve that is painful. The mental or mandibular nerve can be blocked with 0.5–0.75 mL of absolute alcohol to control mandibular division trigeminal neuralgia. The infraorbital and supraorbital nerves can also be injected for pain involving the second and first divisions, respectively. Relief of pain occurs in a high proportion of patients so treated, but relapse is likely in most after 6–18 months. The procedure can be repeated once or twice, but thereafter it is prudent to perform a more proximal and lasting procedure because the further injection of alcohol is likely to be ineffective. The advantages of a peripheral alcohol injection include low morbidity and the temporary nature of sensory loss. Preservation of corneal sensation is also an advantage. For many patients, especially those who are elderly or have complicating medical conditions, percutaneous radiofrequency thermocoagulation of the trigeminal nerve sensory root as it leaves the gasserian ganglion is the procedure of choice. Investigators have reported pain relief in up to 93% of patients. Recurrence rates vary with the period of follow-up. The procedure can be repeated when relapse occurs. Complications include damage to the carotid artery, adjacent cranial

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nerves, and the trigeminal nerve motor root. Corneal sensory loss in V1 lesions can lead to serious eye complications. Troublesome dysesthesias of the face are commonly encountered. Posttraumatic trigeminal neuropathy (previously anesthesia dolorosa), a distressingly painful sensation in the numb area, occurs occasionally. Percutaneous balloon compression of the trigeminal ganglion has been shown to be an effective and technically simple treatment. The early recurrence rate, however, is higher than that reported for radiofrequency thermocoagulation, with pain recurring 2–3 years later. Stereotactic radiosurgery with the Gamma Knife has also been shown to be an effective therapy for trigeminal neuralgia and is a less invasive surgical option. However, it is also associated with a relatively high recurrence rate, and patients who have previously undergone surgical procedures may have an increased risk of facial dysesthesia following Gamma Knife radiotherapy. In patients who are felt to be healthy enough for more invasive surgery, the preferred procedure is microvascular decompression (MVD). This involves craniotomy and posterior fossa exploration to identify the area of neurovascular compression, dissection of the offending vessel away from the trigeminal nerve, and placement of a synthetic padding to prevent future compression. In Jannetta’s series of 1155 patients, 70% had excellent relief of pain continuing 10 years after the trigeminal nerve and the compressing vessel were separated. Relief of pain without the production of anesthesia is the major advantage of the procedure. Disadvantages include the need for a posterior fossa exploration, with a reported mortality rate of 1% and a risk for injury to other cranial nerves, most commonly CN IV, VII, and VIII, dependent on the experience of the surgeon. Despite the inherent risks of a retromastoid craniectomy, MVD is associated with the longest duration of pain relief, preserves facial sensation, and remains the only surgical treatment that directly addresses the presumed mechanism. When no vascular loop is found at the time of operation, the options include performing a partial or complete sensory root section or subsequently performing a radiofrequency procedure. For a young patient unresponsive to medical treatment, posterior fossa MVD should be considered. For an elderly patient or a patient with other medical complications, however, peripheral procedures targeting the trigeminal ganglion, such as radiofrequency thermocoagulation or balloon compression, would be considered procedure of choice because of the ease of performance. Specific recommendations relating to the various interventional or surgical procedures cannot be made. Rather, the treatment must be individualized to the particular needs of the patient.

Glossopharyngeal Neuralgia The pain associated with neuralgia of the ninth cranial nerve is similar in quality and periodicity to that of trigeminal neuralgia. The pain is lancinating and episodic and may be severe. It is felt in the distribution of the glossopharyngeal nerve and the sensory distribution of the upper fibers of the vagus nerve. Pain in the throat, the tonsillar region, the posterior third of the tongue, the larynx, the nasopharynx, and deep in the ear is often described by patients with this rare neuralgia. The pain is usually triggered by swallowing, speaking, laughing, or coughing and is unilateral in most patients. Bilateral involvement does occur, but it is very rare. The age group involved is generally older than 40 years. Bradycardia and syncope can occur when the painful attack strikes. Most glossopharyngeal neuralgia occurrences have been thought to be idiopathic, but vascular compression of the ninth cranial nerve has been described. Secondary glossopharyngeal neuralgia may also be due to oropharyngeal malignancies, peritonsillar infections, and other

lesions at the base of the skull. Therefore, presenting patients should be evaluated with an MRI of the brain and soft tissues of the neck, with specific attention to the glossopharyngeal nerve. Carbamazepine and phenytoin have been administered with mixed success in glossopharyngeal neuralgia. Intracranial section of the glossopharyngeal and upper rootlets of the vagus nerve almost always produces complete pain relief. A series of 47 patients treated with microvascular decompression reported 98% found immediate relief after the procedure (Sampson et al., 2004).

Nervus Intermedius Neuralgia (Geniculate Neuralgia, Hunt Neuralgia) This is a rare disorder characterized by brief paroxysms of pain felt deeply in the auditory canal (IHS, 2018). The intermediate nerve of Wrisberg (the nervus intermedius), a small sensory branch of the facial nerve (cranial nerve VII), and/or the geniculate ganglion are believed to be the affected structures. The accurate incidence, prevalence, and risk factors associated with this condition are unknown, since it is so rare. Middle-aged women seem to be more frequently affected. Clinically the pain is described as brief (seconds to minutes), severe, paroxysmal, and limited to the depths of the ear, associated with a trigger zone in the posterior wall of the ear canal. The pain can be sharp or burning and is not necessarily lancinating, as occurs in other cranial neuralgias. The diagnosis is made on clinical grounds. Importantly, because of the complex ear sensory innervation, other referred sources of ear pain should be considered in the differential diagnosis when evaluating a neuralgic otalgia. Nerves referring pain to the ear include branches of cranial nerves V, VII, IX, and X, and upper cervical roots (De Lange et al., 2014; Fig. 102.7). Nervus intermedius neuralgia can develop during an episode of Ramsay-Hunt syndrome (herpes zoster virus involving the geniculate ganglion/facial nerve, causing ipsilateral facial paralysis); therefore patients with this deep stabbing ear pain should be checked for vesicles in the external auditory canal, pinna, and tonsillar fossa. Because this type of deep stabbing ear pain can be referred from the throat, imaging of the soft tissues of the neck should be included in the evaluation (DeLange et al., 2014). For treatment, a trial with carbamazepine is appropriate. If not effective, other drugs used to treat cranial neuralgias and neuropathic pain (e.g., oxcarbazepine, gabapentin, phenytoin, lamotrigine, baclofen) can be tried. Neurosurgery is a last resort when pharmacotherapy fails, and may involve excision of the nervus intermedius and geniculate ganglion with or without exploration and/or section of CN V, IX, and X. Lovely and Jannetta (1997) reported good long-term results in up to 90% of patients in a series using microvascular decompression of CN V, IX, and X, with or without section of the nervus intermedius.

Occipital Neuralgia Occipital neuralgia can cause a headache in the occipital region. It is a paroxysmal jabbing pain in the greater (C2), lesser (C2–C3), and/ or third (C3) occipital nerve distribution, sometimes accompanied by diminished sensation or dysesthesia in the affected area. The true incidence and prevalence of occipital neuralgia are not known, possibly because the diagnosis is frequently arbitrarily given to any pain in the occipital region (Bogduk, 2004). Injuries to the C2–C3 nerve roots through different mechanisms (entrapment, trauma, inflammation, whiplash, etc.) might contribute to occipital neuralgia. Clinically, the pain has a sudden onset and is described as a severe stabbing, electric shock-like, or sharp shooting pain that starts at

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CHAPTER 102 Headache and Other Craniofacial Pain

CN V

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CN X Branch of Va

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CN IX Branch of Glossopharyngeal Nerve Tonsils and pharynx r e s Fig. 102.7 Sensory Innervation of the Ear and its Surrounding Structures. Boxes with their corresponding colors illustrate each nerve’s distribution. Note that sensory distributions may overlap. (From DeLange, J.M., Garza, I., Robertson, C.E. A 50-Year-Old Woman With Deep Stabbing Ear Pain. American Academy of Neurology; 2014. Used with permission of Mayo Foundation for Medical Education and Research, all rights reserved.)

the nuchal region and then immediately spreads toward the vertex. Paroxysms can start spontaneously or, as in other neuralgias, be provoked by specific maneuvers such as brushing the hair or moving the neck. Most often, occipital neuralgia is unilateral. Between attacks, there may be a dull occipital discomfort as a background. On examination, pressure, palpation, or percussion over the occipital nerve trunks may reveal local tenderness. These maneuvers may also trigger painful paroxysms, exacerbate the background discomfort, or elicit paresthesias following the nerve’s distribution. Cervical range of motion may be restricted, and local posterior neck muscle spasms may be found. The neurological examination may find sensory deficits in the individual occipital nerve distribution but is usually otherwise unremarkable. An abnormal neurological examination should alert the clinician for potential alternative or underlying causes of the symptoms. Since structural and infiltrating lesions can cause occipital neuralgia, a cervical spine and brain MRI is commonly considered when evaluating occipital neuralgia.

In the proper clinical scenario, the diagnosis is confirmed when the pain is transiently relieved by a local occipital anesthetic block. A local anesthetic block, however, is a nonspecific intervention, so symptomatic relief does not indicate a specific etiology.

HEADACHE IN CHILDREN AND ADOLESCENTS Headaches are very common in children, and more so in adolescents. The prevalence of headache of any type is in the range of 37%–51% in 7 year olds, increasing to 57%–82% in 15 year olds (Lewis et al., 2002). Prepubertal boys are more often afflicted than girls, whereas, after puberty, headaches occur more often in girls (Abu-Arafeh et al., 2010; Lewis et al., 2002). Obtaining the child’s history of head pain can be challenging because most patients younger than 10 years old are unable to give clear details about the temporal profile of the headache, its frequency, and its characteristics. For this reason, the clinician must depend on

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parental observations of the child’s behavior. Does the youngster continue to play, want to go to bed, avoid light or sound, refuse food, refuse to go to school, and then appear to recover? The neurological examination in a child should evaluate the same factors as in an older patient, including careful assessment of the optic fundus. In addition, head size should be measured, and developmental markers checked. Laboratory and other investigations are undertaken after a thorough history and physical examination. Neuroimaging is not done routinely. Features associated with the presence of a space-occupying lesion include (1) headache onset of less than 1 month, (2) absent family history of migraine, (3) abnormal neurological findings on examination (including gait abnormalities or papilledema), (4) the presence of seizures, and (5) progressive worsening of headaches. Headache in a child younger than 3 years old is uncommon and is a red flag for a secondary etiology for headache. Therefore, it would be reasonable to perform neuroimaging for new headache in a child less than 6 years old (Gofshteyn and Stephenson, 2016). The child with a constant nonprogressive headache may need a psychological evaluation, and the family dynamics may require full evaluation. Reports from teachers are of value in assessing the child’s performance.

Migraine and Migraine Variants

adolescents (Abu-Arafeh et al., 2010; Slater et al., 2018). Although migraine can manifest all the features seen in older patients, migraine attacks in children are often shorter and occur less often than those in adults. The description of headache tends to evolve as age increases. In younger children, migraine pain tends to be bilateral and non-throbbing, while unilateral pain and headache pulsation tend to become more typical in adolescence (Virtanen et al., 2007). Migraine can be triggered by similar factors at all ages, including stress, fever, head trauma, and sleep and eating pattern changes. In girls, the onset of migraine may coincide with menarche. In addition to headache, approximately 10% of migraine patients in a pediatric neurology practice present with recurrent discreet symptoms thought to be variants or precursors of migraine (Table 102.9). In the ICHD-3 classification, these are referred to as “episodic syndromes that may be associated with migraine,” and include recurrent attacks of stereotyped symptoms such as abdominal pain or nausea/vomiting, episodic attacks of dizziness, unsteadiness, or torticollis (Gelfand, 2015; IHS, 2018; Lagman-Bartolome and Lay, 2015). The complete reference list is available online at https://expertconsult. inkling.com/.

Migraine is the most common cause of headaches in children referred to a neurologist, and is estimated to affect 10%–12% of children and

TABLE 102.9

Episodic Syndromes That May Be Associated With Migraine Typical Age of Onset

Characteristics

Associated Features

Infantile colic

Peaks at 5–6 wk; typically improves by 3–4 mo

Crying tends to be late afternoon and evening hours

Benign paroxysmal vertigo (BPV)

Typically 2–5 years old; may resolve around age 5–6

Excessive frequent crying in an otherwise healthy, well-fed infant Episodes last ≥3 h/day, ≥ 3 days/wk for ≥ 3 wk Brief spontaneous attacks of vertigo lasting minutes to hours

Alternating hemiplegia Starts before 18 mo of childhood

Abdominal migraine

Benign paroxysmal torticollis Cyclic vomiting syndrome

Recurrent attacks of hemiplegia alternating between sides (occasionally quadriparesis)

Around 4–7 yr

Recurrent attacks of abdominal pain (dull, moderate to severe, in the midline abdomen) lasting 2–72 h Starts around 5–6 mo, typically Recurrent episodes of head tilt to either side, resolves by age 3–4 lasting minutes to days. Often in regular intervals (like monthly) Around 4–7 yr Episodic attacks of repeated vomiting (≥4/h) and severe nausea; attacks last hour to 10 days, separated by at least 1 wk

Nystagmus, pallor, ataxia, vomiting, fearfulness Normal audiometric/vestibular testing between attacks Should have one other paroxysmal symptom (tonic spells, dystonic posturing, choreoathetosis, oculomotor abnormalities movements, autonomic disturbance) Anorexia, nausea/vomiting, pallor Symptom free between attacks Exclude gastrointestinal/renal disease Pallor, irritability, drowsiness, vomiting, ataxia May evolve into BPV or migraine with aura Pallor, lethargy

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103 Cranial Neuropathies Janet C. Rucker, Meagan D. Seay

OUTLINE Olfactory Nerve (Cranial Nerve I), 1783 Optic Nerve (Cranial Nerve II), 1783 Oculomotor Nerve (Cranial Nerve III), 1783 Anatomy, 1783 Clinical Lesions, 1783 Trochlear Nerve (Cranial Nerve IV), 1787 Anatomy, 1787 Clinical Lesions, 1787 Trigeminal Nerve (Cranial Nerve V), 1788 Anatomy, 1788 Clinical Lesions, 1789 Abducens Nerve (Cranial Nerve VI), 1790 Anatomy, 1790 Clinical Lesions, 1790 Facial Nerve (Cranial Nerve VII), 1791

Anatomy, 1791 Clinical Lesions, 1792 Vestibulocochlear Nerve (Cranial Nerve VIII), 1794 Glossopharyngeal Nerve (Cranial Nerve IX), 1794 Anatomy, 1794 Clinical Lesions, 1794 Vagus Nerve (Cranial Nerve X), 1795 Anatomy, 1795 Clinical Lesions, 1795 Spinal Accessory Nerve (Cranial Nerve XI), 1796 Anatomy, 1796 Clinical Lesions, 1796 Hypoglossal Nerve (Cranial Nerve XII), 1796 Anatomy, 1796 Clinical Lesions, 1796

OLFACTORY NERVE (CRANIAL NERVE I)

communicating artery (PCOM) and is very near to this vessel at the vessel’s junction with the intracranial internal carotid artery. In the cavernous sinus, the third nerve is located within the dural sinus wall, just lateral to the pituitary gland. From the cavernous sinus, the third nerve enters the orbit via the superior orbital fissure. Just prior to entry, the nerve anatomically divides into superior and inferior divisions in the anterior cavernous sinus, although careful evaluation of brainstem lesions and their corresponding patterns of pupil and muscle involvement suggests that functional division occurs in the midbrain (Bhatti et al., 2006; Vitosevic et al., 2013). Within the orbit, the superior division innervates the superior rectus and the levator palpebrae superioris, and the inferior division innervates the inferior and medial recti, the inferior oblique, and the iris sphincter and ciliary muscles (Fig. 103.2). Prior to innervating the ciliary and sphincter muscles as the short ciliary nerves, parasympathetic third nerve fibers synapse in the ciliary ganglion within the orbit (see Fig. 103.2).

See Chapter 19.

OPTIC NERVE (CRANIAL NERVE II) See Chapters 16 and 43.

OCULOMOTOR NERVE (CRANIAL NERVE III) Anatomy Paired oculomotor nuclei are located in the dorsal midbrain ventral to the periaqueductal gray matter at the level of the superior colliculus. Each nucleus is composed of a superior rectus subnucleus providing innervation to the contralateral superior rectus; inferior rectus, medial rectus, and inferior oblique subnuclei providing ipsilateral innervation; and an Edinger-Westphal nucleus supplying preganglionic parasympathetic output to the iris sphincter and ciliary muscles (Che Ngwa et al., 2014; eFig. 103.1). A single midline caudal central subnucleus provides innervation to both levator palpebrae superioris muscles. A third nerve fascicle originates from the ventral surface of each nucleus and traverses the midbrain, passing through or near to the red nucleus and in close proximity to the cerebral peduncles before emerging ventrally as rootlets in the lateral interpeduncular fossa. In the interpeduncular fossa, the rootlets converge into a third nerve trunk that continues ventrally through the subarachnoid space toward the cavernous sinus, passing between the superior cerebellar artery and the posterior cerebral artery. It travels parallel to the posterior

Clinical Lesions

Oculomotor Nucleus In addition to potentially causing ipsilateral weakness of the medial rectus, inferior rectus, and inferior oblique muscles, an oculomotor nuclear lesion may result in bilateral superior rectus weakness. Ipsilateral subnucleus involvement affects the contralateral superior rectus because of the completely crossed nature of superior rectus innervation (see eFig. 103.1). A unilateral oculomotor nuclear lesion may affect these unilateral originating fibers destined for decussation, as well as those fibers that originated contralaterally and are already decussated. If the single midline levator palpebrae superioris

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Iris sphincter and cilary muscles

Levator palpebrae superioris Superior rectus

Contralateral Medial rectus

Inferior rectus Inferior oblique

E-W

IR

SR

IO CCN MR

Superior colliculus

Paired Oculomotor Nuclei eFig. 103.1 Schematic of the paired oculomotor nuclei with a single midline shared central caudal nucleus (CCN). Each nucleus is composed of a superior rectus subnucleus (SR) providing innervation to the contralateral superior rectus; inferior rectus (IR), medial rectus (MR), and inferior oblique subnuclei (IO) providing ipsilateral innervation. The single midline caudal central subnucleus (CCN) provides innervation to both levator palpebrae superioris muscles. (Courtesy Marc Dinkin, MD.)

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Long ciliary nerve

Nasociliary nerve

Anterior ethmoidal nerve Frontal nerve

Ciliary ganglion

Internal carotid artery

Lacrimal nerve

Levator palpebrae superioris

Optic nerve

Superior rectus Oculomotor nerve Lacrimal nerve

Trochlear nerve

Communication between lacrimal and zygomaticotemporal nerve

Inferior oblique Maxillary nerve

Lateral rectus

Mandibular nerve

Ophthalmic Short Abducens nerve ciliary nerve nerves Infraorbital Inferior rectus nerve Fig. 103.2 Oculomotor, Trochlear, Abducens, and Trigeminal Nerve Distributions in the Orbital Apex and Orbit. (From Standring, G., 2005. Gray’s Anatomy, thirty-ninth ed. Churchill Livingstone, Philadelphia.)

subnucleus is involved in an oculomotor nuclear lesion, bilateral ptosis results. Isolated bilateral ptosis or isolated paresis of a single extraocular muscle is also possible from a small focal nuclear lesion, given the functional division of the subnuclei (Al-Sofiani and Kwen, 2015). Involvement of the rostral and dorsally located Edinger-Westphal nucleus will lead to pupil involvement. Common brainstem lesions include ischemia, hemorrhage, demyelination, infectious and noninfectious inflammation, and neoplasm.

Oculomotor Palsy Appearance A complete oculomotor nerve palsy has the following ipsilateral examination features: eye deviation inferiorly and laterally (“down and out”); absence of ocular elevation, depression, and adduction; and complete ptosis. A complete oculomotor palsy may be further described as complete involving the pupil with an enlarged and nonreactive pupil or as a pupil-sparing otherwise complete oculomotor palsy. A partial, or incomplete, third nerve palsy may present with any combination of deficits of third nerve innervated structures. Great emphasis is often placed on the presence of pupil involvement versus pupil sparing with regard to probable lesion etiology; however, neither this, nor the presence or absence of pain or other demographic features can fully rule out potential neurologically devastating emergent etiologies, such as a PCOM aneurysm or pituitary apoplexy (Newman and Biousse, 2017; Tamhankar et al., 2013) (see section below on Interpeduncular Fossa and Subarachnoid Space and section on Isolated Oculomotor Nerve Palsy).

Brainstem Fascicle Claude syndrome is the combination of an ipsilateral oculomotor nerve palsy and contralateral hemiataxia (Table 103.1 and Videos 103.1 and 103.2; Liu et al., 1994). Although historically the syndrome was described as involving the oculomotor fascicle and the red nucleus, the ataxia is likely due to involvement of the superior cerebellar peduncle

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at the caudal end of the red nucleus or the pedunculopontine nucleus, a component of the mesencephalic locomotor region (Hathout and Bhidayasiri, 2005). Nothnagel syndrome is the combination of ipsilateral oculomotor nerve palsy and ipsilateral hemiataxia from involvement of the oculomotor fascicle and superior cerebellar peduncle or pedunculopontine nucleus (see Table 103.1). Weber syndrome is the combination of an ipsilateral fascicular oculomotor nerve palsy and contralateral hemiparesis from cerebral peduncle involvement (see Table 103.1). Benedikt syndrome involves the oculomotor fascicle and red nucleus, causing an ipsilateral oculomotor nerve palsy and contralateral chorea or tremor (see Table 103.1). Common brainstem lesions include ischemia, hemorrhage, demyelination, infectious and noninfectious inflammation, and neoplasm (Kremer et al., 2013; Ogawa et al., 2016).

Interpeduncular Fossa and Subarachnoid Space The most common etiology of oculomotor dysfunction in this region is compression by a PCOM aneurysm (Fang et al., 2017). Pupillary fibers are located superomedially near the surface of the nerve and are particularly prone to compression by a PCOM aneurysm. As a result, “rules” with regard to interpretation of pupillary involvement have been defined to guide diagnostic evaluation. These will be reviewed for completion’s sake, though it is now fairly well accepted that all oculomotor palsies warrant imaging evaluation for a PCOM aneurysm (Newman and Biousse, 2017; Tamhankar et al., 2013; Trobe, 2009). Without controversy, any pupil-involving or pupil-sparing incomplete oculomotor palsy requires immediate evaluation for a PCOM aneurysm, given the high risk of subarachnoid hemorrhage and mortality if left undiagnosed and untreated (Connolly et al., 2012; Lv et al., 2016). Some patients with an aneurysmal incomplete oculomotor nerve palsy will lack pupillary involvement at initial presentation, but the majority will progress to pupillary involvement within 1 week. Spontaneous improvement in oculomotor nerve function may occur with an aneurysm and should not

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TABLE 103.1

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Named Cranial Nerve Syndromes

Syndrome*

Symptoms and Signs

Involved Structures

Claude

Ipsilateral III Contralateral ataxia Ipsilateral III Ipsilateral ataxia Ipsilateral III Contralateral hemiparesis Ipsilateral III Contralateral chorea or tremor Ipsilateral III, IV, VI Ipsilateral first and second branches of V Ipsilateral Horner syndrome Ipsilateral facial numbness and ↓ pinprick Contralateral hemibody ↓ pain and temperature Dysphagia and ↓ gag reflex Limb ataxia Horner syndrome Vertigo Wallenberg in addition to ipsilateral hemiparesis Facial and mastoid area pain Ipsilateral 1st branch of V Ipsilateral VI and VII Ipsilateral VI and VII Contralateral ataxia Ipsilateral Horner syndrome Ipsilateral deafness Ipsilateral ↓ taste and facial sensation Ipsilateral VI and VII Contralateral hemiparesis Ipsilateral VI Contralateral hemiparesis VII VII Vesicular otic or oral rash ± ↓ hearing VII Facial edema Fissured tongue IX

III—brainstem fascicle Red nucleus/superior cerebellar peduncle III—brainstem fascicle Superior cerebellar peduncle III—brainstem fascicle Cerebral peduncle III—brainstem fascicle Red nucleus Cavernous sinus III, IV, VI, first and second branches of V Sympathetic nerves Spinal trigeminal tract and nucleus Spinothalamic tract Nucleus ambiguus Inferior cerebellar peduncle Sympathetic nerves Vestibular nuclei Corticospinal fibers caudal to pyramidal decussation Petrous apex—temporal bone V, VI, VII

Nothnagel Weber Benedikt Tolosa-Hunt

Wallenberg lateral medullary syndrome

Opalski syndrome Gradenigo

Foville

Millard-Gubler Raymond Bell’s palsy Ramsay Hunt Melkersson-Rosenthal

Eagle Vernet Villaret

VI and VII—brainstem Mid-cerebellar peduncle Sympathetic nerves Vestibulocochlear nerve/fascicle Spinal trigeminal tract/nucleus solitarius VI and VII—brainstem Pyramidal tract VI—brainstem Pyramidal tract VII—intratemporal nerve and geniculate ganglion VII ±VIII VII—distal branches

XI—elongated styloid process or ossified stylohyoid ligament Jugular foramen Jugular foramen Hypoglossal canal Sympathetic nerves Jugular foramen Hypoglossal canal X—brainstem or peripheral Pyramidal tract X and XII—brainstem or peripheral XII—nuclei or fascicle Pyramidal tract Medial lemniscus Hemi-medullary: lateral and medial medulla

IX, X, XI IX, X, XI XII Horner syndrome IX, X, XI XII X Contralateral hemiparesis X and XII Ipsilateral XII Contralateral hemiparesis Contralateral hemisensory deficit Combined symptoms and signs of Wallenberg and Dejerine syndromes

Collet-Sicard Avellis Tapia Dejerine medial medullary syndrome

Babinski-Nageotte

*Descriptions of named syndromes vary slightly, depending on reference used. ↓, Decreased.

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A

B

C D

E Fig. 103.3 Traumatic left oculomotor palsy 3 months following a motor vehicle accident with closed head injury and loss of consciousness. Patient initially had complete left ptosis and complete absence of adduction, elevation, and depression. Results of magnetic resonance imaging and magnetic resonance angiography were normal. A, Central position with slight left ptosis, exotropia (outward deviation), and left pupillary enlargement. B, Impaired adduction of left eye with right gaze. Note aberrant regeneration with anomalous elevation of left lid upon adduction of left eye. C, Normal left gaze. D, Significant impaired elevation of left eye with upgaze. E, Impaired depression of left eye with downgaze.

preclude diagnostic testing. A pupil-sparing otherwise complete oculomotor palsy is exceedingly unlikely to result from PCOM aneurysmal compression and the urgency of imaging in this setting is controversial (Miller 2017; Newman and Biousse, 2017). However, immediate imaging is favored to avoid errors in exam interpretation that increase the risk of a missed diagnosis with high morbidity and mortality and because both basilar aneurysm and pituitary apoplexy have been reported with pupil-sparing otherwise complete oculomotor palsy (Lustbader and Miller, 1988; Tamhankar et al., 2013). Onset of oculomotor dysfunction following mild-moderate head trauma should also prompt investigation for an underlying aneurysm, though one may not always be found (Levy et al., 2005; Tajsic et al, 2017; Fig. 103.3). Magnetic resonance angiography (MRA) and computed tomographic angiography (CTA) are the preferred diagnostic tests for aneurysm detection, but it is important to recognize that reliable interpretation of these studies requires a high level of experience, skill, and time (Chaudhary et al., 2009; Elmalem et al., 2011). The majority of PCOM aneurysms large enough to cause an oculomotor palsy are at least 4 mm in size. For aneurysms larger than 5 mm, the sensitivity of both MRA and CTA are higher than 95%; however, for aneurysms smaller than 5 mm, CTA sensitivity remains above 90% when interpreted by a neuroradiology expert, but MRA sensitivity in some studies is lower, leading some to advocate CTA as the initial diagnostic evaluation for PCOM aneurysms (Chaudhary et al., 2009). Neither MRA nor CTA is 100% sensitive, and conventional angiogram is still warranted when strong clinical suspicion for a PCOM aneurysm is present, and noninvasive studies are unrevealing. Surgical clipping for aneurysms causing oculomotor nerve palsies results in a higher rate of oculomotor recovery compared to endovascular coiling in many (78% for surgery vs. 44% for endovascular coiling in a comparison review of retrospective studies) (Micieli et al., 2017), but not all (Zhong et al., 2019) studies. Furthermore, surgery is associated with higher periprocedural morbidity and decisions regarding treatment must take into account patient status, aneurysmal morphology, and treating physician experience (Micieli et al., 2017).

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Factors such as initial palsy severity and pretreatment palsy time may also play a role in recovery potential (Zhong et al., 2019). In the subarachnoid space, the oculomotor nerve passes in close proximity to the medial temporal lobe. Herniation of the temporal lobe uncus ipsilateral to a space-occupying supratentorial lesion secondary to increased intracranial pressure may result in compression of the oculomotor nerve, manifested clinically as sudden enlargement and poor reactivity of the pupil ipsilateral to the lesion—the Hutchison pupil (Koehler and Wijdicks, 2015). Rarely, a unilateral enlarged and poorly reactive pupil may occur contralateral to the supratentorial lesion (Chung and Chandran, 2007). Oculomotor nerve involvement in the interpeduncular fossa and subarachnoid space may also occur secondary to inflammatory or neoplastic meningitis, in which case it may be isolated or accompanied by signs of meningeal inflammation such as meningismus or additional neurological signs. Enlargement and enhancement of the oculomotor nerve in the subarachnoid and interpeduncular locations may be seen on magnetic resonance imaging (MRI) in meningitis, with oculomotor nerve schwannomas, in association with ganglioside antibodies such as GQ1b (with persistent or transient oculomotor palsy), and in so-called ophthalmoplegic migraine, a rare condition with recurrent oculomotor paresis and pain usually seen in children (see Chapter 102; Choi et al., 2019; Qureshi et al., 2017; Shin, 2015; Wang et al., 2013; eFig. 103.4).

Cavernous Sinus An oculomotor palsy in the cavernous sinus may occur in isolation or accompanied by dysfunction of other structures located in this space, including the abducens and trochlear nerves, the first and second divisions of the trigeminal nerve, and sympathetic fibers. Tolosa-Hunt syndrome is a painful of idiopathic self-limited inflammation of the cavernous sinus, typically responsive to corticosteroids (Mullen et al., 2018; see Table 103.1 and Videos 103.3 and 103.4). Cavernous sinus infiltration by metastatic disease may be clinically and radiographically identical to Tolosa-Hunt syndrome and should be suspected, especially in older patients. Cavernous sinus lymphoma is typically steroid responsive and should be considered, especially if disease recurs with

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eFig. 103.4 Axial T1-weighted MRI with gadolinium at the level of the midbrain demonstrates abnormal bilateral oculomotor nerve enhancement (arrowheads).

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corticosteroid taper. Inflammation associated with systemic rheumatological disease or angioinvasive fungal infection, infiltration from adjacent nasopharyngeal neoplasm, carotid-cavernous fistulas, cavernous sinus thrombosis (more common in the intensive care unit than the outpatient setting), and mass effect from an intracavernous internal artery aneurysm or meningioma may also cause a cavernous sinus syndrome (Weerasinghe and Lueck, 2016). Pituitary apoplexy should be considered in the differential diagnosis for sudden-onset painful unilateral or bilateral oculomotor palsies, with or without accompanying visual loss or other ocular motor cranial nerve involvement (Hage et al., 2016).

TROCHLEAR NERVE (CRANIAL NERVE IV)

Orbital Apex

Anatomy

Oculomotor dysfunction in the orbital apex is typically accompanied by dysfunction of neighboring structures including the abducens and trochlear nerves, the first division of the trigeminal nerve, and the optic nerve. Features of orbital disease such as proptosis, chemosis, and conjunctival injection may be present. Idiopathic inflammation (orbital inflammatory pseudotumor and immunoglobulin G4 [IgG4]-related inflammation), infection (particularly aspergillosis and mucormycosis in diabetic or immunosuppressed patients), neoplastic infiltration, and inflammation or compression from adjacent sphenoid sinus infection or mucocele should be considered (Kashi, 2014; Mombaerts et al., 2017). As in cavernous sinus idiopathic inflammation (TolosaHunt syndrome) versus lymphoma, idiopathic orbital inflammatory pseudotumor and lymphoma at the orbital apex are both likely to be steroid responsive, and lymphoma should be considered, especially if pain is absent and if disease recurs with corticosteroid taper. Anatomical division of the oculomotor nerve into superior and inferior branches occurs just before this location, and isolated involvement of either branch is not uncommon.

Paired trochlear nuclei lie close to the dorsal surface of the midbrain just below the inferior colliculus. The fascicles emerge from the nuclei and course dorsally only 3–9 mm before decussating in the anterior medullary velum, and exiting the brainstem. The trochlear nerves are the only cranial nerves to emerge from the dorsal brainstem surface. After emergence, the nerves wrap around the surface of the midbrain to travel ventrally within the subarachnoid space toward the cavernous sinus. In the cavernous sinus, the trochlear nerve is located in the lateral dural wall, inferior to the oculomotor nerve. From the cavernous sinus, the nerve passes into the superior orbital fissure and ultimately innervates the superior oblique muscle contralateral to the nucleus of origin (see eFig. 103.1). The superior oblique muscle is an intorter of the eye, as well as a depressor of the adducted eye.

Isolated Oculomotor Nerve Palsy Isolated oculomotor dysfunction may occur from any lesion along the course of the nerve. Microvascular ischemia, a common cause in older patients with vascular risk factors (Fang et al., 2017; Keane, 2010), is typically pupil-sparing; however, relative pupil involvement with an average of 0.8 mm of anisocoria may be seen in up to onethird of patients with microvascular oculomotor nerve ischemia, but the pupil generally remains reactive (Jacobson, 1998). Confidence in the absence of a PCOM aneurysm may only be present when all oculomotor-innervated muscles other than the pupil are severely and completely impaired. In this era of modern noninvasive neuroimaging, it is prudent to perform emergent noninvasive vascular neuroimaging for all oculomotor palsies to avoid missing a PCOM aneurysm or other emergent etiology (see above section on Interpeduncular Fossa and Subarachnoid Space). The location of ischemia with a microvascular palsy may be anywhere along the course of the nerve but is typically peripheral and often considered to be in the cavernous sinus, although it is not visible with neuroimaging. Pain in the ipsilateral brow and eye is present in two-thirds of patients and may be severe (Wilker et al., 2009); however, the presence and characteristics of pain do not distinguish microvascular from aneurysmal oculomotor palsies (Fang et al., 2017). Spontaneous resolution over 8–12 weeks is typical for a microvascular etiology. An isolated oculomotor palsy may also arise from temporal arteritis; thus, erythrocyte sedimentation rate (ESR), C-reactive protein, and complete blood cell count (CBC) should be obtained on all elderly patients with an isolated oculomotor palsy and neuroimaging should be considered (Chou et al., 2004; Tamhankar et al., 2013; Thurtell and Longmuir, 2014). In the absence of complete spontaneous resolution with a suspected microvascular oculomotor palsy, neuroimaging is essential.

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Elevation of the eyelid or constriction of the pupil upon adduction or depression of the eye is indicative of aberrant regeneration (anomalous axon innervation). When aberrant regeneration develops following an acute oculomotor palsy, a PCOM artery aneurysm or traumatic etiology is likely (see Fig. 103.3, B). When it develops spontaneously without a pre-existing acute palsy, a cavernous sinus meningioma or internal carotid artery aneurysm is likely, although this may also rarely occur with an unruptured PCOM aneurysm. Aberrant regeneration should not occur following a microvascular oculomotor palsy.

Clinical Lesions

Trochlear Nucleus and Fascicle It is difficult to differentiate a trochlear nuclear lesion from a tegmental (ventral and dorsolateral to the periaqueductal gray matter) fascicular lesion prior to the decussation of the fascicle. Both locations will result in paresis of the contralesional superior oblique muscle. Brainstem lesions posterior to the cerebral aqueduct in the tectal (dorsomedial to the periaqueductal gray matter) fascicle after its decussation may give rise to ipsilesional superior oblique paresis (Jeong et al., 2016). Isolated nuclear or fascicular involvement occurs rarely; it may occur in isolation or in association with other brainstem signs such as Horner syndrome, internuclear ophthalmoplegia, or cerebellar ataxia. Brainstem lesions include ischemia, hemorrhage, demyelination, infectious and noninfectious inflammation, and neoplasm (Jeong et al., 2016; Sudhakar and Bapuraj, 2010).

Trochlear Palsy Appearance Trochlear nerve dysfunction results in impaired intorsion of the eye, impaired depression of the adducted eye, elevation of the affected eye (hypertropia), and vertical or oblique diplopia. The diplopia and hypertropia are worse with downgaze when the eye is in an adducted position, as this is the direction of action of the superior oblique muscle. Impaired depression of the affected eye in the adducted position may be seen but is often subtle (Fig. 103.5). A resting head tilt in the direction away from the paretic eye (e.g., right trochlear palsy, left head tilt) may be present and is considered a sign of chronicity. Because the superior oblique is an intorter of the eye, diplopia is minimized when a contralateral head tilt places the affected eye in an extorted position. The Parks-Bielschowsky three-step test (see Chapter 18 for additional information) is an examination technique utilized to assess the diplopia and hypertropia for conformation to the “pattern of a trochlear palsy” and consists of assessment of (1) which eye is hypertropic, (2) whether the hypertropia is worse in right or left gaze, and (3) whether the hypertropia is worse in right or left head tilt. The pattern of a fourth is a hypertropia on the side of the trochlear palsy, worsening in the

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Orbital Apex See Orbital Apex section above under Oculomotor Nerve, Clinical Lesions.

A

Isolated Trochlear Nerve Palsy

B Fig. 103.5 Right Trochlear Palsy From a Large Right Petroclival Meningioma. Patient also had decreased hearing in right ear and cerebellar truncal ataxia. A, Note impaired depression of right eye in adducted position. B, Preoperative T1-weighted coronal magnetic resonance imaging with gadolinium reveals an extensive mass in the pontine cistern, with significant brainstem compression.

contralateral gaze direction and upon ipsilateral head tilt (Muthusamy et al., 2014). A fourth step is assessment of the hypertropia in the upright versus supine position; reduction in size of the hypertropia in the supine position suggests a skew deviation, given gravity dependence of the otolith vestibular organs (Hernowo and Eggenberger, 2014; Wong, 2010). Evaluation for superior oblique paresis in the setting of oculomotor nerve dysfunction with impaired adduction from medial rectus paresis is best assessed with the affected eye in an abducted position, where intact intorsion during downgaze suggests intact trochlear function.

Subarachnoid Space Within the subarachnoid space, the nerves are near the tentorium cerebelli and are prone to unilateral or bilateral traumatic injury (Keane, 2005). Unlike traumatic oculomotor palsy, which usually occurs following severe head trauma with loss of consciousness, the trochlear nerves are injured more easily by minor degrees of head trauma (Dhaliwal et al., 2006). Trochlear nerve involvement in isolation or accompanied by signs of meningeal inflammation, such as meningismus, or additional cranial nerve palsies, may occur secondary to inflammatory or neoplastic meningitis. Enhancement of the nerve as it travels around the midbrain may be present on MRI. An increasingly recognized cause of such enhancement in the setting of normal cerebrospinal fluid is trochlear nerve schwannoma (Elmalem et al., 2009; Torun et al., 2018; eFig. 103.6).

Cavernous Sinus Trochlear palsy in the cavernous sinus is generally accompanied by dysfunction of other structures including the abducens and oculomotor nerves, the first and second divisions of the trigeminal nerve, and sympathetic fibers. Idiopathic inflammation, inflammation

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Congenital, traumatic, and microvascular ischemic trochlear palsies are common causes of neurologically isolated trochlear paresis (Dosunmu et al., 2018; Hata et al., 2013; Tamhankar et al., 2011). Identification of a long-standing head tilt in old photographs of the patient and increased vertical fusional amplitudes (a test of the amount of image misalignment with which the individual can maintain binocular fusion—tends to be high with congenital lesions) can help confirm the diagnosis of a congenital trochlear nerve palsy. Overaction of the inferior oblique muscle, manifested by excessive elevation upon adduction of the eye ipsilateral to the trochlear weakness, and hypertropia worsening in upgaze rather than downgaze may also suggest a congenital etiology (Ivanir and Trobe, 2017; Siatkowski, 2017).

TRIGEMINAL NERVE (CRANIAL NERVE V) Anatomy The trigeminal nerve consists of afferent sensory, efferent motor, and parasympathetic fibers. The ophthalmic (V1), maxillary (V2), and mandibular (V3) trigeminal sensory nerve branches emerge from the anterior surface of the trigeminal (gasserian) ganglion in the Meckel cave (a dural cavity overlying the apex of the petrous bone) and innervate the facial skin, mucous membranes of the nose and mouth, teeth, orbital contents, and supratentorial meninges (Fig. 103.7; also see eFig. 103.1). The ophthalmic division courses in the lateral wall of the cavernous sinus inferior to the trochlear nerve and exits the skull via the superior orbital fissure. It is the anatomical substrate for the afferent limb of the corneal reflex. The maxillary division also courses in the lateral wall of the cavernous sinus, exiting the skull via the foramen rotundum to enter the sphenopalatine (also called the pterygopalatine) fossa and the inferior orbital fissure. The mandibular division exits the skull through the foramen ovale. Sensory input from these three branches travels centrally from the trigeminal ganglion via the trigeminal sensory root in the prepontine subarachnoid cistern to the trigeminal sensory nucleus, which is composed of a mesencephalic subnucleus receiving proprioceptive input from V3, a principal (main) sensory subnucleus mediating tactile sensation, and descending spinal subnuclei (oralis, interpolaris, and caudalis) that descend to the cervical spinal cord and mediate pain and temperature. Sensory information ultimately ascends to the contralateral thalamus. The motor efferents originate in the motor trigeminal nucleus in the pons, medial to the principal sensory nucleus, emerge from the ventral pons as the motor root, travel inferior to the trigeminal ganglion and then alongside the mandibular sensory division to innervate the muscles of mastication (masseter, temporalis, pterygoids) and the mylohyoid, tensors tympani and palatini, and anterior belly of the digastric. Trigeminal nerve branches carry efferent postganglionic parasympathetic innervation from the pterygopalatine ganglia to the lacrimal gland and from the submandibular ganglia to the salivary glands. Preganglionic parasympathetic fibers travel in the facial nerve.

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eFig. 103.6 T1-weighted axial magnetic resonance imaging with gadolinium at level of inferior colliculus shows enhancing lesion consistent with a schwannoma (arrow) of right trochlear nerve as it courses ventrally around brainstem.

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Nasociliary nerve Frontal nerve Lacrimal nerve Ophthalmic nerve

Supraorbital nerve

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Trigeminal ganglion Motor root Sensory root

Trigeminal nerve

Supratrochlear nerve Chorda tympani nerve

Communication between lacrimal and zygomaticotemporal nerve

Facial nerve

Maxillary nerve

Tympanic membrane

Zygomatic nerve

Middle meningeal artery

Pterygopalatine ganglion Infraorbital nerve

Auriculotemporal nerve

Middle superior alveolar nerve

Maxillary artery

Buccal nerve

Styloid process and stylohyoid

Lateral pterygoid lower head (cut)

Inferior alveolar nerve (cut) Medial pterygoid Nerve to mylohyoid Lingual nerve Submandibular ganglion Facial artery

Mental foramen and nerve

Hyoglossus Submandibular gland (cut)

Inferior alveolar nerve

Nerve to mylohyoid supplying mylohyoid and anterior belly of digastric

Sublingual gland

Digastric (anterior belly)

Submandibular duct Fig. 103.7 Trigeminal nerve ophthalmic (1), maxillary (2), and mandibular (3) branches emerging from the semilunar (trigeminal or gasserian) ganglion. (From Standring, G., 2005. Gray’s Anatomy, thirty-ninth ed. Churchill Livingstone, Philadelphia.)

Clinical Lesions

Trigeminal Nucleus The extension of the trigeminal nuclear complex throughout the entire brainstem renders it susceptible to involvement from any pathological brainstem process. Trigeminal lesions are particularly common with demyelinating disease, may involve either the nuclei or sensory root, and may be clinically silent or symptomatic (Kremer et al., 2013; Zakrzewska et al., 2018). Ischemia, hemorrhage, infectious and noninfectious inflammation, and neoplasm are other causes of trigeminal brainstem involvement (Kim et al., 2013). Additional brainstem signs are frequently present. Wallenberg syndrome from lateral medullary ischemia typically causes ipsilateral facial numbness and impaired pinprick sensation secondary to descending spinal tract and nucleus involvement (see Table 103.1).

Subarachnoid Space: Nerve Roots Classic trigeminal neuralgia is characterized by seconds-long stereotyped episodes of intensely painful electric-like shocks along one or more of the trigeminal nerve branches, though a large percentage of patients also

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have concomitant persistent pain (Maarbjerg et al., 2017). Pain is often elicited by sensory stimuli on the face, such as shaving or wind. There is no accompanying sensory loss or motor weakness in the affected distribution on examination. The second and third branches are most commonly affected, with less than 5% of patients experiencing involvement of the ophthalmic division. Many cases are attributable to compression of the sensory nerve root, typically at the transition between central and peripheral myelin, by a vascular structure, most often the superior cerebellar artery or anterior inferior cerebellar arteries (Haller et al., 2016). Evidence-based support for this vascular compressive etiology is provided by surgical outcome data showing that the pain is often amenable to surgical decompression, especially in cases of classic pain paroxysms (Barker et al., 1996; Sivakanthan et al., 2014). Because vascular contact with the sensory or motor nerve roots is a relatively common finding in cadavers and asymptomatic controls, vascular contact alone may be insufficient to cause trigeminal neuralgia (Yousry et al., 2004). Compression or indentation of the nerve root is likely necessary, with resultant axonal loss and demyelination (Haller et al., 2016;

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Miller et al., 2009). See Chapter 102 for additional discussion of trigeminal neuralgia and other facial pain syndromes. eTable 103.2, available in the online version of this chapter at http://www.ExpertConsult.com, outlines current treatments for facial palsy and trigeminal and glossopharyngeal neuralgia. Classic trigeminal neuralgia must be differentiated from symptomatic trigeminal neuralgia secondary to an underlying neoplastic, inflammatory, paraneoplastic, or meningitic cause, from which the pain characteristics may be clinically indistinguishable (Gronseth et al., 2008; Kalanie et al., 2014; Maarbjerg et al., 2017; Wanibuchi et al., 2012). It must also be carefully differentiated from trigeminal neuropathy with differing qualitative and temporal pain characteristics and sensory deficits on examination. Cerebellopontine angle acoustic schwannomas frequently involve the sensory nerve root, causing ipsilateral facial sensory symptoms accompanied by ipsilateral tinnitus, deafness, and vertigo from vestibulocochlear nerve involvement.

Trigeminal Ganglion Middle cranial fossa malignant infiltration, compressive neoplastic lesions, and autoimmune inflammation are among the most common causes of trigeminal ganglion pathology. The trigeminal ganglion is a location in which the varicella-zoster virus (VZV) often lies latent, sometimes reactivating along the course of the trigeminal ophthalmic branch later in life to cause herpes zoster ophthalmicus and a pain syndrome that may occur with or without an accompanying zoster rash (Birlea et al., 2014; Vrcek et al., 2017). Identification of skin lesions along the side of the nose (Hutchinson sign) corresponding to the nasociliary branch of the ophthalmic division strongly predicts subsequent ocular complications (Nithyanandam et al., 2010).

Trigeminal Nerve Branches

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ABDUCENS NERVE (CRANIAL NERVE VI) Anatomy Paired abducens nuclei are located in the dorsal pons in the floor of the fourth ventricle in close proximity to the fascicle of the facial nerve. Each nucleus contains abducens motoneurons that form the abducens nerve, and interneurons that decussate at the nuclear level and ascend in the medial longitudinal fasciculus (MLF) to the contralateral oculomotor medial rectus subnucleus to facilitate conjugate horizontal gaze in the direction ipsilateral to the abducens nuclear origin of the interneurons. The abducens fascicle exits the ventral surface of the nucleus, traverses the brainstem, emerges from the ventral pontomedullary sulcus at the caudal pontine surface, and travels in the subarachnoid space, where it ascends near the clivus. It pierces the dura and passes under the petroclinoid (Gruber) ligament into the Dorello canal, then travels through the body of the cavernous sinus lateral to the internal carotid artery (unlike the oculomotor, trochlear, and trigeminal nerves, which are housed in the lateral dural wall), and ultimately into the superior orbital fissure to innervate the ipsilateral lateral rectus muscle (see eFig. 103.1).

Clinical Lesions

Abducens Nucleus

Dysfunction of the ophthalmic branch results in numbness or paresthesias in the anterior scalp, forehead, and supraorbital regions, and an abnormal corneal reflex. A lesion of the maxillary branch affects the cheek, lower eyelid, and upper lip. A lesion of the mandibular branch affects the lower lip, chin, and lateral face anterior to the ear. Motor involvement in a trigeminal nerve lesion is often clinically undetectable. Although it is tempting to localize a trigeminal nerve lesion based on symptom distribution, the complex branching pattern and organization of the trigeminal nuclei and ganglion prohibit such simple localization. It is common for lesions proximal to the peripheral nerve branches to evoke symptoms in a single trigeminal branch distribution. Lesions of a single branch may result from inflammation, compression, or neoplasm (Briani et al., 2013; Perera et al., 2014). Damage to small distal branches may occur after dental procedures. The ophthalmic branch may be involved in Gradenigo syndrome in combination with the abducens and facial nerves from a lesion at the petrous apex, most common clinically as inflammation following otitis media in children (Vitale et al., 2017; see Table 103.1). Both the ophthalmic and maxillary branches may be affected by a cavernous sinus lesion, in which setting dysfunction of the oculomotor, trochlear, and abducens nerves is often present. Two particularly ominous clinical scenarios are (1) insidious development of facial numbness or paresthesias in a patient with a history of facial skin malignancy, and (2) the “numb chin” or “numb cheek” syndromes. In the first situation, perineural invasion of the trigeminal branches is likely (Erkan et al., 2017; Warden et al., 2009). This is most frequently seen with head and neck adenoid cystic carcinoma, squamous cell carcinoma, and melanoma. The numb chin syndrome results from involvement of the mental nerve branches of the mandibular division and is most commonly due to focal metastatic nerve infiltration within the mandible, most often from breast, lung, prostate,

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or hematological malignancies (Assaf et al., 2014; Maeda et al., 2018; Sanchis et al., 2008), though it may also be a secondary effect of radiation or pharmacological therapies (Fortunato et al., 2018). This syndrome may rarely be the presenting manifestation of malignancy but more often represents recurrence or progression of known disease. The numb cheek syndrome occurs when branches of the maxillary division are involved.

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Because the abducens nucleus contains the interneurons destined to ascend in the contralateral MLF to the contralateral oculomotor medial rectus subnucleus to permit conjugate horizontal gaze, abducens nuclear lesions cause conjugate horizontal gaze palsy toward the side of the lesion. Isolated horizontal gaze palsy may occasionally occur but accompanying ipsilateral facial palsy with lower motor neuron facial weakness is typically present. Lesions involving both the abducens nucleus and ipsilateral MLF cause the one-and-a-half syndrome, with an ipsilateral conjugate gaze palsy and an ipsilateral internuclear ophthalmoplegia with impaired adduction of the ipsilesional eye and abducting nystagmus of the contralateral eye (see Chapter 21). Common brainstem lesions include ischemia, hemorrhage, demyelination, infectious and noninfectious inflammation, and neoplasm. Periventricular necrosis from Wernicke encephalopathy also frequently results in horizontal gaze or abducens palsy from involvement of the abducens nucleus or fascicle, respectively.

Abducens Palsy Appearance Abducens nerve dysfunction results in impaired ipsilateral abduction of the eye and deviation of the eyes toward one another (esotropia) (Fig. 103.8 and Videos 103.5 and 103.6). Binocular horizontal diplopia and the esotropia are worse with gaze in the direction of the abduction deficit.

Brainstem Fascicle The original Foville syndrome was the combination of ipsilateral abducens palsy, ipsilateral lower motor neuron facial palsy, and contralateral hemiparesis from corticospinal tract involvement (see Table 103.1). It is now more commonly applied to the combination of ipsilateral abducens and facial palsies with contralateral ataxia, ipsilateral Horner syndrome, ipsilateral deafness, and ipsilateral loss of taste and facial

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Facial Palsy and Trigeminal, and Glossopharyngeal Neuralgia Treatments

eTABLE 103.2 Condition

Treatments

Facial palsy

Lubrication and taping

Considerations

Corneal protection during temporary facial weakness with minimal corneal risk External upper eyelid weights, Botox, temporary tarsorrhaphy Corneal protection during temporary facial weakness with corneal exposure Permanent gold upper-eyelid weights or permanent tarsorrhaphy Corneal protection with permanent facial weakness Facial physical therapy or neuromuscular facial retraining May be enhanced by electromyographic feedback; may be helpful for synkinetic dysfunction Brow elevation For visual dysfunction or discomfort from brow ptosis Proximal facial nerve grafting with sural or greater auricular nerve; Facial mobilization procedures; most commonly used after hypoglossal or spinal accessory to facial nerve anastomosis; permanent iatrogenic surgical facial nerve section or for microneurovascular free muscle flap transfer (e.g., with temponeoplastic facial dysfunction ralis or latissimus dorsi muscle) Trigeminal and glossopharyngeal Pharmacological treatment with carbamazepine or oxcarbamaze- Prophylactic pain therapy; often the mainstay of therapy neuralgia pine. Other options include baclofen, gabapentin, lamotrigine, or topiramate Microvascular decompression Typically, the preferred treatment for young patients with medically refractory pain; low pain recurrence rate Percutaneous radiofrequency thermocoagulation; glycerol rhizoly- May be the preferred treatment for older patients at high sursis; balloon microcompression; peripheral branch neurectomy; gical risk with medically refractory pain; higher recurrence nerve root Gamma Knife radiosurgery and complication rates than central surgical treatments (Yuvaraj et al., 2019)

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Petrous Apex Abducens palsy is common in Gradenigo syndrome in combination with trigeminal ophthalmic division and facial nerve involvement from a lesion at the petrous apex (see Table 103.1). This is most commonly seen clinically as inflammation following otitis media in children (Vitale et al., 2017).

Cavernous Sinus

A

B Fig. 103.8 Right Microvascular Abducens Palsy. A, Right gaze with impaired abduction of right eye. B, Normal left gaze.

sensation. Millard-Gubler syndrome is the combination of ipsilateral abducens and facial palsies with contralateral hemiparesis (see Table 103.1). Raymond syndrome is the combination of ipsilateral abducens palsy and contralateral hemiparesis (see Table 103.1). Common brainstem lesions include ischemia, hemorrhage, demyelination, infectious and noninfectious inflammation, and neoplasm. Isolated abducens palsy from fascicular involvement is rarely the presenting manifestation of cavernoma, demyelination, metastatic disease, or paraneoplastic brainstem encephalitis (Hammam et al., 2005; Mallery et al., 2012). Quantitative assessment of the velocity of abducting saccades via eye movement recordings may help differentiate a central fascicular abducens lesion from a peripheral abducens palsy. With an acute abducens palsy (95%). Planning treatment for affected infants, potentially including surgery, is difficult. Initial surgical treatment in utero or in the neonatal period can provide cosmetic repair and decrease the risk for meningitis (Adzick, 2011). Also hydrocephalus can be shunted. Any existing myelopathic or radiculopathic neurological deficit is likely to persist after surgery. Some patients, especially infants with progressive brainstem dysfunction, are treated with decompression of the rostral spinal canal. Less than 30% of such patients survive beyond the first year, and long-term problems including mental retardation and paraplegia are often severe. Few patients with myelomeningocele are mentally normal, but most of those with lumbar meningocele are.

Dandy-Walker Syndrome Dandy-Walker syndrome results from the failure of development of the midline portion of the cerebellum. A cyst-like structure associated with a greatly dilated fourth ventricle, expanding the midline, is often seen (Fig. 104.12). The malformation typically causes the occipital bone to bulge posteriorly and displaces the tentorium and torcula

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Roots

Fig. 104.10 Diagrammatical Representation of Myelomeningocele.

Fig. 104.11 Diagrammatical Representation of Meningocele.

upward. The cerebellar vermis is aplastic, and the corpus callosum may be deficient or absent. There is usually dilation of the aqueduct as well as the third and lateral ventricles. Chiari IV malformation is characterized by cerebellar and brainstem hypoplasia rather than displacement and is probably a variant of the Dandy-Walker malformation.

Tethered Cord Syndromes Congenital abnormalities of the spinal cord or cauda equina can result in spinal cord tethering, in which stretching and tension develops within the cord tissue as the spinal column elongates during early life, resulting in the conus medullaris being found at an abnormally low vertebral

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B

Fig. 104.12 Dandy-Walker Malformation. A, T2-weighted magnetic resonance imaging (MRI). B, T1-weighted MRI. (Courtesy Michael Coffee, MD.)

BOX 104.5

Causes of Tethered Spinal Cord

Primary Causes Dermal sinus tract Diastematomyelia Dural bands Intraspinal lipoma or tumor Meningocele, myelomeningocele, anterior sacral meningocele Neuroenteric cyst Sacral agenesis Tight filum terminale Secondary Causes Arachnoiditis Dermoid Re-tethered spinal cord Suture granuloma Trauma Adapted with permission from McLone, D.G., La Marca, F., 1997. The tethered spinal cord: diagnosis, significance, and management. Semin. Pediatr. Neurol. 4, 192–208.

level (Michelson and Ashwal, 2004; Box 104.5). Imaging studies, such as spinal MRI, showing the conus medullaris caudad to the lower endplate of L2, can be evidence of tethering. A child or even an adult with these abnormalities can develop progressive neurological dysfunction due to traction on the cord or nerve roots. One presentation is lower motor neuron dysfunction in one or both lower extremities, but patients can also have sensory loss, upper motor neuron signs, orthopedic foot deformities, and scoliosis. A tethered spinal cord can, in addition, cause isolated sphincter dysfunction as subtle as intermittent urinary incontinence. The so-called occult tethered cord syndrome is an area of controversy (Drake, 2006; Selden, 2006). Uncontrolled surgical series suggest that children with neurogenic voiding dysfunction and normal spinal MRI might also have cord tethering. For some children, voiding dysfunction reportedly improved after lysis of the filum terminale, which microscopically can be abnormally thickened, fatty, and fibrous, even though the filum and conus

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medullaris appear normal on MRI. A few cases of cerebellar tonsillar herniation seem to be due to occult cord tethering; other features are syrinx development below the T5 level and scoliosis (Milhorat et al., 2009). In contrast to patients with classic CM-I, patients with this variation of CM-I with cord tethering have normal posterior fossa volume and an enlarged foramen magnum. Supporting the role of cord tethering as a cause of the tonsillar descent are reports of increasing herniation of the cerebellar tonsils with somatic growth, cerebellar prolapse following Chiari decompression surgery, and anatomical improvements including ascent of the conus medullaris, ascent of the cerebellar tonsils, and resolution of brainstem elongation following section of the filum terminale. Split spinal cord malformation (SSCM), formally termed diastematomyelia, is a congenital malformation of the spinal cord characterized by sagittal division of a portion of the cord into two hemicords. In most instances, the division is located in the lower thoracic or lumbar regions. SSCM is often accompanied by skin abnormalities such as a tuft of hair at the level of the lesion. Two types of SSCM are described: type I, in which each hemicord has its own dural sheath, and type II in which both hemicords are enclosed in a single dural sheath. Neurological deficits, scoliosis, and congenital foot deformities are more common in type I. Bony and cartilaginous spurs between the hemicords are also more common with type I. Finally, surgical repair is more effective in type I and can be combined with distal untethering if a tethered cord is present as well. The spur tethers the spinal cord, leading to progressive neurological dysfunction when the vertebral column lengthens during growth. The diagnosis can often be suspected on plain radiography, which shows widening of the interpedicular distance and a posterior bony bridge at the level of the lesion. MRI or CT myelography can confirm the diagnosis (eFig. 104.13). Surgical therapy consists of attempts to free all structures tethering the cord by removing the spurs and dura in the cleft and cutting the filum terminale if abnormally tethered.

SYRINGOMYELIA AND SYRINGOBULBIA Hydromyelia is an abnormal dilation of the central spinal canal with “excess” CSF contained within the ependymal lining. When fluid

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C eFig. 104.13 Magnetic Resonance Images of Diastematomyelia. A, Patient 1: Sagittal T1-weighted image shows severe scoliosis and division of spinal cord into right (arrow) and left (curved arrow) hemicords. Patient 2: Axial T1-weighted image (B) and axial T2-weighted image (C) show two separate hemicords. (A, Courtesy Erik Gaensler.)

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A

Fig. 104.14 Diagrammatic representation of persistent central canal extending throughout length of spinal cord.

dissects into the surrounding white matter, forming a cystic cavity or syrinx, the term syringomyelia is applied. A syrinx, then, is a cavity in the spinal cord (syringomyelia) or brainstem (syringobulbia) (Figs. 104.14, 104.15, and 104.16). Hydromyelia and syringomyelia often coexist, and many physicians use the terms interchangeably. The widespread use of spinal MRI has greatly increased the detection of cervical syringomyelia, which often produces nonspecific symptoms such as neck pain and at times no symptoms at all. Estimated prevalence in the United States is between 1:1300 and 1:1900. The central canal of the spinal cord is normally wide open during embryonic life and becomes atretic after birth. It is occasionally patent in adults (see Fig. 104.14). Cervical or thoracic MRI in an adult will occasionally reveal an incidental asymptomatic hydromyelia, which is typically linear or fusiform on sagittal images; extends over several levels, sometimes discontinuously; and is round, central, and up to 4 mm in diameter on axial images (Batzdorf, 2005).

Clinical Presentation The prototypical presentation of a symptomatic syrinx is the presence of lower motor neuron signs at the level of the lesion, usually in the upper extremities, or in the case of syringobulbia, the lower cranial nerves. Furthermore, it can present as a myeloradiculopathy with lower motor neuron findings in the upper extremities and upper motor neuron findings in the lower extremities. In addition, there is often a dissociated, suspended sensory loss with impaired pain and temperature sensation, but preserved dorsal column sensation (i.e., light touch). However, few patients show this total picture. The clinical features vary with the size, location, and shape of the cavity; the rapidity of its evolution; and any associated neurological conditions such as a Chiari

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B Fig. 104.15 A, Sagittal T2-weighted magnetic resonance imaging demonstrates intramedullary signal abnormality posterior to T1–T3 level of spinal cord. Possible causes include edema, myelomalacia, or syringomyelia. B, Axial computed tomographic myelogram performed at a 3-hour delay demonstrates filling of area of signal abnormality with myelographic contrast that had been injected into lumbar subarachnoid space. Filling of cavity with contrast is consistent with syringomyelia but would not be expected in cases of cord edema or myelomalacia.

I malformation. Symptoms are more related to the pace of evolution of the syrinx than to its absolute size. Otherwise healthy patients with slitlike syrinx cavities may present with severe localized spinal and radicular pain. Other patients with syrinx cavities displacing as much as 90% of the spinal cord mass may be virtually asymptomatic. Pain is a prominent symptom in most patients with syringomyelia. Common complaints include neck ache, headache, back pain, radicular pain, and areas of segmental dysesthesia. Painful dysesthesias are most likely to occur at or adjacent to the caudal extent of the syrinx cavity. Some patients have trophic changes corresponding to segmental loss of pain sensation. Syringomyelia can cause neuropathic monoarthritis (Charcot joint), most commonly in a shoulder or elbow. Most syringes are in the cervical spinal cord. Those developing from hydromyelia are usually associated with Chiari I or II malformations,

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Syrinx Associated With Spinal Cord Tumors Syringes are associated with intramedullary tumors often enough that any cystic process in the spinal cord should be considered an intramedullary tumor until proven otherwise. Syringomyelia accompanies 25%–60% of intramedullary spinal tumors; conversely, 8%–16% of syringes are caused by tumors (eFig. 104.17). Intramedullary tumors in von Hippel-Lindau syndrome and neurofibromatosis are particularly likely to be accompanied by syringes. The syrinx extends from the tumor, more often rostrally than caudally. Ependymomas, which represent up to 10% of childhood CNS tumors and affect adults as well, are particularly likely to produce syringes because of their central location. Less than 2% of extramedullary tumors in the spinal canal (e.g., meningiomas, neuromas) are associated with syringes. Fig. 104.16 Magnetic resonance image demonstrates a large syringomyelic cavity in the cervical cord.

communicating hydrocephalus, or abnormalities at the craniovertebral junction. Asymptomatic hydromyelia and syringomyelia may be incidentally discovered by MRI while investigating unrelated cranial symptomatology, such as a Chiari malformation. A syrinx associated with a spinal cord tumor or trauma can occur at any level of the spinal cord. Although either CT or MRI can demonstrate a syrinx, MRI is more sensitive for complete evaluation of the cord and surrounding soft tissues. In patients in whom MRI is contraindicated, CT myelography may be useful in discerning syringomyelia, which will commonly fill with contrast on delayed images due to communication with the CSF through the central canal of the spinal cord (see Fig. 104.15).

Communicating and Noncommunicating Syringes The terms communicating and noncommunicating syringes indicate whether the syrinx is in communication with the CSF pathways. However, it is often difficult to determine this, even at autopsy, so these terms are mainly of use in discussions of etiology. It is better to classify syringomyelia according to its associations.

Abnormalities of the Cervicomedullary Junction Abnormalities of the cervicomedullary junction and posterior fossa, such as Chiari anomalies types I and II and the Dandy-Walker malformation, are the most common cause of nonidiopathic syringes. Up to 70% of nonidiopathic syringes are associated with CM-I. The mechanism of formation of these syringes is controversial (Di Lorenzo and Cacciola, 2005). Patients with cervical syringomyelia and no Chiari malformation often have a small posterior fossa or disturbed flow of CSF near the foramen magnum (Bogdanov et al., 2004). Syringes can extend beyond hydromyelia as an outpouching of the dilated central canal (see Figs. 104.15 and 104.16). One hypothesis is that the posterior fossa abnormalities interfere with the passage of CSF from the fourth ventricle through the foramina of Luschka and Magendie into the subarachnoid space. The consequence is transmission of bulk flow and the various pressure waves of the CSF (arterial, venous, respiratory) down the central canal of the spinal cord, leading to dissection of a syrinx into the substance of the spinal cord. Noncongenital abnormalities at the cervicomedullary junction that sometimes cause syringomyelia include arachnoiditis and meningiomas.

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Syrinx Associated With Spinal Cord Trauma Syringes can develop as a late effect of serious spinal cord trauma (Carroll and Brackenridge, 2005). Estimates of the prevalence of syringes after trauma vary widely from 0.2% to 64%. However, delayed progressive intramedullary cystic lesions complicates 3%–4% of dramatic spinal cord injuries. Symptoms of ascending long-tract or segmental spinal cord dysfunction usually develop within 5 years after the acute traumatic myelopathy has stabilized, improved, or even become asymptomatic. Pain or other sensory symptoms are often prominent. Findings usually evolve gradually but occasionally worsen suddenly after events such as a cough or Valsalva maneuver. The cavities are typically eccentric and can be multiple, arising from areas of posttraumatic myelomalacia and then spreading rostrally or caudally. Severe posttraumatic spinal deformity or arachnoid scarring can also cause posttraumatic syringes.

Syrinx Associated With Other Focal Spinal Cord Pathologies Any illness causing arachnoiditis can lead to formation of a noncommunicating syrinx. Reported causes include meningitis, subarachnoid hemorrhage, spinal trauma, epidural infections, epidural anesthesia, and spinal surgery, but many cases of focal arachnoiditis are idiopathic. Syringes can develop as a complication of various intramedullary pathologies, including trauma and tumors (see previous discussion), spinal ischemic or hemorrhagic strokes, radiation necrosis, or transverse myelitis.

Treatment Indications for and approaches to surgical therapy for syringes are far from standardized. In patients with Chiari I malformations, the syrinx often improves after decompression of the malformation with various combinations of suboccipital craniectomy, upper cervical laminectomy, and/or dural grafting. The exact surgical technique is debated, and remains controversial, but it is agreed that the goal is adequate restoration of normal CSF flow and pressure across the craniocervical junction. Two recent meta-analyses have both concluded that adding a duraplasty to posterior fossa decompression results in improvement in syringomyelia, but is associated with higher rates of CSF leak and aseptic meningitis (Chai, 2018; Lin, 2018). Concerningly, another recent study has concluded that 50% of patients treated with posterior fossa decompression will require an additional surgery for persistent, progressive, and/or recurrent syringomyelia (Soleman et al., 2019). When

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B eFig. 104.17 Magnetic Resonance Image Demonstrates Syrinx Associated With Spinal Cord Tumor (Hemangioblastoma). A, T1-weighted image shows a nodule in upper cervical cord and a low-signal central mass suggestive of a cyst. B, Postgadolinium image shows that nodule intensely enhances, which is classic for hemangioblastoma. (Courtesy Erik Gaensler.)

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the syrinx extends from an intramedullary tumor, resection of the tumor usually leads to regression of the syrinx, so no specific surgical drainage of the cavity is needed. When the syrinx extends from an area of localized arachnoiditis or other obstruction of the subarachnoid space, some patients benefit from resection of the arachnoiditis and restoration of CSF flow patterns with an expansile duraplasty; shunting or entering the cavity (syringotomy) is a less desirable surgical approach (Batzdorf, 2005). In patients with Chiari I malformation and syrinx, pain and other sensory symptoms are more likely to improve if the foramen magnum is decompressed within 2 years of onset of the sensory symptoms (Attal et al., 2004). Among patients undergoing surgery for syrinx in the absence of Chiari malformation, slightly more than half improved or stabilized, but over a third required more than one operation (Batzdorf, 2005).

Clinical Correlations A single patient often has more than one of the conditions discussed (Williams, 1991). Thus, a patient with one of the Chiari hindbrain malformations also may have some combination of bony abnormalities of the foramen magnum or cervical spine, syringomyelia, and myelomeningocele. The clinical manifestations of craniocervical deformities are protean depending on which neural structures and associated anomalies are involved. When a patient has these problems, diagnosis and treatment starts by analyzing each component. MRI and CT scans, especially with measurements of the foramen magnum and posterior fossa, have greatly eased the analytical process. Many patients are asymptomatic or first present with neurological complaints in adult life. Patients may have short necks or abnormal neck posture or movement, particularly if there is an element of skeletal deformity (e.g., Klippel-Feil anomaly, occipitalization of the atlas). Findings attributable to the brainstem or cerebellum may occur with Chiari malformations, compression of the brainstem (e.g., basilar impression, vertical displacement of the dens), or syringobulbia. Uncommonly, AA disease or basilar invagination can cause compromise of vertebrobasilar circulation, causing posterior circulation strokes or transient ischemic attacks. Specific findings suggestive of disease at the foramen magnum include downbeat nystagmus or the combination of long-tract signs with lower motor neuron dysfunction in the lower cervical spinal cord; lower motor neuron dysfunction has been attributed to impaired spinal venous drainage at the foramen magnum. Spinal cord syndromes can be caused by syringomyelia or by extramedullary cord compression (e.g., by the dens with AA dislocation, by spinal stenosis in Klippel-Feil anomaly). Additional neurological dysfunction can occur when the anomalies form part of more widespread developmental failure (e.g., lumbar effects of myelomeningocele in Chiari II malformation, accompanying cerebral malformations in Klippel-Feil anomaly).

SPINAL DEFORMITIES AND METABOLIC BONE DISEASE Osteoporosis Osteoporotic vertebral compression fractures occur most commonly in the thoracic and thoracolumbar spine, especially in postmenopausal women (Fig. 104.18). By age 75 years, nearly a fourth of women have vertebral compression fractures. Although these fractures may lead to kyphosis (“dowager hump”) and loss of body height, most are painless. The presence of a vertebral fracture in a postmenopausal woman or older man is a very strong predictor of subsequent fracture risk and an indication for pharmacological treatment of osteoporosis. In younger men and women, acute traumatic compression fractures are more likely to be painful. The pain usually is centered at the level of the compression and accompanied

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Fig. 104.18 Spinal magnetic resonance image of a patient with vertebral compression fracture secondary to osteoporosis. T1-weighted images of lumbar spine show 70%–80% loss of height of midportion of L1 vertebral body, with relative preservation of height of posterior portion of vertebral body. Bright appearance of vertebra indicates preservation of fat within marrow compartment, which would be dark if replaced by tumor. (Courtesy Erik Gaensler.)

by loss of spinal range of motion. Pain increases with activity, decreases with bed rest, and resolves slowly, though sometimes incompletely. Patients with more disabling pain can be management challenges, sometimes requiring hospitalization. Initial management includes activity modification and pain control utilizing analgesics ranging from nonsteroidal antiinflammatory drugs (NSAIDs) to opioids depending on the severity of the pain. Bracing for a short period of time in the acute phase may prove helpful. For patients not responding to conservative treatments a vertebral augmentation procedure (vertebroplasty or kyphoplasty) may be considered. While controversy continues regarding the overall efficacy of these procedures for pain management and which procedure should be utilized for a given patient, there is some consensus that when administered to properly selected patients with severe pain within a 6-week period of onset there can be some reduction in the severity of pain and a shortening of the length of hospitalization (Rodriquez, 2017; Chandra, 2018). Once pain is controlled, an exercise program—including aquatic therapy, smoking reduction, and, if indicated, reduced alcohol consumption—may help reduce the risk of subsequent compression fractures. Nonmetastatic compression fractures infrequently lead to spinal cord or nerve root compression. When a compression fracture accompanies a focal neurological compression syndrome, a metastatic vertebral lesion should be considered. MRI features that favor a malignant cause of the compression fracture include decreased T1-weighted and increased T2-weighted signal in the vertebral body, with bulging of the posterior cortical wall, pedicle involvement, and associated epidural or paravertebral mass. Use of fluorodeoxyglucose positron emission tomography (FDG-PET)/CT imaging can also be useful in this diagnosis (Cho and Chang, 2011).

Osteomalacia and Rickets Osteomalacia and rickets are conditions of deficient bone mineralization. In adulthood, the most common mechanism for the development

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of osteomalacia is vitamin D deficiency, either due to dietary restriction, malabsorption, chronic kidney disease, or lack of sunlight exposure. The most specific screening test in otherwise normal individuals is a serum 25-hydroxyvitamin D (25[OH]D) level, though additional biochemical findings may include: low serum calcium, low serum phosphate, elevated serum alkaline phosphatase, and elevated parathyroid hormone (Kennel et al., 2010). A technetium (Tc-99m) bone scan can show increased activity as a result of widespread osteoblast activation. Radiographs may reveal pseudofractures, bands of decreased bone density along the cortical surface. Long bones are typically more involved than the spine. Spinal pain, kyphosis, and compression fractures can occur in osteomalacia, but compression of spinal cord or nerve roots is rare. Basilar impression can occur in patients with osteomalacia. Osteomalacia can result in bone pain, fractures, impaired gait, and muscle cramps. A painful proximal muscle weakness, especially in the hip girdle, can also occur. The mechanism of this myopathy is thought to be related to the aforementioned hyperparathyroidism. The physical examination reveals diminished muscle power, hypotonia, atrophy, and a “waddling” quality in the gait. When there is secondary hyperparathyroidism with hypercalcemia, tendon reflexes may be brisk. Needle electromyography (EMG) may show small-amplitude, short-duration, polyphasic motor units, without electrophysiological evidence of active denervation. Muscle biopsy may show type II atrophy. Strength can improve after adequate vitamin D replacement.

Osteopetrosis The osteopetroses are a group of rare inherited diseases characterized by increased bone density due to impaired bone resorption (Jenkins et al., 2013; eFig. 104.19). Varied genetic defects can cause osteopetrosis, resulting in three clinical variants: infantile severe autosomal recessive, intermediate autosomal recessive, and autosomal dominant. Osteopetrosis of the skull can cause cranial neuropathies (most often optic neuropathy), basilar impression, hydrocephalus, or syringomyelia. Osteopetrosis of the spine can contribute to spinal canal stenosis with secondary compressive myelopathy. Other complications include thrombocytopenia, anemia, osteomyelitis, and fractures. Some patients can be treated by hematopoietic stem cell transplantation. Other rare sclerosing bone disorders like progressive diaphyseal dysplasia (Camurati-Engelmann disease) or endosteal hyperostosis occasionally have neurological complications (Grond-Ginsbach and Debette, 2009). Very rarely, infants present with both osteopetrosis and infantile neuraxonal dystrophy and follow a course of neurodegeneration and death in infancy; neuropathology of these children includes neuronal ceroid lipofuscin and eosinophilic axonal spheroids.

Paget Disease Paget disease of the bone (osteitis deformans) is a focal metabolic bone disease of excessive osteoclastic bony destruction coupled with reactive osteoblastic activity (Ralston et al., 2008) (Fig. 104.20). The incidence increases with age and varies among ethnic groups, with a high incidence (nearly 5%) in elderly Caucasians of Northern European descent. Men are slightly more commonly affected. Paget disease appears to be caused by a combination of genetic and environmental factors, including possible roles of calcium or vitamin D deficiency, toxins, and infections, especially with paramyxovirus. Paget disease is usually asymptomatic and discovered only because of laboratory or radiographic abnormalities. However, it may cause symptoms by bone or joint distortion, fractures, compression of neurological tissue by calcification, hemorrhage, or focal ischemia due to a vascular steal by the metabolically hyperactive bony tissue. Uncommonly, neoplasms, especially osteogenic sarcoma, can develop in pagetic bone.

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Fig. 104.20 Radiograph of a patient with Paget disease of the skull. Note thickening of calvaria (white arrows) and bony sclerosis with a cotton-wool appearance (black arrows). Patient has basilar invagination; note high position of dens with respect to clivus. (Courtesy Erik Gaensler.)

A few families have an autosomal dominant illness, which has now been characterized as valosin-containing protein (VCP) disease, and includes the triad of inclusion body myositis, frontotemporal dementia, and Paget disease of bone (Mehta et al., 2013).

Diagnosis Paget disease usually can be diagnosed by characteristic radiographic findings of mixed osteolytic and osteoblastic lesions (see Fig. 104.20). Osteolytic activity can cause well-demarcated round patches of low bone density in the skull (osteogenesis circumscripta). Osteoblastic activity leads to thickening of cortical bone and then to a general increase in bone density, often with distortion of normal organization. Although most patients with Paget disease have elevation of serum bone alkaline phosphatase and markers of bone resorption, focal skeletal disease with neurological complications may occur in patients without laboratory abnormalities. Alkaline phosphatase levels, when elevated, are helpful not only in making the diagnosis but also in following response to treatment. Evaluation of serum calcium and 25(OH)D levels should be completed to exclude other potential causes for the alkaline phosphatase level. Biopsy is often not required but should be considered when radiographic findings are atypical. Potential mimics include blastic lesions from metastatic disease or lytic lesions seen in multiple myeloma.

Cranial Neurological Complications Neurological complications with cranial involvement are common in Paget disease (Rubin and Levin, 2009). Paget disease of the skull can lead to head enlargement. Patients often complain of headache. The most common focal neurological manifestation is hearing loss. Paget disease of the cribriform plate can disrupt olfaction. Other cranial mononeuropathies (e.g., optic neuropathy, trigeminal neuralgia, hemifacial spasm) are much less frequent. Perhaps a third of patients with Paget disease of the skull have some degree of basilar invagination, but symptomatic complications such as brainstem or cerebellar compression, hydrocephalus, or syringomyelia are rare (Raubenheimer et al., 2002). Patients with Paget disease of the skull occasionally develop seizures. The pagetic skull is more vulnerable to bleeding from minor trauma, which can lead to epidural hematoma.

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eFig. 104.19 Radiograph of a Patient With Osteopetrosis; Skull Is Extremely Dense. Radiograph is slightly overexposed; note darkness of the central areas (arrow). Bone of petrous apex (curved arrow) is particularly dense. (Courtesy Erik Gaensler.)

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Spinal Neurological Complications Symptomatic Paget disease of the spine occurs most often in the lumbar region, where it can cause back pain, monoradiculopathies, or cauda equina syndrome. The disease may involve adjacent vertebral bodies and the intervening disk space or may cause root compression by extension from a single vertebral body. The differential diagnosis in patients with Paget disease and neurological dysfunction in a single limb includes peripheral nerve entrapment by pagetic bone. Paget disease of the spine leading to myelopathy is more often thoracic than cervical. A variety of mechanisms are reported, including extradural extension of pagetic bone, distortion of the spinal canal by vertebral compression fractures, spinal epidural hematoma, or sarcomatous degeneration leading to epidural tumor. In a small number of patients with myelopathy, imaging shows no evident spinal cord compression, thus suggesting a vascular steal phenomenon by hypermetabolic bone in the vertebral body resulting in cord ischemia. In support of this hypothesis, drug treatment of Paget disease in these patients can improve spinal cord function, sometimes within a few days.

Treatment Potent nitrogen-containing bisphosphonates (e.g., zoledronic acid, pamidronate, risedronate) are the drugs of choice for treatment of Paget disease. Bone resorption decreases within days. Within 1–2 weeks of treatment, bone pain may improve. Osteoblastic bone formation and falling serum alkaline phosphatase levels occur after 1 or 2 months of therapy. Some patients experience significant neurological improvement after treatment, but improvement is often delayed 1–3 months. In cases with severe cord compression, surgical decompression is indicated, but drug treatment before surgery decreases the risk of operative bone hemorrhage. Calcitonin is an alternative treatment for patients unable to take bisphosphonates or who require more immediate surgery (Wootton et al., 1978). Patients with cranial neuropathy have less impressive responses to drug therapy. Hydrocephalus can be treated successfully with ventriculoperitoneal shunting (Roohi et al., 2005). Additional interventions such as hearing aids, analgesics, physical therapy, and orthotics are often required once the excessive bone turnover has been addressed (Siris et al., 2006).

Juvenile Kyphosis Juvenile kyphosis (Scheuermann disease) manifests as thoracic or thoracolumbar kyphosis in adolescents. This is a self-limited disorder which arises due to uneven vertebral bone growth with respect to the sagittal plane. Spinal pain is more likely to accompany lumbar than thoracic disease. Spinal radiography shows anterior vertebral wedging, increased Cobb angle, and elongated sagittal balance (horizontal distance between the center of C7 and the superior-posterior border of the S1 endplate). Neurological abnormalities are uncommon, but spinal cord compression can occur from thoracic disk herniation or direct effects of severe kyphosis.

Scoliosis Scoliosis can be congenital, acquired secondary to an underlying disease, or idiopathic. The most common form is idiopathic scoliosis, with or without kyphosis, that usually develops painlessly in childhood and adolescence. A few cases of acquired scoliosis are associated with tumor, spondylolisthesis, or neurological pathology such as syrinx, myelomeningocele, or Chiari I malformation. Among patients with acquired scoliosis, indications for spinal MRI include abnormal neurological examination or atypical curve features such as sudden progression, left thoracic curvature, or absent apical segment lordosis (Davids et al., 2004). Spinal cord compression is a rare complication of idiopathic scoliosis and is particularly rare if no kyphosis is present. In

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each patient presenting with scoliosis and myelopathy, an important consideration is whether the myelopathy caused, rather than resulted from, the scoliosis. Patients with congenital scoliosis, unlike those with idiopathic childhood scoliosis, usually have anomalous vertebrae and may have other associated developmental problems such as Klippel-Feil anomaly or diastematomyelia. Scoliosis due to skeletal disease (e.g., achondroplasia) is more likely than idiopathic scoliosis to lead to spinal cord compromise. Myelopathy can result from spinal cord distraction during treatment of scoliosis with traction or surgery. Scoliosis can also be caused by various neurological diseases including cerebral palsy, spinocerebellar degenerations (e.g., Friedreich ataxia), inherited neuropathies (e.g., Charcot-Marie-Tooth disease), myelopathies (e.g., syringomyelia), paralytic poliomyelitis, spinal muscular atrophy, dysautonomia (e.g., Riley-Day syndrome), and myopathies (e.g., Duchenne disease) (Vialle et al., 2013). Excessive curvature of the spine can also be due to various causes of axial extensor muscles weakness (Mika et al., 2005) or due to overactivity of abdominal flexors, as can be seen in stiff-person syndrome. Scoliosis is the most common skeletal complication of neurofibromatosis type 1. Scoliosis that develops in adulthood can often be traced to an underlying cause such as trauma, osteoporotic fracture, degenerative spondylosis, or ankylosing spondylitis; it can result in local back pain, nerve root compression, or spinal canal stenosis.

Diffuse Idiopathic Skeletal Hyperostosis Diffuse idiopathic skeletal hyperostosis (DISH) (Forestier disease, ankylosing hyperostosis) is a syndrome of excessive calcification that develops with aging, more often in men than in women. The diagnosis is made by spinal radiographs that show “flowing” calcifications along the anterior and lateral portion of at least four contiguous vertebral bodies, without loss of disk height and without typical radiographic findings of ankylosing spondylitis (eFig. 104.21). Patients are often asymptomatic but may have spinal pain or limited spinal motion. Large anterior cervical calcifications can contribute to dysphagia, hoarseness, sleep apnea, or difficulty with intubation. A rare complication is myelopathy due to spinal stenosis if the calcifications are also present within the spinal canal. Like patients with ankylosing spondylitis, patients with DISH can develop spinal fractures after relatively minor trauma. Treatment is focused on symptomatic management.

Ossification of the Posterior Longitudinal Ligament or Ligamentum Flavum Ossification of the posterior longitudinal ligament anterior to the spinal canal (Fig. 104.22) and ossification of the ligamentum flavum posterior to the spinal canal are uncommon syndromes of acquired calcification. The posterior longitudinal ligament extends the length of the spine, separating the posterior aspects of the disks and vertebral bodies from the thecal sac. The ligamentum flavum is in the dorsal portion of the spinal canal, attaching the laminae and extending to the capsules of the facet joints and the posterior aspects of the neural foramina. Either ligament can ossify in later life, apparently independently of the usual processes of spondylosis and degenerative arthritis. Ossification of the posterior longitudinal ligament occurs more commonly in Asians than in non-Asians and with a roughly 2:1 male:female ratio. It may be visible on lateral spinal radiography but is usually asymptomatic. It is better seen by CT scan, in which it is distinguished from osteophytes by favoring the middle of the vertebral bodies rather than concentrating at the endplates. Thickness of the calcification can range from 3 to 15 mm. Ossification of the posterior longitudinal ligament is most likely to be symptomatic in the cervical spine, where it can contribute to cord

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eFig. 104.21 Lateral Thoracic Spinal Radiograph Shows Diffuse Idiopathic Skeletal Hyperostosis. Note flowing calcification of anterior osteophytes, with preservation of disk heights. (Reprinted with permission from Rosenbaum, R.B., Campbell, S.M., Rosenbaum, J.T., 1996. Clinical Neurology of Rheumatic Disease. Butterworth-Heinemann, Boston.)

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Fig. 104.22 Computed Tomographic Scan of a Patient With Posterior Longitudinal Ligament Ossification. Note continuous bony ridge present at every level, not just at disk space. In contrast to calcified degenerative spurs, these ligamentous calcifications are not connected to vertebral bodies. (Courtesy Erik Gaensler.)

compression if it is thick or if the canal is further narrowed by congenital and degenerative changes. The ligamentum flavum can contribute by hypertrophy or ossification to spinal stenosis, most often in the lower thoracic or lumbar spine, affecting the cord or cauda equina. Risk factors for development of ossification of the ligamentum flavum include trauma, hemochromatosis, calcium pyrophosphate deposition disease, DISH spondylitis, or ossification of the posterior longitudinal ligament.

DEGENERATIVE DISEASE OF THE SPINE Spinal Osteoarthritis and Spondylosis Osteoarthritis of the spinal facet joints manifests radiographically as joint narrowing, sclerosis, and osteophyte formation. Spondylosis refers to degenerative disease of the intervertebral disks, visible on radiography as disk-space narrowing, vertebral endplate sclerosis, and osteophyte formation. Spinal osteoarthritis and spondylosis are inevitable consequences of aging that are visible on routine spinal radiography in more than 90% of people by the age of 60 years. They are usually asymptomatic, but cause compression of the spinal cord or nerve roots in a minority of people. Nonetheless, they are the most common cause of compressive myelopathy or radiculopathy, accounting for far more neurological disease than all the other conditions discussed in this chapter combined. In youth, the intervertebral disks consist of a gelatinous central nucleus pulposus and a firm collagenous annulus fibrosus. Disk herniation syndromes occur when the nucleus pulposus bursts through a tear in the annulus fibrosus. This herniation can compress the nerve roots or spinal cord, depending on the spinal level

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involved. Rarely, disk material breaks into the thecal sac or a fragment ruptures into an epidural vein. Disk herniation is most likely to occur in young adults. By age 40 years, most adults have some disk degeneration with dehydration and shrinkage of the nucleus pulposus, necrosis and fibrosis of the annulus fibrosus, and sclerosis and microfractures of the subchondral bone at the vertebral endplate. Compression of neurological tissue can develop from a combination of disk herniation, osteophyte formation, ligament hypertrophy, congenital stenosis of the spinal canal, low-grade synovitis, and deformity and misalignment of the spine.

Cervical Spondylosis Cervical osteoarthritis and spondylosis are ubiquitous with increasing age (eFig. 104.23). These disorders can rarely be attributed to specific activities or injuries. An exception is patients with dystonia and other cervical movement disorders, who seem predisposed to premature cervical spinal degeneration. Because cervical osteoarthritis and spondylosis are so commonplace, it is usually difficult to ascertain their role in contributing to the pathogenesis of chronic neck pain or headache. Cervical spine surgery in the setting of degenerative pathology is rarely if ever indicated for treatment of headache or neck pain in the absence of cervical radiculopathy or myelopathy.

Cervical Radiculopathy Clinical Presentation

The symptoms of cervical radiculopathy often appear suddenly (Carette and Fehlings, 2005). Although disk herniation or nerve root contusion can be caused by acute trauma, most cases become

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eFig. 104.23 Lateral Radiograph of Cervical Spine Shows Typical Changes of Spondylosis and Osteoarthritis. (Reprinted with permission from Rosenbaum, R.B., Campbell, S.M., Rosenbaum, J.T., 1996. Clinical Neurology of Rheumatic Disease, Butterworth-Heinemann, Boston.)

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CHAPTER 104 Disorders of Bones, Joints, Ligaments, and Meninges symptomatic without an identifiable preceding traumatic event. Disk herniation is more likely to be the cause in patients younger than 45 years; neuroforaminal stenosis by degenerative changes is more common than disk herniation and becomes more likely with increasing age. Classic cervical radicular pain originates from the neck and radiates down the arm with or without dysesthesias, paresthesias, numbness, or even weakness. Subscapular or interscapular pain is common with lower cervical radiculopathy (C7 especially, but also C6, C8, and/or T1). Radiculopathic arm pain may increase with coughing or Valsalva maneuver. Arm pain may increase with a combination of neck extension, rotation to the side of the pain, and downward axial compression of the head (Spurling maneuver). Spondylosis, osteophytes, and disk herniations at the C4–C5 level can affect the C5 root, causing pain, paresthesias, and sometimes loss of sensation over the shoulder, with weakness of the deltoid, biceps, and brachioradialis muscles. The biceps and supinator reflexes may be lost. Spread of the biceps reflex to the finger flexors, an increased triceps reflex, or a paradoxical biceps reflex (absent or reduced biceps reflex with reflex contraction of the finger flexors, or rarely the triceps) suggest the presence of myelopathy. Pathology at the C5–C6 level can affect the C6 root and cause sensory changes in the first two digits and/ or lateral distal forearm, with possible weakness in the brachioradialis and wrist extensors. The biceps and brachioradialis reflexes may be diminished or inverted. Lesions at the C6–C7 level compressing the C7 root cause sensory changes in the index, middle, and/or ring fingers, and weakness in C7-innervated muscles such as the triceps, wrist flexors, and pronators. The triceps tendon reflex may be diminished. The C5, C6, and C7 roots are the ones most commonly involved in cervical spondylosis because they are at the level of greatest mobility where disk degeneration is greatest in the cervical spine. The relative frequency of root lesions in cervical spondylosis varies in different series. Clinically evident compression of the C8 root or of roots above C5 is less common.

Diagnostic Testing Cervical plain-film radiography is of little value in diagnosing or excluding cervical radiculopathy. MRI scanning of the cervical spine is usually helpful in identifying nerve root compression in patients with cervical radiculopathy, as well as diagnosing causes of myelopathy, and is the imaging study of choice in most cases. Cervical myelography followed by CT scanning is sometimes more sensitive than MRI (Fig. 104.24), and is particularly helpful in patients with MRI-incompatible pacemakers, spinal cord stimulators, severe claustrophobia, and other patients who cannot undergo MRI scanning. MRI images are often degraded by the presence of hardware from prior cervical spine fusion surgeries, making CT myelography particularly useful in these patients as well. However, MRI may show nerve root compression, particularly in the neural foramina, which is invisible by CT myelography if the site of compression is lateral to the subarachnoid space, thus not filled with contrast agent. CT myelography is also better than MRI for distinguishing noncalcified disk herniation from osteophytes or calcified disk herniations. All of that said, cervical MRI or CT myelography must be interpreted with caution because degenerative abnormalities are so commonly seen in the asymptomatic spine. Needle EMG and nerve conduction studies (NCS) can be useful in difficult diagnostic cases, both by identifying an affected motor nerve root and myotome and by helping exclude other diagnoses such as brachial plexopathy or peripheral neuropathy (Hakimi et al., 2013). NCS yield a particular pattern in cervical radiculopathy: there may be loss of amplitude in the affected compound muscle action potential (CMAP), but preservation of sensory nerve action potential (SNAP). This discrepancy occurs with intraspinal nerve root compression, which

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Fig. 104.24 Computed Tomographic Scan of Cervical Spine With Intrathecal Contrast Shows a Herniated Cervical Disk. Spinal cord (gray) and thecal sac (white) are distorted on the left by the disk. (Reprinted with permission from Rosenbaum, R.B., Campbell, S.M., Rosenbaum, J.T., 1996. Clinical Neurology of Rheumatic Disease. Butterworth-Heinemann, Boston.)

effectively separates motor nerve fibers from their cell body, the anterior horn cell within the spinal cord. This same lesion usually affects the root proximal to the dorsal root ganglion, allowing the sensory fibers to remain in continuity with their cell bodies. Needle EMG may reveal electrophysiological evidence of active denervation in the form of fibrillation potentials and/or positive sharp waves. Other spontaneous activity such as fasciculation potentials or complex repetitive discharges can suggest ongoing or remote motor neuron pathology, respectively. With volitional activation of the tested muscle, motor units may be large in amplitude and/or long in duration, suggesting prior denervation with subsequent reinnervation. There are several limitations to consider when interpreting electrodiagnostic (EDX) testing for the diagnosis of radiculopathy. First, the study is of low diagnostic yield in the hyperacute period. The electrodiagnosis of radiculopathy is insensitive in detecting radiculopathy in the absence of axonal loss. Therefore, one must allow for the completion of Wallerian degeneration following an injury before the study is performed. This process typically takes 5–6 days for motor fibers and 8–9 days for sensory fibers. Needle EMG in isolation has been said to have moderate diagnostic sensitivity, with different series citing 50%–71%. Root compression resulting in intermittent ischemia or mechanical deformation may result in isolated root demyelination without secondary axonal loss. In this scenario, a patient may experience classical radicular symptoms without any objective evidence of the disease. For these reasons it is important to have concordant clinical, radiographical, and electrophysiological data when making the diagnosis. A judicious approach helps to avoid unnecessary and potentially harmful surgical procedures.

Treatment Most instances of cervical radiculopathy improve significantly over 4–8 weeks regardless of treatment. Various treatments such as NSAIDs, temporary/situational use of a soft cervical collar, physical therapy, or cervical traction give similar results. Other treatments such as chiropractic manipulation, acupuncture, and epidural steroid injections remain in widespread use despite contradictory, conflicting, controversial, and/or

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Fig. 104.25 Cervical Spondylotic Myelopathy. A, Sagittal T2-weighted magnetic resonance imaging scan shows maximal compression of thecal sac and spinal cord at C5–C6. B, Axial computed tomographic scan with intrathecal contrast at this level shows a large osteophyte arising from posterior aspect of vertebral body; spinal cord at this level is compressed, and thecal sac is so compressed that little of the white intrathecal contrast is visible. (Reprinted with permission from Rosenbaum, R.B., Campbell, S.M., Rosenbaum, J.T., 1996. Clinical Neurology of Rheumatic Disease. Butterworth-Heinemann, Boston.)

lacking scientific data. Patients with a typical clinical presentation and little or no neurological deficit usually can be managed with these noninvasive approaches without imaging or EDX studies. When patients with radiculopathy have marked and/or progressive weakness, intractable pain, or have not improved with nonoperative therapy, surgical nerve root decompression is usually successful; however, there is little randomized controlled comparison of nonoperative therapy and surgery (Nikolaidis et al., 2010). Anterior cervical discectomy, with either fusion or total disk arthroplasty, or posterior cervical laminoforaminotomy, have all been shown to be effective surgical techniques. Selection of one technique versus another is a complex decision and is beyond the scope of this chapter. Such a determination depends on many factors, including sagittal alignment (kyphosis vs. lordosis), site of pathology (dorsal vs. ventral vs. both), number of levels to be treated, and others.

Cervical Spondylotic Myelopathy Cervical myelopathy related to spondylosis and osteoarthritis usually develops insidiously, but it may be precipitated by trauma or progress in stepwise fashion. Typical clinical findings include: leg spasticity; upper-extremity weakness or clumsiness; and sensory changes in the arms, legs, or trunk. Either spinothalamic tract–mediated or posterior column–mediated sensory modalities may be impaired. Sphincter dysfunction, if it occurs, is often preceded by the motor and/or sensory deficits. Commonly, neck pain is not a prominent symptom, and neck range of motion may or may not be impaired. Some patients experience leg or trunk paresthesia induced by neck flexion (Lhermitte sign).

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The anterior-posterior diameter of the cervical spinal cord is usually 10 mm or less. Patients rarely develop cervical spondylotic myelopathy (CSM) if the congenital diameter of their spinal canal exceeds 16 mm. In congenitally narrow canals, disk protrusion, osteophytes, hypertrophy of the ligamentum flavum, ossification of the posterior longitudinal ligament, and vertebral body subluxations can combine to compress the spinal cord. MRI, CT, or myelography provide excellent images of relation between the spinal canal and the spinal cord (Fig. 104.25). MRI is the imaging study of choice in most cases, and provides detailed information about intramedullary pathology such as secondary cord edema or gliosis. CT provides better images of calcified tissues. Even with excellent cross-sectional imaging of the spinal canal, the clinical correlation between neurological deficit and cord compression is imperfect; dynamic changes in cord compression and vascular perfusion undoubtedly contribute to the pathogenesis of CSM. The natural history of CSM is variable. Some patients have stable neurological deficits for many years without specific therapy, whereas other patients have gradual or stepwise deterioration. Some patients improve with treatments such as bed rest, soft collars, or immobilizing collars, but these treatments have not been assessed in controlled trials. Many patients with CSM are treated by surgical decompression, with variable surgical results (Fig. 104.26). Surgical treatment tends to be highly effective at halting progressive loss of function, although recovery of lost function is less reliable, and depends on the severity and duration of symptoms prior to surgery, with better results when symptoms are milder, have been present less than 12 months, and when

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Results of treatment Fig. 104.26 Results of Treatment of Cervical Spondylotic Myelopathy. (Reprinted with permission from Rosenbaum, R.B., Campbell, S.M., Rosenbaum, J.T., 1996. Clinical Neurology of Rheumatic Disease, Butterworth-Heinemann, Boston. [Data from Rowland, L.P., 1992. Surgical treatment of cervical spondylotic myelopathy: time for a controlled trial. Neurology 42, 5.])

the patient is younger than 70 years. Anterior cervical discectomy and fusion, anterior cervical corpectomy and fusion, posterior laminectomy, laminectomy with fusion, and laminoplasty are all potential options. As is the case with choice of surgical options for cervical radiculopathy, the choice of one technique over another is multifactorial and must be tailored to each individual patient’s situation. Currently available literature remains inconclusive regarding which surgical approach is best for CSM; a recent systematic review examined the literature for anterior versus posterior treatment of CSM and concluded that both approaches are highly effective for improving CSM symptoms, that anterior approaches may have slightly higher quality of life (QOL) outcomes, and that posterior approaches have higher direct costs and slightly higher complication rates. However, the authors of this study emphasize that the studies they reviewed were all level 2 and 3 data, and that prospective randomized controlled trials will be necessary to settle this debate (Alvin et al., 2013).

Vertebral Artery Stroke Caused by Cervical Osteoarthritis Compression of a vertebral artery by an osteophyte is a rare cause of stroke in the vertebrobasilar distribution (Bulsara et al., 2006). The vertebral arteries pass through foramina in the transverse processes from C6 to C2. Osteophytes from the uncovertebral joint can compress the arteries. The compression may occur with something as benign as head rotation. However, the rotation often leaves the contralateral vertebral artery uncompressed, so ischemic symptoms are usually limited to those patients who have both osteophytic arterial compression on one side and a contralateral hypoplastic, absent, or occluded artery. Aggressive chiropractic neck manipulation should be discouraged since it can lead to vertebral artery dissection at the AA loop with resultant vertebrobasilar distribution embolic strokes (Devereaux, 2000).

Thoracic Spondylosis Degenerative changes are less common in the thoracic than in the lumbar or cervical spines given the relative lack of mobility and

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B Fig. 104.27 A, Left abdominal “pseudohernia” resulting from weakened abdominal wall musculature within a single thoracic myotome. B, Left, lateral disk bulge compressing the exiting T8 root. (Courtesy Bashar Katirji, MD.)

thus infrequency of spondylosis (Vanichkachorn and Vaccaro, 2000). Thoracic osteophytes are more likely to develop on the anterior or lateral aspects of the vertebral bodies and infrequently cause clinical radiculopathy. Thoracic disk herniations are visible on MRI in many asymptomatic individuals. Thoracic disk herniations occur most often in the lower thoracic spine. When a thoracic nerve root is impinged, the patient may note severe, sharp pain and paresthesias involving the abdominal or chest wall. There can also be associated abdominal muscle weakness resulting in a bulge or “pseudohernia” (Fig. 104.27). While pain may be significant and difficult to control in the acute phase, symptoms are often self-limited (Chaudhuri et al., 1997). Thoracic myelopathy due to disk herniation probably has an annual incidence of approximately 1 case per 1 million. Most cases occur between ages 30 and 60 years. Symptoms often develop insidiously without identifiable preceding trauma. Back pain may or may not be present. Patients have some combination of motor and sensory findings of myelopathy; sphincter dysfunction is present in more severe cases. Thoracic MRI, CT, or myelography can confirm the diagnosis (Fig. 104.28). The treatment is surgical decompression when there is clear clinical and radiographic evidence of thoracic radiculopathy and/ or myelopathy, but should be assiduously avoided when only axial back pain is present. Surgical options include transthoracic discectomy via

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open thoracotomy, thoracoscopy or minimally invasive thoracotomy; if the pathology is located laterally enough, a posterolateral approach such as transpedicular discectomy, open or minimally invasive, could also be considered (Fig. 104.29). Herniation of the thoracic spinal cord into the dura is a very rare cause of thoracic myelopathy (Sasani et al., 2009). The most common

presentation is a Brown-Séquard syndrome that can slowly evolve over a few years. Thoracic spine MRI shows the spinal cord ventrally deviated, often with a kink at one level between T2 and T7, and with increased dorsal subarachnoid space. CT myelography will show similar changes and confirm that there is no subarachnoid space ventrally where the spinal cord is attached to the dura. This condition can be extremely difficult to differentiate radiographically from a dorsal thoracic arachnoid cyst pushing the cord anteriorly, unless very blatant flattening of the dorsal cord surface is present, suggesting pressure from a mass lesion rather than anterior tethering alone. The adjacent vertebral body may appear scalloped. Spinal cord herniation can be idiopathic, presumably due to congenital defects in the dura, or occur after trauma or thoracic spinal surgery. Rare instances are associated with thoracic disk herniation. Some patients improve after surgical reduction of the herniation, but this is a highly technically challenging surgery.

Lumbar Spondylosis Low Back Pain

Fig. 104.28 Thoracic Magnetic Resonance Images of a Patient With Thoracic Disk Herniation. This large acute disk herniation at T10–T11 consists of extrusion of most of the nucleus pulposus into the spinal canal. There is secondary narrowing of the disk space and spinal cord edema (arrows) above and below the level of spinal cord compression. (Courtesy Erik Gaensler.)

Episodes of acute low back pain, which usually resolve within a few days, are experienced by some 80% of persons. These episodes often recur, and approximately 4% report chronic low back pain. Painsensitive structures in the lumbar region include the nerve roots, zygapophyseal joints, sacroiliac joints, intervertebral ligaments, muscles, fascia, annulus fibrosis and circumferential portions of the disks, and vertebral periosteum. Controlled local anesthetic injection studies suggest that in some patients, the cause of low back pain can be localized to specific zygapophyseal or sacroiliac joints. In other patients, injection of contrast media into lumbar disks reproduces pain, suggesting that the lumbar disk is the source of pain. However, this localization cannot be achieved reliably by history or physical examination, and, when attempted, localization of the source of pain is often unsuccessful. Thus, in clinical practice, “nonspecific low back pain” is a commonly made diagnosis. The findings of osteoarthritis and lumbar spondylosis on radiography (osteophytes, endplate sclerosis, disk-space narrowing) appear gradually with increasing age and are rarely absent by age 60 years (see

End plate sclerosis Anterior osteophyte

Lateral osteophytes

Narrow L5-S1 disk space

Narrow L5-S1 disk space End plate sclerosis

B

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Fig. 104.29 Lateral (A) and anteroposterior (B) radiographs of lumbar spine showing osteophytes, disk-space narrowing, and sclerosis of vertebral body articular plates. (Reprinted with permission from Rosenbaum, R.B., Campbell, S.M., Rosenbaum, J.T., 1996. Clinical Neurology of Rheumatic Disease. Butterworth-Heinemann, Boston.)

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convincing radicular symptoms, mild spondylolisthesis and no clear neuroforaminal stenosis by MRI, flexion and extension radiographs can be considered. In some cases, imaging in a neutral position may fail to demonstrate significant foraminal compromise, but flexion/ extension films may reveal an unstable or “dynamic” spondylolisthesis (Even et al., 2014).

Indications for Lumbar Spine Radiography in Patients With Acute Low Back Pain

BOX 104.6

Red Flags for Trauma Major trauma (e.g., motor vehicle accident, fall from height) Minor trauma or even strenuous lifting in older or potentially osteoporotic patient Prolonged corticosteroid use Osteoporosis Age >70 years

Lumbar Radiculopathies The back and leg neurological examination is central to decision making in patients with low back pain. Perhaps 1%–2% of patients with acute low back pain have significant lumbar nerve root compression. Three syndromes merit specific diagnostic consideration.

Red Flags for Tumor or Infection Age >50 years or 14 m/sec velocity difference or 23 m/sec velocity difference and 8 mm2) in about 70% of patients (Visser et al., 2013), and establishes involvement of the anterior fascicles (corresponding to fibers for the deep fibular nerve) in the majority of compressive fibular neuropathies (Bignotti et al., 2016). The prognosis is uniformly good in cases of acute demyelinating lesions, whereas recovery is delayed in those with axonal lesions and stretch injuries. The distal fibular motor amplitude recording tibialis anterior serves as an accurate estimate of the extent of axonal loss and a good prognostic indicator of foot drop. Hence, fibular nerve studies should be performed bilaterally and compared. Bracing with a custom-made plastic ankle-foot orthosis is necessary to improve the gait in the presence of severe foot drop. The few patients who do not improve spontaneously after 3 months, or those who have pain or a slowly progressive fibular nerve lesion, may require MRI studies and surgical exploration (Kim and Kline, 1996).

Tibial Nerve Applied anatomy. The tibial nerve innervates all the hamstring muscles except the short head of the biceps femoris. It then separates from the common fibular nerve, usually in the upper popliteal fossa, and gives off the sural sensory nerve, which is often joined by a branch from the common fibular nerve, the sural communicating nerve, to innervate the skin over the lateral aspect of the lower leg and foot, including the little toe. In the upper calf, the tibial nerve passes underneath the soleus muscle and innervates the gastrocnemius, soleus, tibialis posterior,

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flexor digitorum profundus, and flexor hallucis longus. At the ankle, the tibial nerve passes under the laciniate ligament, which covers the tarsal tunnel through which the nerve passes together with the tendons of the tibialis posterior, flexor digitorum longus, and flexor hallucis longus muscles and the tibial artery and veins. Tarsal tunnel syndrome. Entrapment of the tibial nerve occurs behind and immediately below the medial malleolus. Burning pain is experienced in the toes and the sole of the foot. If the calcaneal sensory branches are involved, pain and numbness also involve the heel. Examination usually reveals plantar sensory impairment and wasting of the intrinsic foot muscles. Percussion at the site of nerve compression or eversion of the foot often elicit pain and paresthesias. EDX study results should confirm entrapment of the tibial nerve at the tarsal tunnel by demonstrating slowing of motor fibers to the abductor hallucis and/or abductor digiti minimi muscles, as well as involvement of the medial and/or lateral plantar mixed potentials fibers, with sparing of the sural nerve sensory action potential. Unfortunately, medial and/or lateral plantar mixed (or sensory) potentials are technically very difficult and may be unelicitable in normal subjects with plantar calluses, foot edema, previous surgical procedures in the foot, or in adults over the age of 45. Needle EMG shows denervation of the abductor hallucis and/or abductor digiti minimi muscles and normal S1-innervated and proximal muscles such as the gastrocnemius, soleus, biceps femoris, and gluteus maximus muscles. The majority of suspected cases of tarsal tunnel syndrome, particularly when symptoms are bilateral, turn out to have generalized peripheral neuropathy, S1 radiculopathy, or nonneurological foot pain such as plantar fasciitis, stress fracture, arthritis, or bursitis. Ultrasound plays an important role in identifying the cause (Samarawickrama et al., 2016). This is particularly useful in elderly or patients with foot edema, calluses, or previous surgery as EDX studies may be difficult to perform or interpret. Local injection with corticosteroids underneath the laciniate ligament may temporarily relieve symptoms. Surgical decompression is needed for permanent results in those rare cases in which objective evidence of this syndrome exists.

Sural Nerve Although the vast majority of sural nerve lesions are iatrogenic as the result of diagnostic sural nerve biopsy or sural nerve harvesting for nerve grafts, mononeuropathy of the sural nerve has been reported with a number of other conditions including lower-limb vein-stripping surgery, ankle liposuction, Baker cyst or ankle joint surgery, local trauma such as with tightly laced high-topped footwear such as ski boots or ice skates, and rarely as the initial presentation of vasculitic mononeuritis multiplex (Li and Lederman, 2014; Stickler et al., 2006; Thammongkolchai and Katirji, 2017).

Femoral Nerve Applied anatomy. The femoral nerve is formed in the pelvis from the posterior divisions of the ventral rami of L2, L3, and L4 spinal roots, where it innervates the psoas muscle. It then passes within the iliacus compartment and innervates the iliacus muscle via a motor branch that originates 4–5 cm before the nerve crosses underneath the inguinal ligament. In the anterior thigh, the femoral nerve innervates the quadriceps and sartorius muscles and the skin of the anterior thigh and gives off the saphenous sensory nerve, which innervates the skin of the medial surface of the knee and medial leg. Femoral nerve lesions. The majority of femoral nerve lesions are iatrogenic (Al-Hakim and Katirji, 1993). Pelvic lesions follow a variety of gastrointestinal, vascular, urological, or gynecological operations such as abdominal hysterectomy, radical prostatectomy, renal transplantation, and abdominal aortic repair. During these

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procedures, the femoral nerve becomes compressed between the lateral blade of the retractor and the pelvic wall. Risk factors include the use of self-retaining retractors, a thin body habitus, and transverse abdominal incision (Chan and Manetta, 2002). Acute retroperitoneal hematoma is often iatrogenic following anticoagulant therapy, pelvic operations, or femoral vessel catheterization such as for cardiac catheterization. At the inguinal ligament, the femoral nerve may become kinked during lithotomy positioning, particularly when the leg is held in extreme hip flexion and external rotation, used during vaginal delivery, vaginal hysterectomy, prostatectomy, and laparoscopy. Total hip replacement, particularly surgical revisions and complicated reconstructions, may result in femoral nerve injury. Femoral nerve injury due to spontaneous retroperitoneal hematoma may occur in hemophiliacs, patients with blood dyscrasias, or following a ruptured abdominal aortic aneurysm. Pelvic lymphadenopathy, primary malignancy of the colon or rectum, and neurofibromas or schwannomas are rare causes of femoral neuropathies. Hip hyperextension, such as in dancers or during Yoga exercise, may also cause a femoral stretch injury. Femoral nerve lesions manifest with acute thigh weakness and anterior thigh and medial leg numbness. Thigh weakness often leads to falls. Pain is usually absent except in cases due to retroperitoneal hematomas. On examination, there is weakness of knee extension, with absent or depressed knee jerk. Thigh adduction is normal. Hip flexion is usually weak when the lesion is within the pelvis, although it may be difficult to assess hip flexion in the setting of severe quadriceps weakness. Needle EMG reveals denervation of the quadriceps muscle. The iliacus muscle is often normal in inguinal lesions but shows denervation in femoral nerve lesions in the pelvis. Needle EMG of the thigh adductor muscles, innervated by the L2, L3, L4 roots via the obturator nerve, helps distinguish femoral nerve lesions from upper lumbar radiculopathy or plexopathy. Nerve conduction studies have prognostic value, since the amplitude and area of the femoral CMAP is a very good quantitative measure of motor axonal loss (Kuntzer et al., 1997). CT or MRI of the pelvis are urgently indicated in patients with suspected retroperitoneal hematoma or pelvic mass lesion. Apart from patients with confirmed retroperitoneal hematoma who may require emergent drainage, most other femoral nerve lesions are treated conservatively. A knee or knee-ankle-foot orthosis is helpful for patients with unilateral severe weakness of the quadriceps and will assist in walking and prevent falls. Prevention of femoral nerve injury is of paramount importance. The surgeon should limit hip flexion, abduction, and external rotation during lithotomy positioning, particularly when “candy cane” stirrups are used. The incidence of femoral nerve lesions after pelvic and gynecological operations is significantly reduced when self-retractors are avoided; the retracting blades should also cradle the rectus muscle without compressing the psoas muscle (Chan and Manetta, 2002).

Saphenous Nerve Saphenous nerve lesions may follow stripping of a long saphenous varicose vein, harvesting the vein for a coronary artery bypass, or surgical and arthroscopic operations on the knee. Entrapment of the saphenous nerve is rare and may occur as it exits the subsartorial (adductor or Hunter) canal or by pes anserine bursitis. Patients with saphenous mononeuropathy have sensory loss or hyperesthesia of the medial leg that may extend into the medial arch of the foot. Saphenous nerve lesions should be differentiated from L4 radiculopathy, lumbar plexopathy, and femoral mononeuropathy. In addition to the clinical examination, EDX studies can confirm that the quadriceps, iliacus, and thigh adductors are normal in patients with

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Other Lower-Extremity Mononeuropathies Lateral femoral cutaneous nerve entrapment (meralgia paresthetica). The lateral femoral cutaneous nerve, which is a pure sensory nerve, passes medial to the anterior superior iliac spine under the inguinal ligament to enter the thigh under the fascia lata that it penetrates to supply the skin of the anterolateral part of the thigh. The site of entrapment is usually at the level of the inguinal ligament. Rarely, the nerve may be affected in its proximal segment by retroperitoneal tumors or be injured during appendectomy. The disorder occurs in about 4 per 10,000 individuals. It is most often seen in association with obesity, diabetes, and advancing age (Parisi et al., 2011). It is a common entrapment neuropathy during pregnancy, particularly the third trimester, and usually recovers after delivery. It may occur with ascites, or in other conditions that increase intraabdominal pressure. Direct compression by a belt, corset, beeper, or cellular phone; fracture of the anterior portion of the ilium; or pelvic tilt causing undue stresses on the abdominal musculature are other causes. Patients develop numbness, painful burning, and itching over the anterolateral thigh. Pressure at the inguinal ligament medial to the anterior superior iliac spine may elicit referred pain and dysesthesias. Some patients report relief of pain when assuming a supine position. Lateral femoral cutaneous nerve SNAP is technically difficult to measure and may be absent in healthy subjects, particularly women and obese individuals. Asymmetrical low-amplitude or absent potential on the symptomatic side is a confirmatory finding. Electrophysiological studies of the femoral nerve and quadriceps femoris and iliacus muscles are normal, which helps exclude lumbar radiculopathy and plexopathy. A local anesthetic nerve block may have diagnostic value (Haim et al., 2006). Treatment consists of symptomatic measures such as rest, analgesics, and weight loss. Postural abnormalities should be corrected. Neurolysis is rarely beneficial. Ilioinguinal neuropathy. The ilioinguinal nerve is analogous to an intercostal nerve. Muscle branches innervate the lower portion of the transverse abdominal and internal oblique muscles. The cutaneous sensory nerve supplies the skin over the inguinal ligament and the base of the scrotum or labia. As the nerve takes a zigzag course, passing through the transverse abdominal and internal oblique muscles, it is subject to mechanical compression such as with a direct inguinal hernia. Trauma, surgical procedures, scar tissue, and increased abdominal muscle tone caused by abnormal posture are frequently responsible. Pain is referred to the groin, and weakness of the lower abdominal wall may result in the formation of an asymmetrical bulging of the lower abdominal wall. Conservative treatment includes rest and NSAIDs. Neurolysis may be required in refractory cases when a mechanical lesion is suspected. Obturator neuropathy. The obturator nerve is vulnerable to entrapment as it passes through the obturator canal (e.g., by an obturator hernia or osteitis pubis). An obturator neuropathy is most often associated with pelvic malignancies (prostate, cervical, or uterine cancers). It can also be seen with trauma and synovial cyst of the hip or as a surgical complication, especially with extensive retroperitoneal surgeries or laparoscopic pelvic lymphadenectomies and during total hip replacement. Entrapment produces radiating pain from the groin down the inner aspect of the thigh, often difficult to distinguish from the pain of a recent procedure or trauma. There is weakness of hip adduction and sensory impairment in the upper medial thigh. Many patients appear

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to have hip-flexor weakness as a false localizing sign. Although this phenomenon may be explained by pain, it is more likely due to mechanical disadvantage of the hip flexors in the presence of weak thigh adductors. CT or MRI scanning of the pelvis is helpful in finding primary or metastatic pelvic tumors. EMG testing is essential for diagnosis by detecting selective denervation of the thigh adductor muscles, with normal quadriceps and iliacus muscles, thus excluding other causes of hip weakness including femoral nerve lesions, upper lumbar (L2, L3, or L4) radiculopathy or plexopathy, and diabetic amyotrophy (diabetic proximal neuropathy or radiculoplexopathy) (Sorenson et al., 2002). This entrapment neuropathy is treated conservatively, which often provides good results, especially in those with acute onset of symptoms. If such treatment fails or if symptoms progress to involve other nerves in the region, a careful search for occult pelvic or retroperitoneal malignancy must be pursued.

Migrant Sensory Neuritis of Wartenberg In this rarely reported but not uncommon condition, a pure and relapsing-remitting sensory mononeuritis multiplex is associated with loss of sensation and pain in the distribution of the affected nerves. The onset is usually sudden, and pain is precipitated by movements and (especially) stretching of the affected limbs. Many different cutaneous nerves may be involved. Commonly involved nerves include the superficial and deep peroneal sensory nerves, the median and ulnar digital nerves, the femoral and saphenous nerves, and the radial sensory nerve (Nicolle et al., 2001). Motor nerve fibers are not affected. Laboratory tests fail to detect any underlying cause, but on occasion a sural nerve biopsy demonstrates inflammatory changes or a vasculitis, with patchy loss of nerve fibers and evidence of axonal degeneration suggestive of an ischemic process. Rarely, immunoglobulin (Ig) G deposits are also observed around blood vessels. The pain and areas of sensory loss often recover over weeks to months, but the improvement may be partial. Symptoms may recur at the same or other sites. The discrete areas of sensory deficit and nerve irritation in several cutaneous nerves should indicate the proper diagnosis. The differential diagnosis should always include conditions like DM, leprosy, vasculitis, sarcoidosis, sensory perineuritis, and rarely HNPP (Nicolle et al., 2001; Zifko and Hahn, 1997).

Localized Perineurial Hypertrophic Mononeuropathy A slowly progressive painless mononeuropathy that cannot be localized to entrapment sites and is caused by a focal fusiform enlargement of the affected nerve, termed localized hypertrophic neuropathy or perineurioma, is an uncommon condition affecting young adults (Simmons et al., 1999). Although any nerve may be involved, it often occurs in the radial, posterior interosseous, tibial, and sciatic nerves. The fusiform enlargement is mainly composed of “onion bulblike whorls” formed by layers of perineurial cells. The lamellae of the whorls stain for epithelial membrane antigen. The cause of the perineurial cell proliferation is unknown. It typically results in painless, slowly progressive weakness and atrophy in the distribution of the affected nerve. Sensory symptoms are minor, although sensory nerve fibers are obviously involved. EDX study shows an axonal mononeuropathy and help in the precise localization of the focal nerve lesion. MRI shows a focal enlargement of the affected nerve, increased signal on T2-weighted images, and enhancement with gadolinium. Surgical exploration and a fascicular biopsy by a surgeon experienced in peripheral nerve microsurgery may confirm the diagnosis and exclude malignant peripheral nerve sheath tumors, which are difficult to exclude without biopsy. Surgical resection of the involved nerve segment with graft repair has been proposed, but because of the benign nature of the “tumor” and its very slow progression, the involved nerve should be preserved if it has even partial function.

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HEREDITARY NEUROPATHIES The hereditary neuropathies constitute a complex heterogeneous group of diseases that usually share the clinical features of insidious onset and indolent course over years to decades. The number of hereditary disorders for which a metabolic or molecular defect is known is rapidly increasing, allowing a more accurate classification. For those inherited neuropathies for which the underlying genetic abnormality has yet to be identified, the classification still depends on the clinical phenotype, mode of inheritance, and class of neurons predominantly affected. Major advances in understanding the molecular basis of inherited neuropathies have come from identifying chromosomal loci or causative genes for a given disease phenotype, leading to identification of an ever-increasing number of genes coding for a specific gene product essential to myelin or axonal function (Bassam, 2014; Berger et al., 2002; Fridman and Reilly, 2015; Kamholz et al., 2000; Scherer, 2006). Hereditary neuropathies are common disorders, accounting for nearly 40% of chronic polyneuropathies, and as many as 50% of previously unidentified peripheral polyneuropathies. Their inherited nature may go unrecognized in a surprisingly large percentage of patients (Klein, 2007). Eliciting historical evidence of long-standing neuromuscular symptoms; obtaining detailed family histories; looking for skeletal abnormalities such as hammer toes, high arches, or scoliosis; performing neurological and electrophysiological evaluations in relatives of patients; and, more importantly, testing for confirmed genes are essential in identifying a previously unsuspected inherited neuropathy. Because of the paucity of positive symptoms, patients may not volunteer information about their own or relatives’ conditions. For example, paresthesias are spontaneously reported three times more commonly in acquired than in inherited neuropathies. Even in the face of a truly negative family history, the possibility of an inherited neuropathy cannot be dismissed. Such a situation may arise in cases of early death of one or both parents, few blood relatives, or autosomal recessive (AR) disease. Also, available diagnostic deoxyribonucleic acid (DNA) testing has shown that about a third of isolated cases of inherited neuropathies may arise from de novo gene mutations (Boerkoel et al., 2002). It is advisable to consider the possibility of an inherited neuropathy in any patient with a chronic polyneuropathy that remains cryptogenic or refractory to treatment.

Charcot-Marie-Tooth Disease (Hereditary Motor and Sensory Neuropathy) The syndrome of peroneal muscular atrophy, or CMT disease, was first described in 1886 by Charcot and Marie in Paris and Tooth in London (Charcot and Marie, 1886; Tooth, 1886). CMT disease is the most common inherited neuropathy, with an estimated prevalence of 1 per 2500 individuals (Martyn and Hughes, 1997). Major advances have been made in recent years in the molecular genetics of CMT disease (Bennett and Chance, 2001; Berger et al., 2002; Kamholz et al., 2000). Mutations in more than 80 genes cause CMT (Inherited Neuropathy Variant Browser: http://hihg.med.miami. edu/neuropathybrowser). These mutations in CMT affect proteins involved in Schwann cell membrane structure (PMP22, MPZ, Cx32) mitochondrial movement (MFN2), signal transduction (GDAP1), cell cycle (MTMR2), cytoskeleton (NEFL, INF2, gigaxonin), transcription factors (EGR2), and protein degradation (LITAF/SIMPLE). CMT may be classified by mode of inheritance (autosomal dominant [AD], X-linked [XL], and AR), electrophysiological studies, chromosomal locus, or causative genes (Table 106.6). CMT1 and the vast majority of subtypes of CMT2 display AD inheritance. A minority of cases occur sporadically or in siblings only and have therefore been attributed to AR inheritance or to de novo gene mutations. Because

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a great variability in clinical expression exists among affected kin in the dominant disorders, a recessive inheritance can only be accepted if the clinical and electrophysiological examinations of both parents have proved to be normal. Even when the cause is nonparental, most of these patients phenotypically resemble CMT1. The majority of CMT neuropathies are demyelinating, although up to one-third are primary axonal disorders. Clinical studies combined with electrophysiological studies of a large number of families allowed a simple separation of CMT into two main groups: (1) the demyelinating form, or CMT1 (sometimes known as hereditary motor and sensory neuropathy [HMSN-I]), in which there are marked reductions in motor NCVs and nerve biopsy findings of demyelination and onion bulb formation; and (2) the axonal form, or CMT2 (HMSN-II), in which motor NCVs are normal or near normal, and nerve biopsy reveals axonal loss without prominent demyelination (Harding, 1995). A more severe phenotype of severe demyelinating polyneuropathy with onset occurring in early childhood and very slow conduction velocities (45 m/sec), with most patients diagnosed as CMT2; Group 3 are patients with intermediate velocities (35–45 m/sec), diagnosed as CMTX, but also sometimes CMT1; and Group 4 are patients with extremely slow velocities ( pm Pm Pm Pm Pm Pm

Yes Yes Yes Yes Yes Yes

CMTX CMTX1 CMTX4 CMTX5 CMTX6

Xq13.1 Xq24 Xq22.3 Xq22.11

GJB1 (Cx32) AIFM1 PRPS1 PDK3

Pm Pm Pm Pm

Yes Yes Yes Yes

CMT2 CMT2A2 CMT2A1 CMT2B CMT2B1 CMT2B2 CMT2C CMT2D CMT2E CMT2F CMT2I CMT2J CMT2K

1p36.22 1p36.22 3q21.3 1q22 19q13.33 12q24 7p15 8p21 7q11-21 1q23.3 1q23.3 8q21.11

MFN2 KIFBβ RAB7 LMNA MED25 TRPV4 GARS NEFL HSPB1 MPZ MPZ GDAP1

Pm Pm Pm Pm Pm Pm Pm Pm Pm Pm Pm Pm

Yes — Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes

HNPP HNPP

17p11.2

PMP22

Deletion > pm

Yes

DSD Phenotype DSD-A DSD-B DSD-C

17p11.2 1q22-q23 10q21-q22

PMP22 MPZ EGR2

Pm Pm Pm

Yes Yes Yes

AR CMT (CMT4) CMT4A CMT4B1 CMT4B2 CMT4C CMT4D CMT4E CMT4F CMT4G CMT4H CMT4J

8q21 11q22 11p15.4 5q23-q33 8q24 10q21-q22 19q13 10q23 12q11.1-q13.11 6q21

GDAP1 MTMR2 SBF2 SH3TC2 NDRG1 EGR2 Periaxin HK1 FGD4 FIGURE4

Pm Pm Pm Pm Pm Pm Pm Pm Pm Pm

Yes — Yes Yes Yes Yes Yes — — Yes

AIFM1, Apoptosis-inducing factor, mitochondria-associated, 1; AR, autosomal recessive; CMT, Charcot-Marie-Tooth disease; CMTX, X-linked CMT; Cx32, connexin-32; DSD, Dejerine-Sottas disease; EGR2, early growth response 2 gene; FGD4, FYVE, RhoGEF, and PH domain-containing protein 4; FIGURE4, factor-induced gene 4 protein (polyphosphoinositide phosphatase); GARS, glycyl tRNA synthetase; GDAP1, ganglioside-induced differentiation-associated protein 1; HK1, hexokinase 1; HNPP, hereditary neuropathy with liability to pressure palsies; HSPB1, HSPB8, heat shock proteins; KIF1Bβ, microtube motor KIF1Bβ; LITAF, lipopolysaccharide-induced tumor necrosis factor-α factor; LMNA, Lamin A/C; Med25, Mediator complex subunit 25; MFN2, Mitofusin 2; MPZ, myelin protein zero gene; MTMR2, myotubularin-related protein 2; NDRG1, N-myc downstream regulated gene 1; NEFL, neurofilament light chain gene; PDK3, pyruvate dehydrogenase kinase, isoenzyme 3; pm, point mutations; PMP22, peripheral myelin protein-22; PRPS1, phosphoribosylpyrophosphate synthetase 1; RAB7, RAS associated protein 7; SH3TC2, SH3 domain and tetratricopeptide repeats-containing protein 2.

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Fig. 106.8 Leg atrophy, pes cavus, and enlarged great auricular nerve (arrow) are evident in a patient with Charcot-Marie-Tooth type 1 disease.

symmetrical weakness and wasting in the intrinsic foot, peroneal, and anterior tibial muscles are often present. In two-thirds of patients, the upper limbs are involved later in life. Inspection reveals pes cavus and hammer toes in nearly 75% of adult patients, mild kyphosis in approximately 10%, and palpably enlarged hypertrophic peripheral nerves in 25% of patients (Fig. 106.8). The foot deformities occur because of long-term muscular weakness and imbalance between the intrinsic extensor and long extensor muscles of the feet and toes (a similar process causes clawing of the fingers in more advanced cases). Absent ankle reflexes are universal and frequently associated with absent or reduced knee and upper limb reflexes. Some degree of distal sensory impairment (diminished vibration sense and light touch in the feet and hands) is usually discovered by examination but rarely gives rise to positive sensory symptoms. Occasionally, patients have an essential or postural upper-limb tremor. Such cases have been referred to as Roussy-Lévy syndrome, but current evidence suggests that this is not a separate clinical or genetic entity. Severity of neuropathy in affected family members varies considerably. Approximately 10% of patients with slowed NCVs may remain asymptomatic. In women with CMT1, the disease may exacerbate during pregnancy. Such worsening is temporary in about a third of patients but becomes progressive in the remainder. Slow deterioration in strength and decline in axonal function continues throughout adulthood, although much of this deterioration likely represents the effects of aging superimposed on decreased reserves (Verhamme et al., 2009). SNAPs are usually absent with surface recordings. Motor nerve conduction studies show uniform slowing to less than 75% of the lower limits of normal in all nerves. Motor conduction velocities of upper-limb nerves prove more useful than studies of lower-extremity nerves because distal denervation in the feet is often severe and sometimes complete. A motor conduction velocity below 35 m/sec in the forearm segment of the median or ulnar nerves is a proposed cutoff value to distinguish CMT1 from CMT2 and CMTX. Although this cutoff is useful, it can be misleading if applied too rigidly. The conduction slowing evolves over the first 5 years of age and does not change appreciably afterward. Neurological deficits correlate with reductions in CMAP and SNAP amplitudes rather than conduction velocity, indicating that clinical weakness results from loss of axons.

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Uniform conduction slowing is often used to differentiate CMT1 from acquired demyelinating neuropathies. Uniform slowing along the entire length of nerves and among neighboring nerves suggests an inherited myelinopathy affecting conduction in all nerves and nerve segments in the upper extremities or lower extremities to the same degree. In contrast, acquired demyelinating neuropathies result in multifocal or nonuniform conduction slowing together with excessive temporal dispersions and conduction blocks. Uniform conduction slowing is found in CMT1A with PMP22 duplication or point mutations; CMT1B with MPZ point mutations; DSD phenotype, including PMP22, MPZ, and EGR2 gene mutations; as well as metachromatic leukodystrophy (MLD); Cockayne disease; and globoid cell (Krabbe) leukodystrophy (Lewis et al., 2000). Neuromuscular ultrasound in adults and children with CMT1 displays significantly larger nerve CSA compared with control (Zaidman et al., 2013). Nerve enlargement is commonly diffuse and more pronounced than in acquired demyelinating polyneuropathies (such as CIDP and MMN), where the enlargement is often regional. In children with CMT1A, the CSA correlates with neurological disability and the expected increase in nerve CSA with age is disproportionately greater in CMT1A, suggesting ongoing nerve hypertrophy throughout childhood (Yiu et al., 2015). Routine hematological and biochemical studies are normal. CSF is also normal, which helps differentiate the condition from chronic inflammatory demyelinating polyneuropathy (CIDP), in which the CSF protein is usually elevated. Sural nerve biopsy typically shows the changes of a hypertrophic neuropathy, characterized by onion bulb formation, increased frequency of fibers with demyelinated and remyelinated segments, an increase in endoneurial area, and loss of large myelinated fibers (Fig. 106.9). Gene mutations, predominantly affecting genes for myelin and Schwann cell proteins, have been recognized that account for more than three-quarters of families with CMT1 (Fig. 106.10). CMT1A is the most common CMT subtype, accounting for 70%–80% of CMT1 cases and more than 50% of all CMT cases. The disease is caused by duplication of a 01.5-Mb fragment in the short arm of chromosome 17p11.2-12 harboring peripheral myelin protein 22 (PMP22). Rarely, the disease is caused by PMP22 point mutation. PMP22 is a membrane glycoprotein found in the compact portion of the peripheral myelin sheath. The precise function of PMP22 in normal nerve remains unknown. Deletion of the same 1.5-megabase region on chromosome 17p11.2 results in a

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EGR2 LITAF NCV decreased

Node of Ranvier

CMT1 HNPP CMTX DSD CMT4

NCV normal

Myelin

Axon

CMT2 KIF1B NF-L MPZ

Cx32 PMP22

Basal lamina

P0

Periaxin

C

A A B

B Fig. 106.9 Charcot-Marie-Tooth Type 1 Disease. A, Semi-thin transverse section of sural nerve showing numerous onion bulbs. (Toluidine blue; bar = 20 µm.) B, Electron micrograph of an onion bulb formation; two small myelinated fibers are surrounded by multiple layers of Schwann cell processes. (Bar = 0.5 µm.)

single copy of the normal PMP22 gene, a finding observed in 85% of patients with HNPP. The CMT1A duplication or HNPP deletion is caused by reciprocal recombination events that occur in male germ cell meiosis. The PMP22 duplication or deletion can be detected in blood samples using pulse-field electrophoresis followed by hybridization with specific CMT1A duplication junction fragments or cytogenetic testing with a PMP22 probe by fluorescence in situ hybridization. CMT1B is clinically indistinguishable from CMT1A but it only accounts for 4% to 5% of CMT1 cases. It is caused by mutations in the myelin protein zero (P0; gene symbol, MPZ) gene, mapped to chromosome 1q22-23. MPZ is the major peripheral myelin glycoprotein and is thought to function as an adhesion molecule in the formation and compaction of peripheral myelin. It is a member of the immunoglobulin superfamily, with distinct extracellular transmembrane and intracellular domains. Mutations in the gene encoding for MPZ have also been associated with DSD, and congenital hypomyelination neuropathy. Different MPZ mutations result in divergent morphological effects on myelin sheaths, consisting of uncompacting of myelin or focal myelin foldings (Gabreëls-Festen et al., 1996). Motor conduction block was reported rarely in CMT1B patients with specific MPZ mutations (Street et al., 2002). Specific MPZ missense mutations have also been reported with a CMT2 phenotype, showing only mild slowing of NCVs (Marrosu et al., 1998). The Thr124 Met mutations in the MPZ gene have been detected in several families with a distinct CMT2 phenotype (CMT2J) characterized by late onset, marked sensory loss, and sometimes deafness, chronic cough, and pupillary abnormalities (De Jonghe et al., 1999). CMT1C is caused by a mutation in lipopolysaccharide-induced tumor necrosis factor-alpha (LITAF/SIMPLE) gene, mapped to

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P0

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Cx32

Fig. 106.10 A, Charcot-Marie-Tooth disease (CMT) and related disorders: CMT1, CMT with X-linked inheritance (CMTX), hereditary neuropathy with liability to pressure palsies (HNPP), Dejerine-Sottas disease (DSD), and most of CMT4 are inherited disorders of myelin. CMT2 is a primary axonal disorder. Alterations in dosage of peripheral myelin protein 22 (PMP22) gene account for the majority of patients with CMT1A and HNPP. B, Point mutations of these genes (connexin-32 [Cx32], myelin protein zero [MPZ, P0], PMP22, EGR2, periaxin) result in CMTX, CMT1B, CMT1A, DSD, and CMT4. Mutations of the LITAF gene result in CMT1C. C, Point mutations of the KIF1B and NF-L genes and specific MPZ missense mutations result in CMT2. NCV, Nerve conduction velocity. (Adapted with permission from Lupski, J.R., 1998. Molecular genetics of peripheral neuropathies. In: Martin, J.D. (Ed.), Molecular Neurology. Scientific American, New York. All rights reserved.)

chromosome 16p13-12 expressed on Schwann cells. This gene encodes a lysosomal protein that may play a role in protein degradation pathways (Street et al., 2003). Affected individuals in these families manifest characteristic CMT1 symptoms. CMT1D is mapped to chromosome 10q21-q22 and is due to mutation of the early growth response 2 gene (EGR2) which encodes a zinc-finger transcription factor expressed in myelinating Schwann cells that regulates the expression of myelin proteins including PMP22, P0, Cx32, and periaxin (Kamholz et al., 2000). EGR2 gene missense mutations have also been reported in patients with DSD, or congenital hypomyelination neuropathy (Timmerman et al., 1999; Warner et al., 1998). Respiratory compromise and cranial nerve dysfunction are commonly associated with EGR2 mutations (Szigeti et al., 2007). Other rare CMT1 subtypes include CMT1E and CMT1F.

Charcot-Marie-Tooth Disease Type 2 CMT2 constitutes about one-third of all AD CMT disease. It is associated with mutations in genes affecting intracellular processes such as axonal transport, membrane trafficking, and translation (see Chapter 48). Clinical symptoms begin later than in CMT1, most commonly in the second decade, but may be delayed until middle age or beyond. Foot and spinal deformities tend to be less prominent than in CMT1. The clinical features closely resemble those of CMT1 but differ in that peripheral nerves are not enlarged, and upper limb involvement, tremor, and diffuse areflexia occur less frequently. However, in individual cases, it is often impossible to determine the type of CMT disease on the basis of clinical manifestation alone. Approximately 20% of affected individuals are asymptomatic. CMT2A is the most common CMT2 subtype and accounts for 30% of CMT2 cases (see Table 106.6). CMT2A2, which is responsible for most CMT2 families, shares clinical features of weakness and

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atrophy with other CMT variants, but has an earlier onset and is more severe, often resulting in earlier disability and wheelchair dependence. It may also be associated with optic atrophy. It is caused by mutations in the mitofusin 2 (MFN2) gene, with a locus on chromosome 1p36.22. MFN2 protein is a mitochondrial fusion protein ubiquitously expressed in many tissues including peripheral nerves. CMT2A1, linked to chromosome 1p36.22, is caused by a mutation in kinesin protein involved in axonal transport of synaptic vesicles (Saito et al., 1997; Zhao et al., 2001). In CMT2B, which is linked to chromosome 3q1322, there is prominent sensory loss with foot ulcerations (De Jonghe et al., 1997). A mutation in the RAB7 gene, which encodes a small guanosine triphosphatase (GTPase) late endosomal protein, has been found to be causative (Verhoeven et al., 2003). This form of CMT is clinically very similar to hereditary sensory neuropathy type 1 (HSN1) but lacks spontaneous lancinating pain. CMT2B1 and CMT2B2 are AR disorders, caused by mutation in the lamin A/C gene on chromosome 1q22, and mediator of RNA polymerase II transcription, subunit 25 gene (MED25) on chromosome 19q13.33, respectively. Another distinct subgroup of severely affected patients, designated CMT2C (mapped to chromosome 12q24), develop vocal cord, intercostal, and diaphragmatic muscle weakness (Klein et al., 2003). Because of respiratory failure, the life expectancy of these patients is shortened. CMT2D, mapped to chromosome 7p14, is characterized by weakness and atrophy that is more severe in the hands than in the feet (Ionasescu et al., 1996b). In CMT2E, some patients within the same kindred and with an otherwise typical CMT2 phenotype may exhibit slowed motor nerve conduction that is much below the forearm cutoff value of 38 m/ sec and a more severe clinical phenotype. This form of CMT is caused by mutations in genes that encode neurofilament light (NEFL) subunit, and patients may have axonal swelling (giant axons) and significant secondary demyelination on sural nerve biopsies (Fabrizi et al., 2006; Jordanova et al., 2003). CMT2F, caused by mutations in small heat shock protein 27 (Hsp27), is characterized by later onset (35–60 years), mild sensory impairment, and moderate to severely slowed NCVs of lower limbs but normal or mildly reduced velocities in the upper limbs. Mutation in Hsp27 may impair formation of the stable neurofilament network that is essential for the maintenance of peripheral nerves. CMT2G has the same gene locus as CMT4H (see later discussion on type 4 disease) on chromosome 12q12-q13.3, with the age onset from 9 to 76 years. CMT2I and CMT2J are designated as CMT2 with MPZ (myelin protein zero) gene mutations. CMT2J is associated with pupillary abnormalities (Adie pupil) and hearing loss. Motor NCV may be normal or mildly reduced. SNAPs are either absent or reduced in amplitude. Sural nerve biopsy specimens show preferential loss of large myelinated fibers, without significant demyelination; there may be clusters of regenerating myelinated fibers, a hallmark of axonal regeneration.

X-Linked Charcot-Marie-Tooth Disease X-linked Charcot-Marie-Tooth disease (CMTX) is phenotypically similar to CMT1. CMTX1 is caused by many mutations in gap junction protein B1 (GJB1), the gene that encodes connexin 32 (Cx32), on chromosome Xq13.1. Affected male subjects tend to be more severely affected, and females with the gene mutation are asymptomatic or may have a mild neuropathy. CMTX1 should be considered in any patient whose family history does not exhibit a male-to-male transmission. CMTX1 accounts for 7%–16% of all forms of CMT, making it the second most common form of CMT (following CMT1A). The connexins are a family of highly related genes encoding a group of channel-forming proteins. Cx32 is a gap junction protein found in noncompacted paranodal loops and Schmidt-Lanterman incisures of Schwann cell cytoplasm, which is encoded by a four-exon gene located on chromosome Xq. As a gap junction protein, Cx32 forms small F ECF

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channels that facilitate transfer of ions and small molecules between Schwann cells and axons. More than 200 different mutations in Cx32 have been identified in CMTX1 families. Genotype-phenotype correlations among patients with Cx32 mutations suggest that most missense mutations result in a mild clinical phenotype, whereas nonsense and frameshift mutations produce more severe phenotypes (Ionasescu et al., 1996a). Cx32 is expressed in Schwann cells and oligodendrocytes, regions of noncompact myelin (incisures and paranodes), as well as other non-neural cells. Some mutations of Cx32 have been reported to be associated with central nervous system (CNS) involvement with white-matter MRI and MR spectroscopy abnormalities, abnormal brainstem auditory evoked potentials, and deafness (Murru et al., 2006). An interesting phenomenon of transient and acute ataxia, dysarthria, and weakness occurring after visiting high altitudes and associated with CNS white-matter MRI abnormalities has been described in patients with two mutations: R142W and C168Y (Paulson et al., 2002). This suggests that CMTX1 patients should be cautioned about travel to high-altitude locations. It has been proposed that Cx32 mutations may cause these abnormalities by reducing the number of functional gap junctions between oligodendrocytes and astrocytes, making them more susceptible to changes in intercellular ions and small-molecule exchange that occur in situations of metabolic stress (e.g., high altitude or physical activity). Men with CMTX1 show significant slowing in NCV, and brainstem auditory evoked responses are often abnormal. A picture of both axonal loss and demyelination is revealed on nerve biopsy. There is debate as to whether CMTX1 should be classified as a primary axonal or demyelinating disorder (Birouk et al., 1998). However, careful studies of individual patients suggest nonuniform conduction slowing consistent with demyelination (Gutierrez et al., 2000; Lewis, 2000). NCVs in males with CMTX1 with Cx32 mutations are often slow, usually in the intermediate, slowing between 35 and 45 m/sec. Conduction slowing in heterozygous women may be subtle and frequently is in the range found in patients with axonal polyneuropathies leading to a suspected diagnosis of CMT2. The absence of male-to-male transmission on family history, the presence of mild to intermediate conduction velocities (>42 m/sec) in female carriers, and delayed brainstem auditory evoked response latencies in affected men is highly suggestive of CMTX1 and Cx32 mutations (Nicholson et al., 1998). Much less common X-linked CMT subtypes have been described (see Table 106.6)

Dejerine-Sottas Disease (Charcot-Marie-Tooth Disease with Dejerine-Sottas Phenotype) DSD, previously designated as CMT3, is an uncommon progressive hypertrophic neuropathy with onset in childhood. Although originally the disorder was thought to be AR, most cases are sporadic and in some instances have been shown to result from a de novo dominant mutation. The majority of patients have mutations that are common in other types of CMT, including PMP22 duplication or point mutation, MPZ mutation, or EGR2 mutation. Motor development is delayed; proximal weakness, global areflexia, enlarged peripheral nerves, and severe disability are the rule. Motor conduction velocities are markedly slowed, often to less than 10–15 m/ sec in the forearms. Temporal dispersion and amplitude reduction on proximal stimulation may be found in such cases, owing to high electrical stimulation thresholds in hypertrophic nerves. CSF protein is frequently increased. Pathologically, pronounced onion bulb changes are associated with hypomyelination and loss of myelinated fibers. Defective myelination is confirmed by an increased axon-to-fiber diameter ratio. Cases of congenital hypomyelination neuropathy probably represent a variant of DSD at the far end of a spectrum of defective myelination. DSD is genetically heterogeneous and is caused by different structural myelin protein and transcription factor gene mutations (see Chapter 48). 02 .4.(1( 4 (

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TABLE 106.7

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Test

CMT1

HNPP

CMTX

CMT2

DSD/CHN

PMP22 dup/del FISH DNA sequencing: Cx32 PMP22 MPZ EGR2 Periaxin NEFL

X, duplication

X, deletion

—

—

X, duplication

X X X X

X X X X X

CMT1, Charcot-Marie-Tooth disease type 1; CMTX, X-linked CMT; Cx32, connexin-32, DSD/CHN, Dejerine-Sottas syndrome/congenital hypomyelination neuropathy; EGR2, early growth response 2 gene; FISH, fluorescence in situ hybridization; HNPP, hereditary neuropathy with liability to pressure palsies; MPZ, myelin protein zero; NEFL, neurofilament light chain gene; PMP22 dup/del, peripheral myelin protein 22 duplication or deletion is detected by pulse field gel electrophoresis or cytogenetic testing with FISH.

Charcot-Marie-Tooth Disease Type 4 The majority of Charcot-Marie-Tooth disease type 4 (CMT4) patients have AR inheritance. They are less common, accounting for less than 10% of all CMT cases. They are characterized by onset in early childhood and progressive weakness leading to inability to walk in adolescence. Both demyelinating and axonal types have been identified (Dubourg et al., 2006). Common to all the demyelinating subgroups is a disturbance in normal myelination of the axons; clinical and electrophysiological features are similar in several of these subtypes with severe forms of CMT1 or DSD. Conduction velocities are slowed (20– 30 m/sec). CSF protein is normal. Nerve biopsy shows loss of myelinated fibers, hypomyelination, and onion bulbs. CMT4 consists of several subgroups (see Table 106.6). Each subgroup is rare and tends to be more common in certain inbred populations. CMT4A is the most common and accounts for 25%–30% of all AR cases. The disease has been mapped to chromosome 8q13 because of ganglioside-induced differentiation-associated protein 1 (GDAP1) mutations, the most common cause of CMT4, and may result in demyelinating as well as axonal phenotypes (Nelis et al., 2002). CMT4B1 is mapped to chromosome 11q21 caused by myotubularin-related protein 2 (MTMR2) mutations, with findings of redundant loops of focally folded myelin (Houlden et al., 2001b), while CMT4B2 is mapped to chromosome 11p15.4 caused by set-binding factor-2 gene (SBF2) mutations. In both, irregular folding and redundancy of loops of myelin are evident on nerve biopsies. Children affected with CMT4B2 also exhibit congenital glaucoma, leading to loss of vision. CMT4C, characterized by frequent and severe scoliosis, is linked to chromosome 5q31-q33 and is caused by SH3TC2 gene mutation (Azzedine et al., 2006). CMT4D has onset in childhood but may progress into the fifth decade of life. It is associated with dysmorphic features and hearing loss. CMT4E is a form of congenital hypomyelinating neuropathy, often diagnosed as DSD, associated with mutations in PMP22 and ERG2 (early growth response) genes. The phenotypic presentation of CMT4F is also severe, similar to that for DSD phenotype, but the mutations occur in the periaxin gene, which produces a membrane-associated protein solely expressed in myelinating Schwann cells. Periaxin is a cytoskeleton-associated protein that links the cytoskeleton of the Schwann cell with the basal lamina, a necessary function to stabilize the mature myelin sheath (Takashima et al., 2002). CMT4H is similar to CMT2G in terms of genetic locus but is more severe clinically, with an onset in early childhood and prominent nerve hypomyelination.

Complex Forms of Charcot-Marie-Tooth Disease Some dominant forms of CMT have displayed features intermediate between CMT1 and CMT2, with conduction velocities between 35

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and 45 m/sec. These forms have been classified separately as dominant intermediate CMT (DI-CMT) and include types A, B, C, and D. DI-CMTA maps to chromosome 10q24-25, but its gene defect has not been discovered. DI-CMTB is caused by mutations in the dynamin 2 (DNM2) gene and maps to chromosome 19p12-13. This typically presents as a classic mild to moderately severe CMT phenotype. Some families with this variety have developed neutropenia and early cataracts (Claeys et al., 2009). A mutation in tyrosyl-tRNA (transfer ribonucleic acid) synthetase has been found to be the cause of DI-CMTC, which maps to chromosome 1p34-35 and typically displays a mild, very slowly progressive course (Jordanova et al., 2006). DI-CMTD maps to chromosome 1q22 MPZ gene mutations. A number of families with CMT exhibit additional features such as optic atrophy, pigmentary retinal degeneration, deafness, and spastic paraparesis. Cardiac involvement is encountered in occasional patients, but prospective family studies find no association between cardiomyopathy and CMT disease. A syndrome of CIDP responding to prednisone and immunosuppression has been reported in patients with inherited CMT disease due to MPZ mutation (Watanabe et al., 2002), providing evidence that nongenetic factors may play a role in clinical expression of the mutant gene. It has been suggested that any patient with a hereditary neuropathy who suffers a recent rapid deterioration should be considered as having a secondary CIDP and be treated with immunosuppressants such as corticosteroids or high-dose intravenous immunoglobulin (IVIG).

Practical Molecular Diagnostic Testing for Patients with Charcot-Marie-Tooth Disease and Related Disorders Molecular diagnostic testing should be considered in CMT and related peripheral neuropathies. Commercial reference laboratories can detect point mutations or PMP22 duplication/deletion by DNA sequencing of PMP22, Cx32, MPZ, EGR2, periaxin, GDAP1, and NEFL, among others, in samples of peripheral blood (Table 107.7). It is, however, advisable to use the clinical and EDX findings supplemented by a detailed family history and plan a logical approach to obtaining DNA studies. An all-inclusive “battery” of available genetic tests of CMT disease is tempting but interpretation of results may be more difficult because of frequent detection of genes with variants of unknown significance. Population studies confirmed that CMT1A (PMP22 duplication or PMP22 deletion), CMT1X (Cx32 mutation), CMT1B (MPZ mutation), and CMT2A (MFN2 mutation) account for about 65%– 70% of all CMT cases (Bassam, 2014; Boerkoel et al., 2002). male-to-male transmission, and uniform conduction slowing ( large MF sensory loss, distal weakness, onset in second to fourth decade Pansensory loss in infancy Sensory loss, autonomic dysregulation, absent tears, fungiform tongue papillae Insensitivity to pain, anhidrosis at birth, mental retardation, nl SNAPs Insensitivity to pain at birth, nl SNAPs, no mental disability, absent small MF

*Molecular gene testing is clinically available. AD, Autosomal dominant; AR, autosomal recessive; FD, familial dysautonomia; HSAN, hereditary sensory and autonomic neuropathies; IKBKAP, the protein encoded by IKBKAP gene is a member of the human elongator complex; MF, myelinated fibers; NGFB, nerve growth factor beta; nl SNAP, normal sensory nerve action potential; NTRK1/NGF, NTRK1 encodes for the high-affinity NGF (nerve growth factor) receptor; SPTLC1, SPTLC1 encodes serine palmitoyltransferase long chain 1; WNK1/HSN2, HSN2 is a nervous system-specific exon of the with no lysine(K)-1 gene.

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synthesis. Since ceramide plays a role in the regulation of programmed cell death, the neuronal degeneration in HSAN-I may be caused by ceramide-induced apoptosis. Molecular genetic testing for HSAN-I is clinically available. Families without linkage to chromosome 9q22 have been described, suggesting genetic heterogeneity (Auer-Grumbach et al., 2000). A subtype, HSAN-IB, is associated with paroxysmal cough, cough syncope, and gastroesophageal reflux (Spring et al., 2005). Additional features include hoarseness of voice and hearing deficit; motor involvement, acral mutilations and ulceration are usually absent. The association of cough and gastroesophageal reflux is not unique to HSAN-IB, as it has also been associated with CMT2 with MPZ mutation.

Hereditary Sensory and Autonomic Neuropathy Type II HSAN-II is recessively inherited and rarely begins later than infancy. All sensory modalities of distal upper and lower limbs and, to a lesser extent, of trunk and face are affected. The hands, feet, lips, and tongue are at risk for mutilation because of generalized sensory loss and insensitivity to pain. Autonomic symptoms are minimal, and mental development is normal. There is loss of tendon reflexes. Rarely, associations with spastic paraplegia, retinitis pigmentosa, mild motor weakness, or neurotrophic keratitis have been described. The clinical course is slowly progressive, with progressive axonal loss. SNAPs are absent. Sural nerve biopsy specimens show almost complete absence of myelinated fibers and reduced unmyelinated fiber populations (eFig. 106.14). Mutations in the HSN2 nervous-system-specific exon of the with-no-lysine(K)-1 (WNK1) gene on chromosome 12q13.33 cause HSAN-II (Shekarabi et al., 2008). All mutations result in a truncation of the HSN2 protein, with the protein loss or inactivation (or both) causing the peripheral neuropathy. The exact function of HSN2 protein remains unknown, but it may play a role in the development or maintenance of sensory neurons or accompanying Schwann cells.

Hereditary Sensory and Autonomic Neuropathy Type III (Familial Dysautonomia, Riley-Day Syndrome) HSAN-III, or familial dysautonomia (FD) or Riley-Day syndrome, is an AR inherited sensory neuropathy with prominent autonomic manifestations particularly affecting children of Ashkenazi Jewish ethnicity. Symptoms begin at birth and include poor sucking, uncoordinated swallowing due to esophageal dysmotility, episodes of vomiting, recurrent pulmonary infections largely due to oropharyngeal incoordination, attacks of fever, and cardiovascular instability. Emotional

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eFig. 106.14 Sural nerve fiber size-frequency histograms of myelinated fibers (MF; left) and unmyelinated fibers (UF; right) of two affected siblings with hereditary sensory and autonomic neuropathy type II (green bars) and control nerve (white bars). In the patients, the number of myelinated fibers was less than 500/mm2 and that of the unmyelinated fibers less than 10,000/mm2.

stimuli provoke episodic hypertension, profuse sweating, and marked skin blotching caused by defective autonomic control. Hypotonia in infancy contributes to delayed motor milestones. Later in childhood, hyporeflexia, insensitivity to pain, gait ataxia, stunted growth, and scoliosis become apparent. Defective lacrimation (absence of overflow tears with crying), absence of fungiform papillae of the tongue giving it a smooth appearance, and pupillary hypersensitivity to parasympathomimetic agents are telltale signs. Patients with FD are susceptible to periodic episodes of paroxysmal hypertension, tachycardia, excessive sweating, and vomiting, often termed dysautonomic crises. These episodes are caused by uncontrolled catecholamine releases and occur in 40% of patients, usually in response to stress, either emotional or physical. They are also at risk to develop profound hypoxemia and tachypnea following anesthesia or with high-altitude travel as a result of diminished respiratory response to hypercapnia and hypoxia. In older patients, clinical manifestations of orthostatic hypotension may become apparent but because of adaptation of cerebrovascular autoregulation rarely lead to syncope. As affected children grow older, sexual maturation is delayed, but normal pregnancies have occurred and male patients have fathered children. The number of neurons in the sympathetic, parasympathetic, and spinal ganglia is reduced. Peripheral blood vessels also demonstrate lack

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CHAPTER 106 Disorders of Peripheral Nerves of autonomic nerve terminals. A marked reduction in the density of unmyelinated axons and small myelinated fibers is seen in sural nerve biopsy specimens, even in the youngest patients. Recent studies have confirmed that FD is a disorder of afferent nerve function, with relative sparing of the efferent motor neurons. This is confirmed by selective failure of baroreceptor afferent reflex and impaired brainstem reflexes involving the trigeminal nerves (Gutierrez et al., 2015; NorcliffeKaufmann et al., 2010). On tilt-table study, there is a significant drop in blood pressure and heart rate. Plasma norepinephrine and vasopressin levels do not increase with head-up tilt (Norcliffe-Kaufmann et al., 2010). Motor NCVs are generally normal, whereas SNAP amplitudes are frequently reduced. Linkage studies have mapped the gene locus to chromosome 9q31-q33. The disease is caused by a point mutation in the IKBKAP gene that affects the splicing of the elongator-1 protein (ELP-1, also known as IKAP), an essential protein of the human elongation complex. The major FD mutation is a splice mutation that results in aberrant tissue-specific messenger (m) RNA splicing (Slaugenhaupt and Gusella, 2002). The elongator complex is thought to be involved in the regulation of cell-surface transport of exocytosis, and its impairment results in the dysregulation of neural endocytosis. FD is a potentially life-threatening disorder with a high mortality rate due to aspiration pneumonia or autonomic crises. Improved supportive treatment has extended the survival of patients into adulthood. There is a greater than 50% probability for infants with FD to reach 30 years of age (Gold-Von Simson and Axelrod, 2006).

Hereditary Sensory and Autonomic Neuropathy Type IV HSAN-IV is a rare AR disorder characterized by congenital insensitivity to pain and thermal sensation as well as anhidrosis. This leads to repeated episodes of fever, thick and calloused skin, dystrophic nails, self-mutilating behavior, and mild mental retardation associated with emotional lability and hyperactivity. Tendon reflexes, muscle strength, and SNAPs are preserved, but sympathetic skin responses are absent. Biopsy of sensory nerves shows selective total or near-total loss of unmyelinated axons and small myelinated fibers. Confirmation of a neuropathic abnormality in cases of congenital indifference to pain without apparent neurological signs therefore depends on the morphometric study of unmyelinated and myelinated fiber populations in nerve biopsy specimens, and is supported by quantitative sensory testing and lack of sweating by the QSART. Intradermal histamine injection produces a wheal but no flare response. Skin biopsy has demonstrated a lack of intradermal nerve fibers and sweat glands devoid of nerve fibers (Verzé et al., 2000). The gene locus for HSAN-IV maps to chromosome 1q21-22. Mutations in the NTRK1 (formerly trkA) gene encoding the tyrosine kinase receptor for nerve growth factor (NGF) have been described in patients with HSAN-IV (Indo, 2002). These findings indicate that the NGF-trkA system plays a crucial role in the development of unmyelinated nociceptive and sudomotor fibers. Clinically similar cases with selective loss of only small myelinated fibers have been designated HSAN type V. These patients do not have mental retardation. Mutations in the NTRK1 gene have been found in some cases, suggesting that the two disorders may be allelic (Houlden et al., 2001a). A related disorder with loss of deep pain perception but normal sweating has been linked to chromosome 1p13.2-p11.2, encoding the NGFB gene (Minde et al., 2004).

Treatment and Management The prevention of stress fractures and plantar ulcers is of utmost importance in most patients with HSAN. This can be achieved by meticulous foot care, avoiding barefoot walking, daily inspection of feet and shoes, and proper skin care with moisturizing lotions. Whenever plantar

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ulcers develop, weight bearing should be discontinued until the ulcers heal. Infusion of pamidronate, a bisphosphonate, has been suggested to be helpful in the management of Charcot neurogenic arthropathy. Treatments for patients with AF are also limited, and mainly preventive and symptomatic. They include managing dysphagia, protecting airway passages, prompt treatment of aspiration pneumonia, and using nighttime noninvasive ventilation for apneas and hypercapnia. At present, no specific treatment effectively delays the progression of any of the HSANs. Clinical trials of compounds that slow the progression of FD by increasing levels of ELP-1 (IKAP) are in progress.

Neuropathy Associated with Spinocerebellar Ataxias Friedreich ataxia is an AR neurodegenerative disease characterized by degeneration of large sensory neurons and spinocerebellar tracts, cardiomyopathy, and increased incidence of diabetes (see Chapter 96). Even in the early stages of the disease, examination reveals lower-limb areflexia and impaired joint position and vibration sense, with preserved pain and temperature sensation. Pes cavus and hammer toes occur in approximately 90% of cases. SNAPs are invariably reduced in amplitudes or absent. However, motor nerve conduction studies are normal or slightly reduced. A selective loss of large myelinated fibers occurs in the sural nerve. Friedreich ataxia is the result of a large GAA triplet repeat expansion on chromosome 9q13-q21.1, leading to loss of frataxin expression (see Chapter 96). Peripheral nerve involvement in spinocerebellar ataxias (SCAs) is inconsistent. This is a mainly axonal sensorimotor peripheral polyneuropathy or pure sensory polyneuropathy. The prevalence of peripheral neuropathy, based on nerve conduction studies, in SCA1, SCA2, and SCA3 ranges from 87% to 96% (Yadav et al., 2012). SCA4, SCA18, and SCA25 have also an associated peripheral polyneuropathy.

Primary Erythromelalgia Inherited or primary erythromelalgia is a rare AD neuropathic condition with an incidence of 0.36–1.1 per 100,000 persons. The onset of symptoms is often in the first decade of life. It is characterized by recurrent attacks of erythema and intense burning pain of the hands and feet in response to mild warmth or moderate exercise. To get relief, patients often attempt to cool the affected areas. The most frequently affected areas are the feet, involved in 90%–100% of patients, followed by the hands in 25%–60%. The head and neck are rarely involved, reported in 2%–15% of patients. These symptoms may lead to significant disability. Patients may function normally between episodes. Sensory and motor nerve conduction studies are normal in all patients, confirming the absence of large-fiber polyneuropathy. QSART and thermoregulatory sweat testing showed evidence of a small-fiber neuropathy in about half of children (Cook-Norris et al., 2012). Mutations in the voltage-gated sodium channel Na(v)1.7, encoded by the gene SCN9A, are responsible for this syndrome. Na(v)1.7 is preferentially expressed in small dorsal-root ganglia neurons. Gain-of-function mutations in Nav1.7 that enhance activation and impair fast inactivation cause the sensation of pain (Choi et al., 2006; Dib-Hajj et al., 2017; Han et al., 2012; Waxman, 2007). Other mutations in SCN9A that cause a loss of Na(v)1.7 function result in the opposing condition of “congenital inability to experience pain,” emphasizing the importance of sodium channels in nociception (Cox et al., 2006). A third disorder has also been linked to Na(v)1.7: paroxysmal extreme pain disorder, which was formerly known as familial rectal pain syndrome (Fertleman et al., 2007). The linkage between pain and temperature in erythromelalgia is in keeping with other diseases of sodium channels.

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eTABLE 106.9 Type

Neurological Diseases and Their Treatment

Familial Amyloid Neuropathies

Aberrant Protein

Decade of Onset

Associated Organ Involvement

Neuropathy

FAP I and II

TTR

FAP III

Apolipoprotein A1

Early onset: Third through fourth decade Late onset: Sixth through eighth decade Third through fourth decade

FAP IV

Gelsolin

Third to fourth decade

Length-dependent sensorimotor neuropathy, life-threatening autonomic neuropathy, carpal tunnel syndrome

Heart, eye

Sensorimotor neuropathy (not prominent) Cranial neuropathy

Kidney, liver, gastrointestinal tract Cornea (lattice dystrophy) and skin (cutis laxa)

FAP, Familial amyloid polyneuropathy; TTR, transthyretin.

No treatment is consistently effective and has to be individualized. Sodium channel blockers such as lidocaine (gel, patch, or infusion), carbamazepine, and mexiletine are frequently used (Tang et al., 2015). Aspirin, tricyclic antidepressants (TCAs), and vasoactive drugs have been used with varying success.

Familial Amyloid Polyneuropathy FAP is a group of AD disorders characterized by the extracellular deposition of amyloid proteins in peripheral nerves and other organs. Amyloid is a fibrillar conformation of a protein characterized by (1) green birefringence of Congo red-stained sections viewed in polarized light, (2) the presence of nonbranched 10-nm amyloid fibrils on electron microscopy, and (3) a β-pleated sheet structure on x-ray diffraction. More than 20 different proteins are known to undergo conformational changes leading to the generation of amyloid deposits in tissues. These deposits may be widespread or restricted to certain organs (localized amyloidosis). The clinical presentation depends on the organs involved and the size of amyloid fibrils. In FAP, one of three aberrant proteins (transthyretin, apolipoprotein A1, or gelsolin [Falk et al., 1997; Planté-Bordeneuve and Said, 2011]) may be found in the peripheral nerves. The latter two are rare and restricted to a few families. In acquired primary systemic amyloidosis, polypeptides of immunoglobulin light-chain origin are deposited in tissues as amyloid, which leads to the term amyloid light (AL) amyloid (see Primary Systemic Amyloidosis, later). The classification of FAP was traditionally based on clinical presentation. However, progress in understanding the protein composition and molecular genetics of these disorders justifies a different approach (eTable 106.9).

Transthyretin Familial Amyloid Polyneuropathy (TTR-FAP, Familial Amyloid Polyneuropathy Types I and II) The majority of patients with FAP have mutations of the plasma protein TTR. This is a bifunctional transport protein for thyroxin and retinol-binding protein. It is predominantly synthesized in the liver and choroid plexus and consists of a single polypeptide chain of 127 amino acid residues. The gene for TTR is located on chromosome 18q11.2-q12.1. Most patients are heterozygous for TTR gene mutations (more than 90 described) that result in transcriptions of aberrant proteins with predisposition toward amyloid formation and deposition in peripheral nerve, heart, kidney, eye, and (rarely) leptomeninges. TTR-FAP is rare, with endemic populations predominantly in Portugal, Sweden, Japan, and Brazil. TTR amyloidosis demonstrates two disparate clinical phenotypes. The original cases described by Andrade in Portugal are referred to as FAP type I. Two other large foci of patients are found in Sweden and Japan. This is the most common form of FAP and has been observed in 30 different countries and in many ethnic

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groups (Ando et al., 2005). The neuropathy begins insidiously in the third and fourth decades with dissociated sensory impairment (loss of pain and thermal sense) in the lower extremities, often associated with lancinating pain and paresthesias. Because of its similarity to other neuropathies, it may be difficult to diagnose this condition (Ikeda, 2007; Planté-Bordeneuve et al., 2007). Autonomic dysfunction commonly includes impotence, postural hypotension, bladder dysfunction, distal anhidrosis, and abnormal pupils with scalloped margins. Gastrointestinal symptoms characterized by constipation alternating with diarrhea, delayed gastric emptying, and weight loss may be prominent. Eventually panmodality sensory loss, distal wasting, weakness, and areflexia develop. Systemically, amyloid is deposited in the ocular vitreous, heart, and kidneys. Cardiac manifestations include cardiac hypertrophy, arrhythmias, ventricular blocks, or cardiomyopathy. The pattern of myocardial involvement varies according to specific TTR mutations. The disorder is relentlessly progressive. Untreated patients usually die, often of cardiac disease and less often from renal failure or malnutrition 10–15 years after the onset (Coelho et al., 2018). EDX studies reveal a distal axonal neuropathy that affects sensory fibers earlier and more prominently than motor fibers. Early changes include low-amplitude or absent SNAPs, mild reduction in CMAP amplitudes, and preserved motor conduction velocities. Evidence of denervation is found in distal leg muscles. Until specific biochemical and genetic studies became available, the diagnosis was confirmed by the demonstration of amyloid in tissue biopsy specimens. In early cases, sural nerve biopsy specimens show a predominant loss of unmyelinated and small myelinated fibers. Amyloid deposits of variable size are usually seen within the endoneurium or around vasa nervorum. Immunostaining with antibodies to TTR can identify the specific type of amyloid. Many but not all mutations have evidence of myocardial infiltration on echocardiography. The mechanisms of nerve fiber injury and their relationship to amyloid deposits are incompletely understood. It has been proposed that the preferential deposition of amyloid in sensory and autonomic ganglia interferes with or is toxic to neuronal function, leading to a length-dependent axonal degeneration. An alternative theory suggests that endoneurial edema associated with amyloid deposition in blood vessels and the endoneurium results in ischemic nerve fiber injury. However, this does not explain the selective involvement of smaller nerve fibers. A more restricted form of the disease, referred to as FAP type II, has a later onset than FAP I in the sixth to eighth decade, may present with CTS, and slowly progresses to peripheral polyneuropathy. Autonomic manifestations are also less prominent. Vitreous opacities are common and cardiac involvement may develop. Surgical decompression of the carpal tunnel provides symptomatic relief despite the fact the CTS is often more severe than in patients with idiopathic CTS. Demonstration of amyloid infiltration of the flexor retinaculum obtained at surgery or in other tissues establishes the diagnosis.

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CHAPTER 106 Disorders of Peripheral Nerves More than 90 different amino acid substitutions of the TTR protein have been identified as causing the clinical TTR-FAP phenotypes. Among these, substitution of valine by methionine at position 30 (Val30Met) is by far the most frequent; it is found in clusters in distinct areas of Portugal, Sweden, and Japan and accounts for 50% of mutations worldwide. Other TTR variants, including isoleucine 33, alanine 60, and tyrosine 77 substitutions, have similar features of generalized polyneuropathy with varying degrees of autonomic involvement. A serine substitution at position 84 and histidine at position 58 are the two TTR mutations seen most commonly in FAP-II. The age of onset varies greatly with specific TTR mutations. Even in families with the Val-30Met mutation, variation in age of onset is observed in different geographic regions (Ikeda et al., 2002). Specific TTR mutations may produce unique phenotypes with predominantly cardiac or leptomeningeal amyloidosis (Hund et al., 2001).

Apolipoprotein A1 Amyloidosis (Familial Amyloid Polyneuropathy Type III, Iowa, Van Allen) This is a rare form of familial amyloidosis, described first by Van Allen and colleagues in Iowa. The clinical manifestations of the type III variant have much in common with those of type I, except for a less prominent length-dependent sensorimotor polyneuropathy and for early renal involvement and a high incidence of duodenal ulcers. Uremia is the most common cause of death, typically occurring 12–15 years after the onset of neuropathy. Sixteen mutations of apolipoprotein A1 are known to cause FAP. Those involving codons 1–75 more commonly cause hepatic and renal amyloidosis, while those involving codons 173–178 cause cardiac, laryngeal, and cutaneous amyloidosis (Eriksson et al., 2009).

Gelsolin Amyloidosis (Familial Amyloid Polyneuropathy Type IV, Meretoja)

Diagnosis of Familial Amyloid Polyneuropathy The diagnosis of FAP requires high index of suspicion. In patients presenting with progressive symmetric peripheral polyneuropathy, the diagnosis of TTR-FAP should be seriously considered if the patient has more than one of the following findings: (1) positive family history, (2) early autonomic dysfunction (e.g., erectile dysfunction or postural hypotension), (3) heart disease (e.g., myocardial hypertrophy, arrhythmias, ventricular blocks, or cardiomyopathy), (4) bilateral CTS (especially if also present in family members), (5) renal abnormalities (e.g., albuminuria or mild azotemia), or (6) vitreous opacities (Conceicao et al., 2016). In contrast, screening for hereditary TTR-FAP in patients with idiopathic mixed sensorimotor or small-fiber neuropathy without

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any additional clinical characteristics of disease in a Nordic population appeared to be of little value (Samuelsson et al., 2019). Initially, the diagnosis could be established by confirming the presence of amyloid in nerve and muscle, rectal biopsies, a sample of subcutaneous abdominal fat, or any other tissues removed at the time of unrelated procedures. Sampling error, however, confounds these tests. Nerve biopsies have shown 83% sensitivity, and salivary gland biopsies 67% (Planté-Bordeneuve et al., 2007). Immunostaining using specific antibodies against one of the three aberrant proteins may identify the responsible protein. In sporadic cases, the more common AL amyloidosis should be excluded by a search for clonal plasma cell dyscrasia (see Primary Systemic Amyloidosis, later). If no evidence of plasma cell dyscrasia exists, TTR can be identified by isoelectric focusing of the serum, which separates variant and wild-type TTR. In highly suspected patients or after finding of a variant TTR in tissue should prompt genetic testing. DNA isolated from peripheral leukocytes or tissue can be amplified with the polymerase chain reaction (PCR) and specific oligonucleotide primers used to amplify regions of the gene of interest, thereby demonstrating specific point mutations. DNA testing for the most common TTR mutations (Met30, lle-33, Ala-60, Tyr-77, and Ser-84) is available in reference laboratories. A negative result, however, does not exclude a TTR mutation. Mutation analysis of the entire TTR gene detects more than 99% of amyloidogenic mutations. Genetic testing has become the most reliable form of testing for FAP and should be considered in appropriate patients with cryptogenic progressive axonal neuropathy affecting small-fiber nerves in a length-dependent fashion and the autonomic nervous system.

Treatment

Gelsolin amyloidosis is an AD condition first described in Finland, but subsequently isolated cases have also been reported elsewhere. Symptoms begin in the third or fourth decade, with corneal clouding caused by a fine, strand-like network of amyloid filament deposits referred to as lattice corneal dystrophy. This is followed in the fifth decade by progressive cranial neuropathies with prominent facial palsy and skin changes producing a typical baggy skin over the atrophic face (cutis laxa). Other cranial nerves (VIII, XI, and XII) may be affected, and bulbar signs may develop, at times leading to aspiration, together with mild peripheral neuropathy and CTS but without significant autonomic dysfunction. Gelsolin, the amyloid protein isolated from tissues of patients with FAP type IV, is an actin-binding protein found in plasma, leukocytes, and other cell types. Plasma gelsolin is largely derived from muscle. It presumably functions as the clearing agent for actin by binding to it in the plasma. The gelsolin gene maps to chromosome 9. Amino acid substitutions (asparagine or tyrosine at position 187) result in amyloid-forming mutant gelsolin. The mutant plasma gelsolin is deposited in the tissues, particularly nerves and skin.

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The prognosis of untreated TTR amyloidosis varies with the specific mutation, age of onset, and organ involvement. If untreated, the disease progresses rapidly in patients with TTR-FAP and the Val30Met mutation, leading to death, usually within the first decade after symptom onset (Coelho et al., 2018). Supportive measures are essential for both the neuropathy and specific organ system involved, including cardiac pacing, hemodialysis, parenteral nutrition, hydration, elastic stockings, and physical therapy. Symptomatic treatment includes the use of anticonvulsants or antidepressants for neuropathic pain, and midodrine, droxidopa and fludrocortisone for orthostatic hypotension. Because over 90% of TTR is synthesized in the liver, orthotopic liver transplantation has been considered as definite therapy for this disorder. Transplantation results in rapid clearance of the variant TTR from serum; it may halt progression of neurological deficits in patients with mild neuropathy and stop the rate of axonal degeneration; autonomic dysfunction remains largely unchanged (Adams et al., 2000; Stangou and Hawkins, 2004). The reported 5-year survival rate after liver transplantation in patients with Val30Met in Sweden is approximately 92%, with many surviving more than 20 years (Yamamoto et al., 2007). Overall, 60% stabilize, 20% improve, and 20% do poorly. Liver transplantation is recommended for patients who are younger than 50 years, have mild neuropathy (walking unaided), and have no significant cardiac or renal involvement. In some cases of non-Val30Met mutation, despite liver transplantation, the amyloidogenic TTR continues to be deposited in the heart, vitreous, and peripheral nerves, which is thought to be due to wild-type TTR complexing with already deposited mutant TTR (Liepnieks et al., 2010; Stangou et al., 1998). Combined liver and renal transplantation has been performed in a few patients with severe renal involvement. Dissociation of TTR tetramers is the rate-limiting step of amyloidogenesis in patients with TTR-FAP. Slowing TTR tetramer dissociation appears to minimize clinical disease expression. TTR stabilization

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includes using diflunisal, a NSAID, which prevents dissociation of the TTR tetramer and amyloid fibril formation by binding to the thyroxinebinding sites on TTR. A randomized, placebo-controlled trial of diflunisal in patients with FAP showed a reduction in progression of neuropathy in the diflunisal arm, with preservation of quality of life, after 2 years of treatment (Berk et al., 2013). This agent may worsen renal function and cause volume overload in FAP patients who often have renal disease and cardiomyopathy. Tafamidis is a novel, small-molecule TTR stabilizer, reduces all-cause mortality and the decline in functional capacity and quality of life as compared with placebo (Maurer et al., 2018). Suppression of TTR expression is another treatment concept by using small interfering RNA agents that bind to conserved sequences on TTR messenger RNA (mRNA), leading to degradation of the mRNA. Patisiran has been shown, in a phase 3 trial, to reduce serum TTR levels in patients with FAP, and significantly improves gait and modified neuropathy impairment score (Adams et al., 2018). Antisense oligonucleotides (ASOs) promote degradation of mRNA and reduce TTR suppression. A phase 2/3 trial of IONIS-TTRx in patients with FAP is ongoing. Finally, doxycycline, tauroursodeoxycholic acid, epigallocatechin-3-gallate (the predominant polyphenol in green tea), and curcumin (the principal ingredient of turmeric) may be useful in TTR disruption and prevention of amyloid fibril aggregation. Larger trials are needed to explore the efficacy of these treatments. In patients with non-Val30Met mutations, the prognosis is not as good and progressive neuropathy and cardiomyopathy may continue after liver transplantation. Combined liver and heart transplantation in one patient with the same mutation resulted in mild improvement of the peripheral neuropathy. Medical therapy with agents that interfere with amyloid fibril formation and gene therapy are promising future therapeutic strategies.

Porphyric Neuropathy Acute hepatic porphyrias are a group of AD inherited metabolic disorders that manifest as acute or subacute severe life-threatening motor neuropathy, abdominal pain, autonomic dysfunction, and neuropsychiatric manifestations (Albers and Fink, 2004). Its gene is thought to be present in one in 80,000 people, although only one-third of affected persons ever manifest symptoms of the disease. The main forms of porphyria include acute intermittent porphyria (AIP), variegate porphyria, and hereditary coproporphyria. The basic defects are a 50% reduction in hydroxymethylbilane synthase (also known as porphobilinogen

Clinical Features of the Acute Porphyric Attack The neurological manifestations of all forms of the acute porphyrias are identical. All clinical symptoms may be explained by the dysfunction of the autonomic nervous system, peripheral nervous system (PNS), and CNS. Characteristically, porphyric attacks first occur during the second to fourth decades of life and are five times more common and severe in women than men. The diagnosis is often delayed by a mean of 15 years (Bonkovsky et al., 2014). Abdominal pain, neurological dysfunction, and psychiatric disturbances form the classic triad of AIP. The most frequent presenting symptom is recurrent abdominal pain, often with nausea, vomiting, and severe constipation. Many patients undergo appendectomies and cholecystectomies prior to the diagnosis of porphyria. Anxiety and depression are very common, occurring in at least half of patients. Abdominal symptoms may occur several days before overt neurological manifestations. The autonomic manifestations are prevalent and include persistent tachycardia, labile hypertension, orthostatic hypotension, and difficulty with micturition. Only a few patients progress to develop the more ominous motor neuropathy or CNS involvement, including psychosis and seizures. Onset of the predominantly motor neuropathy is subacute, with generalized, proximal, or asymmetrical muscle weakness developing over days or weeks. The arms rather than the legs may be affected first, and proximal muscles as well as the radial nerves may be preferentially involved. Muscular activity before the onset

Porphyric Neuropathies

eTABLE 106.10 Enzyme defect Inheritance Chromosome Photosensitive eruption Porphyrin excretion: Urine: PBG ALA Uro Copro Feces: Copro Proto

deaminase [PBGD]) in AIP, of protoporphinogen IX oxidase in variegate porphyria, and of coproporphinogen oxidase in coproporphyria, all of which result in abnormalities of heme synthesis. Each abnormality of enzyme activity provokes a compensatory overproduction of porphyrins and their precursors through the negative feedback regulation by heme of the first and rate-limiting enzyme of the heme biosynthetic pathway, δ-aminolevulinic acid synthase (ALAS). A fourth disorder, referred to as plumboporphyria, is inherited as an AR trait and is caused by a deficiency of δ-aminolevulinic acid dehydratase (ALAD) (eTable 106.10). More than 90 mutations in the PBGD gene have been identified that decrease enzyme activity and cause AIP (Elder et al., 1997). These partial enzyme defects remain latent until precipitating factors trigger acute attacks. Precipitating factors include certain drugs, the menstrual cycle, alcohol, hormones, and fasting (either intentional or during an intercurrent illness). Precipitating factors induce hepatic δ-ALAS, the rate-limiting enzyme in heme biosynthesis, leading to the overproduction and overexcretion of PBG and δ-ALA.

Acute Intermittent Porphyria

Variegate Porphyria

Hereditary Coproporphyria

Plumboporphyria

PBG deaminase AD 11q24 None

Protoporphyrinogen oxidase AD 1q22 Present

Coproporphyrinogen oxidase AD 3q12 Present

ALA dehydratase AR 9q34 None

+++ +++ + Negative

+++ +++ + ++

+++ +++ + +++

0 +++ Negative +

Negative Negative

+ +++

+++ +

Negative +

+++, ++, +, Relative indication of quantity excreted. AD, Autosomal dominant; ALA, aminolevulinic acid; AR, autosomal recessive; Copro, coproporphyrin; PBG, porphobilinogen; Proto, protoporphyrin; Uro, uroporphyrin.

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and hereditary tyrosinemia. CSF is normal. Hyponatremia related to inappropriate antidiuretic hormone release is common, possibly due to hypothalamic pathology (Suarez et al., 1997). EDX studies in patients with porphyric neuropathy reveal low-amplitude CMAPs but normal or borderline-slow motor conduction velocities. SNAPs are reduced in amplitude or are absent. EMG obtained early in the course reveals poor recruitment of normal MUAPs. Denervation changes appear later, first in the paraspinal and proximal muscles and subsequently in distal muscles. Patients with chronic disorder will exhibit an axonal length-dependent, often asymmetrical, polyneuropathy. Morphological study results support axonal degeneration and preferential loss of large myelinated axons.

Clinical symptoms plus positive Watson-Schwartz or Hoesch test At once Elimination of inducing drugs and circumstances 400 g carbohydrates/day

Typing of porphyria

1–2 days Improved

Not improved

Family studies

Continue carbohydrates prn

Add hematin 4 mg/kg bid for 3 days

Prophylaxis

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Pathogenesis

eFig. 106.15 Management of Acute Porphyric Attack. bid, Twice a day; prn, as needed. (Adapted from Bosch, E.P., Pierach, C.A., 1987. Acute hepatic porphyria. In: Johnson, R.T. (Ed.), Current Therapy in Neurologic Disease. Decker, Toronto.)

The mechanism of the neuronal axonal injury remains uncertain. The two leading hypotheses implicate neuronal heme deficiency with impaired energy metabolism or direct neurotoxicity of ALA and neurotoxic porphyrins.

Treatment and Management of symptoms may influence the pattern of weakness. Facial and bulbar weakness is common. In severe cases, flaccid quadriplegia with respiratory failure ensues. This picture may resemble GBS and, often only after a second attack of neuropathy is the diagnosis of porphyric neuropathy considered because of the infrequency of a repeated episode of GBS. Rapidly progressive muscle wasting is a striking feature. Tendon reflexes are diminished or absent, but, paradoxically, ankle jerks may be retained. Sensory impairment may occur in a distal stocking-glove distribution or may affect the trunk and proximal limbs in an unusual bathing-suit pattern. In exceptional cases, a bilateral radial motor neuropathy without abdominal pain may be the only manifestation of AIP (King et al., 2002). The rate of improvement varies. Some patients rapidly recover, suggesting a reversible acute toxic-metabolic neuronal injury. Those with fixed weakness caused by axonal degeneration improve slowly (mean time to recovery is 10.6 months for proximal muscles and nearly twice as long for distal muscles). The protean CNS manifestations during severe attacks include seizure, posterior reversible encephalopathy syndrome (PRES), confusion, delirium, and coma (Zheng et al., 2018). Patients with variegate porphyria and hereditary coproporphyria develop cutaneous photosensitivity during adult life. The skin manifestations consist of blisters, hyperpigmentation, hypertrichosis, and increased skin fragility. AIP occurs in all ethnic groups but is most common in individuals of Scandinavian or English descent. Variegate porphyria is also common among South Africans of Afrikaans descent.

Laboratory Studies The biochemical hallmark of the porphyric attack is marked elevation of PBG and ALA in blood and urine. Enzyme assays may mislead and should not be used in place of porphyrin analysis. Rapid screening tests for urinary PBG (e.g., Watson-Schwartz and Hoesch tests) give positive test results during virtually all acute attacks and are useful in an emergency. A positive screening test result must be confirmed with quantitative determinations of urinary PBG and ALA. Levels of urinary ALA and PBG may decrease rapidly after an attack of variegate porphyria or hereditary coproporphyria but remain elevated in AIP. Subsequently, stool assays for protoporphyrins and coproporphyrins are necessary to distinguish variegate porphyria and hereditary coproporphyria from AIP. The diagnosis of ALAD-deficiency porphyria (ADP) is supported by increased urinary excretion of ALA without accompanying PBG elevation. Certain medications and disorders other than porphyrias are associated with increased urinary porphyrins, including lead poisoning, liver disease, alcoholism, chronic renal failure during hemodialysis,

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The treatment of patients with acute hepatic porphyria involves three important steps: (1) attempts to repress hepatic ALA activity, thereby reducing porphyrin production; (2) supportive care; and (3) prevention of attacks. The porphyric attack must be treated promptly, as outlined in eFig. 106.15. First, all offending drugs are removed, and any intercurrent infection is treated. A high-carbohydrate diet orally or by nasogastric feeding (at least 400 g daily or the equivalence of glucose or levulose infusions) results in reduced porphyrin precursor production. Intravenous hematin is the treatment of choice for acute attacks (Bonkovsky et al., 2014). Hematin (a hydroxide of heme) represses the activity of hepatic ALA and may restore cytochrome functions by replenishing an endogenous heme deficit. Hematin therapy at the recommended dose of six infusions of 4 mg/kg body weight at 12-hour intervals has resulted in consistent reduction of porphyrin precursors in serum and urine and clinical improvement in more than 80% of attacks. The only placebo-controlled study suggested a more modest clinical benefit of IV hematin. Early administration of hematin is advocated to correct the metabolic insult before neuronal damage becomes irreversible. Supportive treatment consists of the correction of fluid imbalance, close attention to respiratory function, and physical therapy. Supplemental vitamin B6 and beta-blockers for control of tachycardia may become necessary. Abdominal pain can often be controlled with simple analgesics but may require narcotics. Sedation with chlorpromazine is often helpful. The treatment of seizures poses a difficult therapeutic problem because most anticonvulsants may exacerbate the disease. Intravenous diazepam and parenteral magnesium sulfate are both effective and safe for immediate seizure control. All at-risk relatives should be screened for latent disease. Ideally, attacks should be prevented by avoiding drugs and situations that induce them. Among the inducing drugs, barbiturates are the most common precipitants, followed by sulfonamides, analgesics, nonbarbiturate hypnotics, anticonvulsants, and female sex hormones. Intentional fasting and alcohol consumption should be avoided. Gonadotropin-releasing hormone agonists may benefit women with recurrent attacks related to the menstrual cycle. Prophylactic and repeated administration of intravenous hematin is of benefit to those prone to recurrent attacks (Bonkovsky et al., 2014).

Fabry Disease Fabry disease (angiokeratoma corporis diffusum) is an X-linked lysosomal storage disorder caused by a deficiency of the lysosomal enzyme

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Neurological Diseases and Their Treatment as an intravenous infusion. Minor reactions include flushing, chest discomfort, skin rash pruritus, and nasal congestion. Approximately 1% of patients developed anaphylactic or severe allergic reactions (angioedema, bronchospasm, hypotension, or generalized urticarial) during infusions. Reactions have included localized dysphagia, rash, dyspnea, flushing, chest discomfort, pruritus, and nasal congestion. Most patients, particularly those exhibiting infusion reactions, should be pretreated with antipyretics, antihistamines, and corticosteroids. Renal transplantation may correct the biochemical defect, resulting in relief from pain and partial restoration of sweating.

Leukodystrophies with Neuropathy eFig. 106.16 Fabry Disease. Typical angiokeratomas are clustered over the lower part of the trunk.

α-galactosidase A, which results in the accumulation of the glycolipid globotriaosylceramide (ceramide trihexoside) within vascular endothelial cells of the kidneys, heart, brain, and skin. Over time, progressive vascular disease leads to renal failure, cardiac disease, and strokes. Skin involvement gives rise to the typical angiokeratomas, which are dark red, punctate telangiectasias found mainly over the lower part of the trunk, buttocks, and scrotum (eFig. 106.16). A painful small-fiber neuropathy develops in childhood or adolescence. In fact, any boy or young man with severe painful sensory neuropathy should be suspected as having Fabry disease, and skin lesions should be carefully scrutinized because they are usually sparse and may be easily overlooked. Distal paresthesias and lancinating pain are intensified by exertion, fever, or hot environments. Autonomic dysfunction includes diminished sweating, impaired tear and saliva formation, and decreased intestinal motility. Some patients have hearing loss (Barras and Maire, 2006; Vibert et al., 2006). Except for impairment of temperature sensation, overt neurological signs are absent. Female carriers often show clinical involvement but rarely develop renal failure, which is characteristically seen in affected men. On nerve conduction studies, the conduction velocities are mildly reduced in two-thirds of patients. Deposition of glycolipid in small neurons of sensory and peripheral autonomic ganglia results in neuronal degeneration and selective loss of small myelinated and unmyelinated fibers in sural nerve biopsy specimens. Ultrastructurally, perineurial, endothelial, and perithelial cells contain characteristic lamellated glycolipid inclusions. Leukocyte preparations or skin fibroblasts are used for the diagnostic α-galactosidase assay. Although screening for Fabry disease was recommended for patients with small-fiber neuropathy of unknown cause, studies of Nordic populations has recently shown that screening for Fabry disease in patients with idiopathic small-fiber or mixed neuropathy without any additional disease-specific symptoms is of little value in a clinical setting (Samuelsson et al., 2019). Analgesics, phenytoin, or carbamazepine, along with avoidance of aggravating factors, are effective for pain relief. Recombinant α-galactosidase-A replacement therapy with recombinant α-galactosidase A (agalsidase beta) is safe and effective in the removal of microvascular endothelial deposits of globotriacylceramide from target organs (Eng et al., 2001). Enzyme replacement therapy results in slowing the progression of renal, cardiac, and cerebrovascular complications and death (Banikazemi et al., 2007) and in improvement of autonomic function (Ries et al., 2006). Agalsidase alfa has also been shown to be beneficial in cardiac, renal, neuropathic pain, and quality-of-life measures (Mehta et al., 2009). Enzyme therapy before irreversible end-organ damage may provide greater clinical benefit. The recommended dosage of agalsidase beta is 1.0 mg/kg body weight infused every 2 weeks

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The leukodystrophies result from inherited abnormalities of myelin metabolism that may affect both the CNS and PNS. Overall incidence of the leukodystrophies in the United States is 1 in 7663 live births (Bonkowsky et al., 2010). Peripheral nerve involvement is seen in MLD, Krabbe disease, adrenomyeloneuropathy (AMN), and Cockayne syndrome. Recognition of an associated neuropathy may be helpful in the differential diagnosis of the underlying leukodystrophy. Missense mutations in proteolipid protein, a major protein component of CNS myelin, cause a spectrum of X-linked CNS disorders without peripheral neuropathy, including Pelizaeus-Merzbacher disease and hereditary spastic paraparesis. Proteolipid protein is also expressed in Schwann cells and compact peripheral myelin. Absence of proteolipid protein expression caused by a frameshift mutation has been reported to produce a demyelinating neuropathy with less severe CNS manifestations (Gabern et al., 1997).

Metachromatic Leukodystrophy MLD is an AR disorder of sulfatide metabolism caused by deficiency of the lysosomal enzyme arylsulfatase A (ASA) and subsequent accumulation of sulfatides in brain, peripheral nerves, and other tissues. The storage of sulfatides affects central and peripheral myelin, leading to progressive demyelination. The ASA gene is localized to chromosome 22q13, and, thus far, over 60 mutations have been identified. Some gene mutations have been correlated with different clinical phenotypes. Three main clinical forms have been divided by age of onset: late-infantile (6 months–2 years), juvenile (3–16 years), and adult. Peripheral nerve involvement characterized by a progressive gait disorder, hypotonia, and lower-limb areflexia is an early manifestation that frequently precedes CNS involvement in late-infantile and early-juvenile MLD. In contrast, behavioral abnormalities and progressive dementia predominate over subtle neuropathic signs in adult-onset MLD. A homozygous missense mutation has been described in an adult patient presenting with an isolated polyneuropathy without CNS involvement (Felice et al., 2000). Marked uniform slowing of nerve conduction is seen in late-infantile and juvenile cases. Reduced NCVs and delayed visual and somatosensory evoked potential latencies are present in most adult cases. Extensive segmental demyelination and abnormally thin myelin sheaths are seen in nerve biopsy specimens of all MLD variants, along with metachromatic inclusions within Schwann cells and macrophages. Peripheral nerve biopsy therefore offers a means of confirming the diagnosis, although this is rarely needed now. The diagnosis of MLD is supported by MRI of the brain and confirmed by an increased urinary sulfatide excretion and abnormal ASA enzyme assays in leukocytes or fibroblasts. Bone marrow transplantation may increase brain levels of ASA sufficiently to stop disease progression.

Globoid Cell Leukodystrophy (Krabbe Disease) Globoid cell leukodystrophy, or Krabbe disease, is an AR disease caused by an inherited deficiency of the lysosomal enzyme galactocerebroside

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CHAPTER 106 Disorders of Peripheral Nerves β-galactosidase. The gene for Krabbe disease has been localized to chromosome 14q31. The disorder is characterized by extensive CNS and peripheral nerve demyelination and the presence of multinucleated macrophages (globoid cells) in the cerebral white matter. The classic presentation in early infancy consists of rapidly progressive deterioration in intellectual and motor development, accompanied by hypertonicity, opistotonic posture, optic atrophy, and seizures. In the late-onset form, peripheral neuropathy and spasticity may be the only manifestations. Peripheral nerve involvement is demonstrated by marked uniform slowing of motor conduction velocities. Segmental demyelination, together with ultrastructurally characteristic tubular or crystalloid inclusions within Schwann cells and macrophages, is seen in the sural nerve. Hematopoietic stem cell transplantation provides a source of the missing enzyme and can thereby prevent and reverse the CNS manifestations (Krivit et al., 1998).

Adrenomyeloneuropathy AMN, the adult phenotype of adrenoleukodystrophy, is an X-linked recessive disorder of fatty acid metabolism characterized by adrenal insufficiency, progressive myelopathy, and peripheral neuropathy. A defect in beta-oxidation of saturated very-long-chain fatty acids (VLCFAs) in peroxisomes leads to the accumulation of tetracosanoic (C24:0) and hexacosanoic (C26:0) acid in tissues and body fluids in affected patients. A significant increase of VLCFA levels in plasma, fibroblasts, or both allows reliable detection in patients and heterozygote female carriers. The defective gene (ABCD1) is located in the region Xq28 and codes for a peroxisomal membrane protein referred to as ALD protein that belongs to the ABC transporter protein family (Moser, 1997). AMN manifests in the second to third decades with progressive spastic paraparesis, distal muscle weakness, sensory loss, and sphincter disturbances. Neurological features frequently are preceded by clinical or laboratory evidence of hypoadrenalism. Approximately 10% of patients have primary adrenal insufficiency without evidence of nervous system involvement. At least 20% of female carriers develop spastic paraparesis similar to that in men, but less severe and later in onset. Electrophysiological studies are helpful in identifying peripheral nerve involvement that may escape clinical detection because of prominent upper motor neuron signs. Nerve conduction studies demonstrate a distal axonopathy with low CMAP amplitudes and mildly reduced NCVs. Fewer than 10% of patients have significant nerve conduction slowing suggestive of demyelination (van Geel et al., 1996). Sural nerve biopsy shows loss of myelinated fibers, occasional small onion bulbs, and curvilinear lamellar lipid inclusions in Schwann cells. Brain MRI study results are abnormal, demonstrating white-matter changes in roughly half of patients with AMN at some time in the course of their disease. Dietary restriction of VLCFA combined with the administration of oleic and erucic acids (Lorenzo oil) lower plasma levels of VLCFA but have no effect in arresting the rate of neurological progression (van Geel et al., 1999). Adrenal insufficiency responds readily to corticosteroid replacement. In contrast to the cerebral form, patients with AMN are not considered suitable candidates for bone marrow transplantation.

Phytanic Acid Storage Disease (Refsum Disease) Refsum disease, heredopathia atactica polyneuritiformis, is a rare AR disorder of phytanic acid metabolism. The gene defect has been localized to chromosome 10 and encodes the peroxisomal enzyme phytanoyl-CoA-hydroxylase. The defect in the enzyme that initiates the alpha-oxidation pathway of β-methyl-substituted fatty acids leads to phytanic acid accumulation in serum and tissues. Phytanic

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acid is derived exclusively from dietary sources, mainly chlorophyll, dairy products, meats, and fish oils. Clinical onset spans from childhood to the third decade of life. The cardinal manifestations include pigmentary retinal degeneration with night blindness or visual-field constriction, chronic hypertrophic neuropathy, ataxia, and other cerebellar signs such as nystagmus and intention tremor. Initially, the neuropathy affects the lower limbs with distal leg atrophy, weakness, areflexia, large-fiber sensory impairment, and sometimes palpably enlarged nerves. Weakness becomes generalized later in the illness. In addition to pes cavus, overriding toes caused by symmetrically short fourth metatarsals are a helpful sign for Refsum disease. Progressive sensorineural hearing loss, anosmia, cardiomyopathy, and ichthyosis are common. The course may be either progressive or fluctuating with exacerbations and remissions. Exacerbations are often precipitated by fasting, which mobilizes phytanic acid from endogenous fat stores. Motor conduction velocities are markedly slowed, and SNAPs are reduced or absent. CSF protein is increased in the range of 100–700 mg/dL. Sural nerve biopsy reveals a hypertrophic neuropathy with prominent onion bulb formation. The diagnosis is confirmed by elevated serum levels of phytanic acid. Chronic dietary treatment, by restricting the exogenous sources of phytanic acid (1) is fairly specific and distinguishes GBS from other axonal polyneuropathies such as diabetic neuropathies. Conduction block

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of motor axons, the electrophysiological correlate of clinical weakness, is recognized by a decrease of greater than 50% in CMAP amplitude from distal to proximal stimulation in the absence of temporal dispersion. Conduction block at non-entrapment sites is highly specific for demyelination, but it occurs only in 15%–30% of early GBS, depending on the number of nerves and nerve segments studied. Patients with weakness that is related primarily to conduction block tend to have a faster and more complete recovery than those with diffusely low motor amplitudes. Prolonged distal motor latencies, reduction in distal CMAP amplitudes, significant CMAP dispersion, and slowing of motor conduction velocities are less common and tend to occur later in the course of the disease (Cleland et al., 2006; Cros and Triggs, 1996; Gordon and Wilbourn, 2001). Needle EMG is mostly complementary in GBS, initially showing decreased motor unit recruitment. Subsequently, if any amount of axonal degeneration occurs, fibrillation potentials appear 2–4 weeks after onset. In general, the EDX studies become more specific for multifocal demyelination during the third and fourth weeks of illness (Albers and Kelly, 1989). In fact, about half of the patients have normal NCSs during the first 4 days of illness (except for absent H reflexes), while only about 10% of them have normal studies by the first week of illness (Gordon and Wilbourn, 2001). Additionally, several EDX criteria have been advocated over the years, with sensitivities ranging from 20% to 70% (Alam et al., 1998). In general, about two-thirds of patients fulfill the criteria for highly suggestive or definite AIDP in the first 2 weeks of illness, with high specificity (95%–100%). EDX parameters are the most reliable indicators of prognosis. Mean distal CMAP amplitude of less than 20% of the lower limit of normal (LLN) was associated with poor outcome in the North American GBS study (Cornblath et al., 1988). However, low distal CMAPs may be due to distal demyelination with distal conduction block and often mimics axonal loss. Rapid recovery of low distal CMAPs and SNAPs on sequential studies is a necessary

BOX 106.12

Differential Diagnosis Care should be taken to distinguish GBS from other conditions leading to subacute motor weakness (Box 106.12). Among the polyneuropathies with acute onset, acute porphyria, diphtheria, and occasional

Differential Diagnostic Considerations in Guillain-Barré Syndrome

Muscle Disorders Polymyositis Dermatomyositis Necrotizing autoimmune myopathy Rhabdomyolysis (drugs, toxins, exercise, trauma, metabolic myopathies, etc.) Critical illness myopathy Muscle Membrane Disorders Familial periodic paralysis Secondary hypokalemic paralysis (thyrotoxicosis, malabsorption, barium salt poisoning, or abuse of diuretics, laxatives, or licorice) Neuromuscular Junction Disorders Myasthenia gravis (myasthenic crisis) Botulism Drug-induced neuromuscular blockade Toxic: Organophosphate Nerve gas Tick Black widow spider Snake venoms Metabolic: Hypermagnesemia (toxemia of pregnancy treated with parenteral magnesium, magnesium-containing antacids, or cathartics)

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confirmatory sign of distal demyelination. Inability to distinguish demyelinating conduction block from reversible conduction failure and axon-discontinuity conduction block has caused erroneous classification in up to one-third of GBS patients where the initial classification changed after serial recordings (Rajabally et al., 2015). The value of specific serological tests in the diagnosis of GBS is limited except in MFS and AMAN (Yuki and Hartung, 2012). There is no specific ganglioside antibody that appears to be associated with AIDP. Hence, these ganglioside antibodies are not clinically useful. However, elevated anti-GQ1b ganglioside antibodies are consistently found in about 95%–98% of patients with MFS. Preceding C. jejuni infection has been linked to AMAN variant and high titers of anti-GM1, antiGD1b, anti-GD1a, and anti-GalNAc-GD1a ganglioside antibodies of the IgG class (Jacobs et al., 1996). Serological tests for C. jejuni infection are difficult both to perform and interpret. Other studies confirmed the presence of IgG antiglycolipid antibodies in 10%–40% of patients with GBS but failed to show a correlation with C. jejuni infection (Ho et al., 1995). Elevated serum antibodies to Mycoplasma, CMV, or C. jejuni can pinpoint the preceding infection. Antigalactocerebroside antibodies have been detected in patients with precedent Mycoplasma infection. Complement-fixing antibodies to peripheral nerve myelin are present in most patients during the acute phase of GBS. Imaging studies, more specifically MRI of the brain and spine, are most useful to exclude brainstem or spinal cord disease as a cause of the weakness. MRI of the lumbar spine with gadolinium, however, may be abnormal in GBS and may show nerve root enhancement of the cauda equina, particularly in children with GBS (Yikilmaz et al., 2010).

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Hypophosphatemia (parenteral hyperalimentation, phosphate-bindings antacids, acute alcohol intoxication, and severe respiratory alkalosis) Peripheral Nerve and/Root Disorders Guillain-Barré syndrome Acute intermittent porphyria Diphtheritic polyneuropathy Critical illness polyneuropathy Vasculitic neuropathy Heavy metal acute poisoning (thallium, arsenic) Diffuse polyradiculopathy: Infectious (Lyme, cytomegalovirus [CMV]) Inflammatory (sarcoidosis) Neoplastic (solid tumors, lymphomas) Anterior Horn Cell Disorders Acute poliomyelitis (wild-type polio viruses, West Nile virus, enteroviruses) Spinal Cord Disorders Transverse myelitis Cord compression (disc herniation, fracture/dislocation, epidural malignancy) Cord infarction (anterior spinal artery syndrome) Brainstem Disorders Central pontine myelinolysis Pontine infarct (basilar artery thrombosis)

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CHAPTER 106 Disorders of Peripheral Nerves toxic neuropathies (arsenic, thallium, buckthorn, acrylamide, organophosphate compounds, and n-hexane) must be considered. Flaccid general weakness and failure to wean from the ventilator are common features of critical illness polyneuropathy that develops in patients confined to the intensive care unit (ICU) with sepsis and multiorgan failure. EDX features of an axonal neuropathy and normal CSF findings distinguish critical illness neuropathy from the classic form of GBS. A related syndrome, critical illness myopathy, follows the use of nondepolarizing neuromuscular blocking agents or IV corticosteroids or both. Metabolic disturbances (severe hypophosphatemia, hypokalemia, or hypermagnesemia), rhabdomyolysis, and inflammatory myopathies may result in rapidly progressive generalized weakness. Elevated creatine kinase (CK), abnormal serum electrolytes, and needle EMG help distinguish these disorders from GBS. Disorders of neuromuscular transmission including myasthenic crisis, botulism, and tick paralysis should also be considered. Myasthenic crisis is often associated with CMAP decrement on slow-frequency repetitive nerve stimulation. Botulism develops after the consumption of contaminated foods, with ophthalmoparesis and facial and bulbar weakness. Nerve conduction studies reveal low-amplitude CMAPs, and high-frequency repetitive nerve stimulation or maximal voluntary contraction leads to an incremental response that is typical of presynaptic neuromuscular transmission defect. Acute brainstem infarct, spinal cord compression, epidural abscess, and transverse myelitis may present diagnostic difficulties before upper motor neuron signs develop and before results of EDX and CSF studies become available. Among other signs, early urinary retention and a sharply demarcated sensory level on the trunk suggest spinal cord disease and call for urgent spinal MRI. CSF pleocytosis (>50 cells per µL) casts doubt on the diagnosis of uncomplicated GBS and suggests inflammatory or neoplastic meningoradiculopathies such as secondary to Lyme disease, HIV infection, or CMV in AIDS. Poliomyelitis caused by the wild-type polio viruses may produce a rapidly evolving asymmetrical weakness accompanied by fever and CSF pleocytosis. Poliomyelitis due to West Nile virus may lead to flaccid paralysis in up to 27% of patients with neurological complications.

Pathology Classic pathological studies of AIDP have demonstrated endoneurial perivascular mononuclear cell infiltration together with multifocal demyelination. The peripheral nerves may be affected at all levels from the roots to distal intramuscular motor nerve endings, although most lesions usually occur on the ventral roots, proximal spinal nerves, and lower cranial nerves. Intense inflammation may lead to axonal degeneration as a consequence of a toxic bystander effect. Ultrastructural studies have shown that macrophages play a major role in demyelination by stripping off myelin lamellae from the axon. The inflammatory infiltrates consist mainly of class II-positive monocytes and macrophages, and T lymphocytes. The expression of class II antigen is increased in Schwann cells, raising the possibility that Schwann cells may present the antigen to autoreactive T cells and activate the destruction of myelin. Pathological studies in patients with AMAN using electron microscopy have demonstrated the presence of macrophages in the periaxonal space of myelinated internodes. Extensive primary wallerian-like degeneration of motor and sensory roots and nerves without significant inflammation or demyelination is found in cases of AMSAN.

Pathogenesis The bulk of experimental and clinical evidence suggests that GBS is an organ-specific, immune-mediated disorder caused by a synergistic interaction of cell-mediated and humoral immune responses against peripheral nerve antigens that are still incompletely characterized (Kieseier et al., 2006a).

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Approximately two-thirds of patients report a preceding event, most frequently an upper respiratory or gastrointestinal infection, surgery, or immunization 1–4 weeks before the onset of neurological symptoms (Govoni and Granieri, 2001; Table 106.11). The agent responsible for the prodromal illness often remains unidentified. Specific infectious agents linked to GBS include CMV, Epstein-Barr virus, varicella-zoster virus (VZV), hepatitis A and B, HIV, Mycoplasma pneumoniae, and H. influenzae. Recent evidence from Colombia, French Polynesia, and Puerto Rico have shown that infection with Zika virus, a mosquitoborne RNA Flavivirus, plays an important role in the development of GBS (Parra et al., 2016). The most common identifiable bacterial organism linked to GBS and particularly its axonal forms is C. jejuni, a curved gram-negative rod that is a common cause of bacterial enteritis worldwide. Evidence of C. jejuni infection from stool cultures or serological tests was found in 26% of patients with GBS admitted to hospitals in the United Kingdom, compared with 2% of case controls (Rees et al., 1995). Retrospective studies from the United States, Holland, Germany, and Australia report serological evidence of recent C. jejuni infection ranging from 17% to 39% of patients with GBS. It should be noted that in the United States alone, an estimated 2.4 million cases of enteric infection with C. jejuni are reported per year, yet only about 2500 individuals develop GBS. This suggests that host-related factors or certain polymorphisms of C. jejuni determine the development of GBS. C. jejuni infection may play an even greater role in northern China, where the infection rates are 76% in patients with AMAN and 42% in patients with AIDP (Ho et al., 1995). Molecular mimicry between GM1 ganglioside and C. jejuni lipo-oligosaccharide is established as the pathogenic link for this association. Epidemiological data suggested a slight increase in cases of GBS following the 1976 A/New Jersey influenza vaccine, although no excess risk of developing GBS was seen with subsequent influenza vaccines. The most recent studies suggest an even further decline of reported cases of GBS after influenza vaccination from the low levels reported a decade earlier, indicating that the risk of GBS after influenza vaccination now stands at only one additional case per 2.5 million persons vaccinated (Haber et al., 2004). A UK study also provides reassurance that the great majority of sporadically occurring GBS is not associated with immunization (Hughes et al., 2006b). For these reasons, prior GBS should not preclude administration of influenza vaccines in high-risk individuals. Other vaccines (notably tetanus and diphtheria toxoids, rabies, oral polio, and meningococcal conjugate vaccines); drugs including

Antecedent Events of Guillain-Barré Syndrome

TABLE 106.11 Antecedent Event

Percentage

Respiratory illness Gastrointestinal illness Respiratory and gastrointestinal illness Surgery Vaccination Other

58 22 10 5 3 2

Serological Evidence of Specific Infectious Agents

Campylobacter jejuni Cytomegalovirus Human immunodeficiency virus Epstein-Barr virus Mycoplasma pneumonia Hepatitis A and B Zika virus

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streptokinase, suramin, gangliosides, and heroin; and Hymenoptera stings have been associated in a few cases. Several cases have occurred in immunocompromised hosts with Hodgkin lymphoma or in pharmacologically immunosuppressed patients after solid organ or bone marrow transplantation. A preceding infection may trigger an autoimmune response through “molecular mimicry,” in which the host generates an immune response against an infectious organism that shares epitopes with the host’s peripheral nerves. At the onset of disease, activated T cells play a major role in opening the blood–nerve barrier to allow circulating antibodies to gain access to peripheral nerve antigens. T-cell activation markers (interleukin [IL]-6, IL-2, soluble IL-2 receptor, and interferon γ [IFN-γ]) and tumor necrosis factor α (TNF-α), a proinflammatory cytokine released by T cells and macrophages, particularly IL-23 (Hu et al., 2006), are increased in patient serum. In addition, adhesion molecules and matrix metalloproteinases are critically involved in facilitating recruitment and transmigration of activated T cells and monocytes through the blood–nerve barrier. Soluble E-selectin, an adhesion molecule produced by endothelial cells, and metalloproteinases are increased in patients with GBS during the early stages of disease. A cell-mediated immune reaction against myelin components is supported by experimental allergic neuritis, the accepted animal model for AIDP. Experimental allergic neuritis can be produced by active immunization with whole peripheral nerve homogenate, myelin, or PNS-specific myelin basic protein P2, P0, or galactocerebroside. Several observations indicate that humoral factors also participate in the autoimmune attack on peripheral nerve myelin, axons, and nerve terminals: (1) immunoglobulins and complement can be demonstrated on myelinated fibers of affected patients by immunostaining; (2) MFS and AMAN are strongly associated with specific antiganglioside antibodies; (3) serum from MFS and AMAN patients contains IgG antibodies that block peripheral nerve transmission in a mouse nerve-muscle preparation; (4) complement C1-fixing antiperipheral nerve myelin antibody can be detected in the serum of patients during the acute phase of GBS; (5) intraneural injection of GBS serum into rat sciatic nerve results in secondary T-cell infiltration of the injection site at the time of the appearance of the hind limb weakness; and (6) plasmapheresis or immunoglobulin infusions result in clinical improvement. Understanding of the immune mechanisms of GBS, including AIDP and its axonal subtypes, was enhanced by the detailed immunohistochemical and ultrastructural studies of clinically well-defined autopsied cases from northern China. The earliest changes seen in AIDP within days of onset consisted of deposition of complement activation products and membrane attack complex on the outermost Schwann cell surface, followed by vesicular myelin changes at the outermost myelin lamellae, with subsequent recruitment of macrophages and progressive demyelination (Hafer-Macko et al., 1996). Previously, the role of complement had been suggested by the finding of increased levels of complement activation products in CSF and soluble terminal complement complexes in serum of patients with AIDP. The immune attack in AIDP appears to begin with binding of autoantibodies to specific epitopes on the outermost Schwann cell membrane, with consequent activation of complement (Fig. 106.17). The nature of the epitope in AIDP, although still uncertain, is likely to be a glycolipid. Pathological studies of early cases of AMAN found deposition of activated complement components and immunoglobulins at the nodal axolemma. This was followed by disruption of the paranodal space, allowing the entry of complement and immunoglobulins along the axolemma, with subsequent recruitment of macrophages to affected nodes. Finally, macrophages were shown to invade the periaxonal space, leading to wallerian-like degeneration of motor fibers

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Th* AIDP Increasing severity of immune attack

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B

IL-2 TNF-α IFN-γ

↑ E-selectin ↑ CAM

Antimyelin antibody

M* Proteases TNF-α C C3d

C5b-9

? Glycolipid

M* M* M*

Secondary axonal degeneration M*

M*

M* M*

M*

M* M*

Fig. 106.17 Immune Injury to Nerve Fibers in Acute Inflammatory Demyelinating Polyradiculoneuropathy (AIDP). Preceding infection may trigger formation of antimyelin autoantibodies and activated T-helper cells (Th*). Proinflammatory cytokines (tumor necrosis factor alpha [TNFα], interferon gamma [INF-γ]), and upregulation of adhesion molecules (E-selectin, intercellular adhesion molecule [ICAM]) facilitate breakdown of blood–nerve barrier to activated T cells, macrophages, and antimyelin antibodies. Antimyelin antibodies react with epitopes on the abaxonal Schwann cell membrane, with consequent activation of complement. Deposition of complement activation products (C3d) and membrane attack complex (C5b-9) on the outermost Schwann cell membrane leads to vesicular myelin changes, followed by recruitment of macrophages (M*) and progressive demyelination. Intense inflammation may lead to secondary axonal degeneration. B, B cell; IL-2, interleukin 2. (Adapted from Bosch, E.P., 1998. Guillain-Barré syndrome: an update of acute immune-mediated polyradiculoneuropathies. Neurologist 4, 211–226.)

(Hafer-Macko et al., 1996; Fig. 106.18). These findings suggest that AMAN is caused by an antibody- and complement-mediated attack on axolemmal epitopes of motor fibers. The most attractive candidate targets are GM1- and asialo-GM1-like gangliosides, which are present in nodal and internodal membranes of motor fibers. Certain C. jejuni strains associated with axonal GBS and MFS variants contain GM1like epitopes in their polysaccharide coats. Anti-GM1 and GQ1b antibodies that cross-react to these lipopolysaccharide epitopes are found in a high proportion of patients with AMAN and MFS, respectively, as well as in some patients with AIDP. These observations have led to the concept of molecular mimicry in which epitopes of the infectious agent elicit antibodies that cross-react with shared epitopes on axons. The nerve fibers thereby become the inadvertent targets of an immune response directed against an infectious organism. The antiganglioside antibodies obtained from AMAN and MFS patients block neuromuscular transmission in an in vitro nerve-muscle preparation. The blocking activity of these IgG antibodies can be neutralized by IVIG (Buchwald et al., 2002). Furthermore, rabbits immunized with GM1 develop AMAN, thereby fulfilling the postulates for confirming an autoimmune pathogenesis (Sheikh and Griffin, 2001). AMSAN may be caused by a more severe immune injury triggered by axonal epitopes because similar pathological changes affecting motor and sensory fibers have been observed in cases of AMSAN. In addition to C. jejuni and gangliosides, molecular mimicry for GBS is also shown with for Mycoplasma pneumonia and galactocerebroside, and CMV infection and moesin (Sawai et al., 2014).

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Infection

GM1 epitope

Th*

AMAN

B

Increasing severity of immune attack

Blood–nerve barrier (“leaky”) Anti-GM1 antibody

M*

GM1 epitope

M*

M*

M*

GM1 epitope

M*

M*

C3d M* M*

C5b-9

Motor nerve terminals M*

M* M*

M* M*

Motor-sensory axonal pattern

AMSAN Fig. 106.18 Immune Injury to Nerve Fibers in Acute Motor Axonal Neuropathy (AMAN). Molecular mimicry of GM1-like epitopes common to both lipopolysaccharide coats of certain Campylobacter jejuni strains and axonal membranes may cause an autoimmune response. Activated complement components (C3d, C5b-9) and immunoglobulins are found at nodes of Ranvier and along axolemma of motor fibers. Macrophages (M*) are recruited to targeted nodes and invade periaxonal space, leading to wallerian degeneration. Lack of blood–nerve barrier at motor nerve terminals may make these distal axons vulnerable to circulating GM1 antibodies. AMSAN, Acute motor sensory axonal neuropathy; B, B cell; Th*, activated T-helper cells. (Adapted from Bosch, E.P., 1998. GuillainBarré syndrome: an update of acute immune-mediated polyradiculoneuropathies. Neurologist 4, 211–226.)

Treatment General supportive management is the mainstay of treatment. Patients with rapidly worsening acute GBS should be observed in the hospital until the maximum extent of progression has been established. The reduction in mortality to less than 5% reflects improvements in modern critical care. The prevention of complications, of which respiratory failure and autonomic dysfunction are the most important, provides the best chance for a favorable outcome (Bosch, 1998). Respiratory and bulbar function, ability to handle secretions, heart rate, and blood pressure should be closely monitored during the progressive phase. Respiratory failure requiring mechanical ventilation develops in up to 30% of patients with GBS. Predictors of future need for mechanical ventilation include rapid disease progression (onset to admission in 40 bpm in subjects 300 mL; Sood et al., 2002) and a gastric-emptying test with a solid and liquid diet. Upper-bowel dysmotility may benefit from promotility agents such as metoclopramide, 10 mg two or three times daily. However, metoclopramide is contraindicated in PD, owing to brain barrier passage and central effect. It should also be used with extreme caution because of the risk of tardive dyskinesia. Other motility agents are also available, including erythromycin at an adult dose of 250 mg two to three times daily. Erythromycin is a motilin agonist that improves gastric emptying and foregut motility. Octreotide is also useful in improving foregut motility, although it may produce delayed gastric emptying. It has some effect in increasing blood pressure and has been used in postprandial hypotension. Lower-bowel dysfunction may present as constipation or diarrhea. Constipation usually requires a nonstimulating laxative such as PEG or lactulose given in generous doses until bowel function normalizes, when doses can be reduced to routine maintenance levels. A sitz marker study swallowing a capsule with many nonabsorbable rings followed by an x-ray a few days later (several protocols are available) can help determine if the constipation is due to a generalized motility disorder. When severe constipation with obstipation supervenes and is unresponsive to the standard regimen, a “home cleanout” regimen may be prescribed, consisting of bisacodyl 10 mg (2 × 5 mg tablets), followed by 1 capful of PEG in 8 ounces of liquid every 30 minutes for a total of 8–10 doses, followed by another dose of bisacodyl 4 hours later. Lubiprostone produced marked clinical improvement in a randomized double-blind placebo-controlled trial in subjects with PD, increasing daily stools in 64% of the subjects (Ondo et al., 2012). Lower-bowel dysmotility may also present with diarrhea, with a broader possible set of causes. Diarrhea may actually be a manifestation of obstipation, with liquid stool overflowing around the hard stool in the distal colon. A flat-plate abdominal radiograph is diagnostic. Other causes include small-bowel bacterial overgrowth, which may be determined by a hydrogen breath test and responds to antibiotics, in particular rifaximin, which is the current standard of care. Metronidazole should be avoided, since it may cause or worsen an autonomic neuropathy. Finally, primary lower-bowel hypermotility sometimes responds to low-dose clonidine (0.1–0.2 mg) once or twice daily. In conclusion, autonomic disorders constitute a continuously growing field over the last decade, both in terms of pathophysiological understanding and in terms of management strategies. The discipline seems poised for an explosion of new understanding, particularly in the area of functional autonomic disorders, where new fundamental links between brain, behavior, and end-organ control may emerge.

ACKNOWLEDGMENTS We thank Ian Worcester for preparing the manuscript and acknowledge our friend and teacher David Robertson, whose authorship of this chapter in the fifth edition we built upon. Supported by Advancing a Healthier Wisconsin Endowment, Grant 5520298, and NIHNIDDK R01DK083538. The complete reference list is available online at https://expertconsult. inkling.com/.

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108 Disorders of Neuromuscular Transmission Jeffrey T. Guptill, Donald B. Sanders OUTLINE Myasthenia Gravis, 1958 Epidemiology of Myasthenia Gravis, 1958 Clinical Presentation of Myasthenia Gravis, 1958 Physical Findings in Myasthenia Gravis, 1959 Immunopathology of Myasthenia Gravis, 1960 Myasthenia Gravis Subtypes, 1962 Genetics of Myasthenia Gravis, 1963 Diagnostic Procedures in Myasthenia Gravis, 1963 Treatment of Myasthenia Gravis, 1965 Summary, 1969 Treatment Plan for Myasthenia Gravis, 1970 Association of Myasthenia Gravis With Other Diseases, 1970 Special Situations, 1972 Congenital Myasthenic Syndromes, 1973 Acetylcholine Receptor Deficiency, 1973 Choline Acetyl Transferase Deficiency, 1974

Normal muscle contraction and force production require the efficient transmission of an electrical impulse from a motor axon to the muscle fibers it innervates. The neuromuscular junction (NMJ), a specialized synapse with a complex structural and functional organization, is the site of electrochemical conversion of nerve impulses into muscle fiber action potentials. The NMJ is particularly vulnerable to autoimmune disorders caused by circulating immune factors (myasthenia gravis and Lambert-Eaton myasthenia) since it has no blood–nerve barrier. Genetic abnormalities and certain toxins disrupt neuromuscular transmission (NMT) as well. Disorders of NMT produce several characteristic clinical syndromes, described in this chapter. Treatment options for autoimmune NMJ disorders remained relatively unchanged for many years, but a greater understanding of the pathophysiology of these disorders and an increasing number of targeted monoclonal antibodies and small molecules are expanding the number of treatment options.

MYASTHENIA GRAVIS Acquired myasthenia gravis (MG) is the most common primary disorder of NMT. In MG, the binding of autoantibodies to proteins, most commonly the acetylcholine receptor (AChR), disrupts normal NMT. This results in muscle weakness that typically predominates in certain muscle groups and fluctuates in response to effort and rest. The diagnosis depends on recognition of a distinctive pattern of weakness on history and examination, and confirmation by diagnostic tests. A number of effective therapeutic options are available, and treatment can result in minimal long-term morbidity in most patients.

Congenital Acetylcholinesterase Deficiency, 1974 Slow-Channel Congenital Myasthenic Syndrome, 1974 Fast-Channel Syndrome, 1974 Rapsyn Mutations, 1974 DOK-7 Mutations, 1974 GFPT1 and DPAGT1 Mutations, 1974 Lambert-Eaton Myasthenia, 1974 Diagnostic Procedures in Lambert-Eaton Myasthenia, 1975 Immunopathology of Lambert-Eaton Myasthenia, 1975 Treatment of Lambert-Eaton Myasthenia, 1975 Myasthenia Gravis/Lambert-Eaton Myasthenia Overlap Syndrome, 1976 Botulism, 1976 Clinical Features of Botulism, 1976 Electromyographic Findings in Botulism, 1976 Treatment of Botulism, 1976 Other Causes of Abnormal Neuromuscular Transmission, 1977

Epidemiology of Myasthenia Gravis MG may begin at any age from infancy to very old age. Epidemiological studies report considerable variability in incidence and prevalence around the world (Deenen et al., 2015). While methodological differences may explain some of this variability, biological and genetic factors may also play a role. Estimates indicate that the US prevalence is approximately 20/100,000, or 60,000 patients total (Phillips, 2004). Epidemiological studies have shown an increasing prevalence over the past 50 years, related to an increase in the frequency of diagnosis in elderly patients, but also likely due to improved ascertainment, reduced mortality rates, and an increased longevity of the population (Carr et al., 2010). Gender and age influence the incidence of MG, women being affected nearly three times more often than are men before age 40, while the incidence is higher in males after age 50 and roughly equal during puberty. As the population ages, the average age at onset has increased correspondingly. More men are now affected than are women, and the majority of MG patients in the United States are over age 50. Detailed population-based data on clinical and serological subtypes of MG are largely lacking.

Clinical Presentation of Myasthenia Gravis Patients with MG seek medical attention for specific muscle weakness or dysfunction that typically worsens with activity and improves with rest. Although they may also have generalized fatigue or malaise, it is not usually the major or presenting complaint. Drooping eyelids or double vision is the initial symptom in approximately two-thirds of patients; nearly all will develop both within 2 years. Difficulty chewing, swallowing, or talking is the initial symptom in one-sixth of patients, and limb weakness in 10%. Rarely, the initial weakness is limited to

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1959

B

C

E

D

Fig. 108.1 Ocular Motility Abnormalities In Myasthenia Gravis Due To Weakness Of Multiple Periocular Muscles In Both Eyes. A, B, Progressive right lid ptosis during sustained forward gaze from fatigable weakness of the right levator palpebrae. C, Attempted upward gaze. There is incomplete superior movement of both eyes, worse in the right eye. Note the asymmetric furrowing of the forehead and elevation of the eyebrows. D, On left left lateral gaze, there is skew deviation with incomplete medial movement of the right eye and incomplete abduction of the left eye. E, On right right lateral gaze, there is incomplete movement of both eyes from weakness of right lateral rectus and left medial rectus muscles.

single muscle groups, such as neck, elbow or finger extensors, hip flexors, or ankle dorsiflexors. Myasthenic weakness typically fluctuates during the day, usually being least in the morning and worse as the day progresses, especially after prolonged use of affected muscles. Ocular symptoms may be intermittent in the early stages, typically becoming worse in the evening or while reading, watching television, or driving, especially in bright sunlight. Many patients find that dark glasses reduce diplopia and hide drooping eyelids. Jaw muscle weakness typically becomes worse during prolonged chewing, especially of tough, fibrous, or chewy foods. Careful questioning often reveals evidence of earlier, unrecognized myasthenic manifestations, such as frequent purchases of new eyeglasses to correct blurred vision, avoidance of foods that became difficult to chew or swallow, or cessation of activities that require prolonged use of specific muscles, such as singing. Friends may have noted a sleepy or sad facial appearance caused by ptosis or facial weakness. The course of disease is variable but usually progressive. Weakness remains restricted to the ocular muscles in approximately 10%–15% of cases (See Ocular Myasthenia Gravis section, later in this chapter) although up to 58% has been reported in Asian populations, mainly in children (Zhang et al., 2007). In the rest, weakness progresses to involve nonocular muscles during the first 3 years and ultimately involves facial, oropharyngeal, and/or limb muscles (generalized MG). Maximum weakness occurs during the first year in two-thirds of patients. Before the introduction of immunosuppression for treatment, approximately one-third of patients improved spontaneously, one-third became F ECF

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worse, and one-third died of the disease. Improvement, even remission, may occur early on but is rarely permanent (i.e., there is a subsequent relapse). Symptoms typically fluctuate over a relatively short period and then become more severe (active stage). Left untreated, an inactive stage follows the active stage, in which fluctuations in strength still occur but are attributable to fatigue, intercurrent illness, or other identifiable factors. Although rare today, untreated weakness becomes fixed after many years, and the most severely involved muscles are frequently atrophic (burnt-out stage). Factors that worsen myasthenic symptoms are emotional upset, systemic illness (especially viral respiratory infections), hypothyroidism or hyperthyroidism, pregnancy, the menstrual cycle, surgeries, drugs affecting NMT (see Treatment of Associated Diseases and Medications to Avoid section, later in this chapter), and fever.

Physical Findings in Myasthenia Gravis Perform the examination so as to detect variable weakness in specific muscle groups. Assess strength repetitively during maximum effort and again after rest. Performance on such tests may also fluctuate in diseases other than MG, especially if effort varies or testing causes pain. The symptoms of MG do not always vary, particularly in long-standing disease, which can make the diagnosis difficult.

Ocular Muscles Most MG patients have weakness of ocular muscles (Fig. 108.1; Box 108.1). Asymmetrical weakness of several muscles in both

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BOX 108.1

Gravis

Neurological Diseases and Their Treatment

Ocular Findings in Myasthenia

Weakness usually involves one or more ocular muscles without overt pupillary abnormality (Video 108.1—Ocular examination in MG). Weakness is typically variable, fluctuating, and fatigable. Ptosis that shifts from one eye to the other is virtually pathognomonic of MG. With limited ocular excursion, saccades are superfast, producing ocular “quiver.” After downgaze, upgaze produces lid overshoot (“lid twitch”) Pseudo-internuclear ophthalmoplegia—limited adduction, with nystagmoid jerks in abducting eye (Video 108.2—pseudo-INO in MG). In asymmetric ptosis, covering the ptotic eye may relieve contraction of the opposite frontalis. Passively lifting a ptotic lid may cause the opposite lid to fall: “enhanced ptosis” or “curtain sign” (Video 108.3—“curtain sign”). Edrophonium may improve only some of several weak ocular muscles; others may actually become weaker. Edrophonium may relieve asymmetric ptosis and produce retraction of the opposite lid from frontalis contraction. The opposite lid may droop further as the more involved lid improves after edrophonium. Cold applied to the eye may improve lid ptosis: “Ice-pack test” (see Fig. 108.7) MG, Myasthenia gravis.

Fig. 108.2 Typical Myasthenic Facies. At rest (left), there is slight bilateral lid ptosis, which is partially compensated by asymmetric contraction of the frontalis muscle, raising the right eyebrow. During attempted smile (right), there is contraction of the medial portion of the upper lip and horizontal contraction of the corners of the mouth without the natural upward curling, producing a “sneer.”

eyes is typical, the medial rectus being more frequently and usually more severely involved. The pattern of weakness cannot be localized to lesions of one or more nerves, and the pupillary responses are normal. Ptosis is usually asymmetrical (Fig. 108.2) and varies during sustained activity. To compensate for ptosis, chronic contraction of the frontalis muscle produces a worried or surprised look. Patients may also tilt their head back in compensation, which may hide subtle ptosis. Unilateral frontalis contraction is a clue that the lid elevators are weak on that side (see Fig. 108.1). When mild, ocular weakness may not be obvious on routine examination and appear only upon provocative testing, such as sustained upward gaze or red lens testing. Eyelid closure is usually weak, even when strength is normal in all other facial muscles, and may be the only residual weakness in otherwise complete remission. This is usually asymptomatic unless it is severe enough to allow soap or water in the eyes during bathing or to produce dry eyes when sleeping. With moderate weakness of these muscles, the eyelashes are not “buried” during forced eye closure (Fig. 108.3). Fatigue in these muscles may result in slight involuntary opening of the eyes as the patient tries to keep the eyes closed, the so-called peek sign (see Fig. 108.3). F ECF

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Fig. 108.3 “Peek” Sign In Myasthenia Gravis. During sustained forced eyelid closure the man is unable to bury his eyelashes (left) and, after 30 seconds, the man is unable to keep the lids fully closed (right). (Reproduced from Sanders, D.B., Massey, J.M., 2008. In Engel AG et al., Handbook of Clinical Neurology, Elsevier, figure 5, with permission.)

Oropharyngeal Muscles Oropharyngeal muscle weakness causes changes in the voice, difficulty chewing and swallowing, and inadequate maintenance of the upper airway. The voice may be nasal, especially after prolonged talking, and liquids may escape through the nose when swallowing because of palatal muscle weakness. Weakness of laryngeal muscles causes hoarseness. A history of frequent choking or throat clearing or coughing after eating indicates difficulty in swallowing. Respiratory dysfunction and isolated dysphagia (without dysarthria) are rarely the initial symptoms of MG. Myasthenic patients may have a characteristic facial appearance. At rest, the corners of the mouth often droop downward, giving a depressed appearance. Attempts to smile often produce contraction of the medial portion of the upper lip and a horizontal contraction of the corners of the mouth without the natural upward curling, which gives the appearance of a sneer (see Fig. 108.2). Manually opening the jaw against resistance shows jaw weakness; this is not possible when strength is normal. The patient may support a weak jaw (and neck) with the thumb under the chin, the middle finger curled under the nose or lower lip, and the index finger extended up the cheek, producing a studious or attentive appearance.

Limb Muscles Weakness begins in limb or axial muscles in about 20% of MG patients (Kuks et al., 2004). Any trunk or limb muscle may be weak, but some are more often affected than are others. Neck flexors are usually weaker than neck extensors, and the deltoids, triceps, and extensors of the wrist and fingers and ankle dorsiflexors are frequently weaker than other limb muscles. Rarely, MG presents initially with focal weakness in single muscle groups, such as a “dropped head syndrome” due to severe neck extensor weakness, or isolated triceps weakness. In untreated patients with long-standing disease, weakness may be fixed, and severely involved muscles may be atrophic, giving the appearance of a chronic myopathy; atrophy is particularly likely in muscle specific tyrosine kinase (MuSK)-ab positive MG (See Anti-MuSK-Antibody Positive MG, later in this chapter).

Immunopathology of Myasthenia Gravis In about 80%–85% of MG patients, weakness results from the effects of circulating anti-AChR antibodies (Table 108.1). These antibodies bind to AChR on the terminal expansions of the junctional folds (Fig. 108.4) and cause complement-mediated destruction of the folds, accelerated internalization and degradation of AChR, and in some cases, they block ACh-AChR binding. Destruction of the junctional folds results in distortion and simplification of the postsynaptic region (Fig. 108.5) and 02 .4.(1( 4 (

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TABLE 108.1

1961

Myasthenia Gravis Clinical Subtypes

MG subtype

Age at onset

Thymic histology

Autoantibodies

Comments

Ocular Early Onset Late Onset

Adult in United States and Unknown Europe; childhood in Asia < 50 years Hyperplasia > 50 years Normal

AChR (50%)

*

Normal

AChR AChR Titin Ryanodine AChR Titin, ryanodine MuSK

30-50 years

Unknown

LRP4

Variable

Hyperplasia in some

Abs against clustered AChR, agrin, or cortactin in some cases

M:F = 1:3 M>F Anti-titin, ryanodine antibodies associated with severe disease May be associated with other paraneoplastic disorders Marked female predominance; selective oropharyngeal, facial, respiratory weakness in some; IgG4 antibodies Response to therapy similar to AChR MG; IgG1 antibodies *; presumed unidentified Abs in those without low-affinity AChR Abs; agrin antibodies. See text.

Thymoma

>40 years (usually)

Neoplasia

MuSK

< 40 years

LRP4 Seronegative (generalized)

*Low-affinity AChR Abs have been reported in some patients. Abs, antibodies; AChR, acetylcholine receptor; IgG, immunoglobulin G; LRP4, lipoprotein receptor-related protein 4; MG, myasthenia gravis; MuSK. muscle-specific tyrosine kinase.

Fig. 108.4 Localization of immunoglobulin G (IgG) at an endplate in acquired myasthenia gravis. IgG deposits have a patchy distribution, occurring on some junctional folds but not on others and on debris in the synaptic space (arrow). In one region there is degeneration of junctional folds (*). (From Engel, A.G., Lambert, E.H., Howard, F.M., 1977a. Immune complexes (IgG and C3) at the motor endplate in myasthenia gravis: ultrastructural and light microscopic localization and electrophysiologic correlation. Mayo Clinic Proc. 52, 267–280, figure 6, by permission.)

loss of functional AChR. This leads to NMT failure and muscle weakness. MG is a paradigm for an antibody-mediated disease: the physiological abnormality is passively transferrable by injection of MG immunoglobulin G (IgG) into mice, and clinical improvement follows removal of circulating antibodies by plasma exchange (PLEX; see Treatment of Myasthenia Gravis section later in this chapter). Approximately 10% of MG patients (up to 50% of anti-AChR negative, generalized myasthenia gravis [GMG] patients) have circulating antibodies to MuSK, a surface membrane component essential in the development of the NMJ (see Table 108.1). These anti-MuSK antibodies, which are predominantly IgG4 and do not fix complement, adversely affect the maintenance of AChR clustering at the muscle endplate, leading to reduced numbers of functional AChRs (McConville et al., 2004; Niks et al., 2008a). The precise pathophysiology of the weakness and prominent muscle atrophy in MuSK-antibody myasthenia gravis (MuSK MG) is unknown. Muscle biopsy studies have shown little AChR loss, but no detailed studies of NMT in the most affected muscles are available. The events leading to autosensitization to MuSK are unknown contradicts a statement on next page. F ECF

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Fig. 108.5 Ultrastructural localization of acetylcholine receptor (AChR) at the muscle endplate in a control subject (A) and in a patient with generalized myasthenia gravis (B). The AChR staining seen in A (arrowheads) is virtually absent in B, in which only short segments of simplified postsynaptic membrane react. (From Engel, A.G., Lindstrom, J.M., Lambert, E.H., Lennon, V.A., 1977b. Ultrastructural localization of the acetylcholine receptor in myasthenia gravis and its experimental autoimmune model. Neurology 27, 307–315, figure 3A/B, by permission.)

Patients with no identifiable antibodies by these conventional assays have been termed “double-seronegative” patients. These patients may improve with conventional immunosuppressive (IS) treatments, PLEX, or even thymectomy. Recent discoveries have begun to clarify the immunopathology of these previously double-seronegative MG patients as additional autoantibodies targeting NMJ proteins have been identified. Low-affinity IgG antibodies have been found in about two-thirds of MG patients who were seronegative using conventional anti-AChR and anti-MuSK antibody assays (Leite et al., 2008). These antibodies bind to AChRs that have been clustered into high-density arrays, suggesting that they have relatively low affinity and cannot bind strongly to AChR in solution but do bind to immobilized AChRs in a native conformation. Antibodies against the proteoglycan agrin, which is released from motor neurons and binds to low-density lipoprotein receptor-related protein 4 (LRP4), have been detected in some MG patients though the clinical significance is unclear (Zhang et al.,

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2014). In addition, some MuSK MG patients and 3%–54% of double-seronegative patients have IgG1 LRP4 antibodies that appear to be pathogenic (Higuchi et al., 2011; Pevzner et al., 2011; Shen et al., 2013). Additional antibodies against titin (Cordts et al., 2017; Nagappa et al., 2019), cortactin (Cortes-Vicente et al., 2016; Gallardo et al., 2014), ryanodine receptor (Nagappa et al., 2019), and agrin (Yan et al., 2018) have been reported in variable percentages of patients, but more work is needed to clarify the role of these autoantibodies in nonthymomatous MG, particularly those against intracellular proteins that are less likely to be directly related to disease pathogenesis. T lymphocytes play a pivotal role in the initiation and maintenance of the autoimmune response against the AChR and MuSK proteins. However, the precise mechanism by which this response initiates and is maintained is incompletely understood. Activation of T cells through the T-cell receptor by major histocompatibility complex (MHC) class molecules bound with antigenic peptide ultimately leads to B-cell activation, class switching, clonal expansion, and production of autoantibodies by plasma cells. Potentially autoreactive T cells are normally controlled by a variety of immune regulatory mechanisms, including regulatory T cells, which are likely deficient or dysfunctional in MG. Accumulating research highlights the extensive dysfunction in T- and B-cell activity that contributes to MG pathogenesis (Mantegazza R, 2018; Yi et al., 2017).

The Thymus in Myasthenia Gravis The thymus is abnormal in most MG patients—70% have lymphoid follicular hyperplasia and more than 10% have a thymoma. Hyperplastic thymus glands from MG patients contain all the components necessary for the development of an immune response to the AChR: T cells, B cells, and plasma cells, as well as muscle-like myoid cells that express AChR. It is unlikely that the cellular alterations in the thymus are secondary to an ongoing peripheral immune response because they are absent in experimental autoimmune MG (Hohlfeld et al., 2008). In addition, thymocytes in culture spontaneously generate anti-AChR antibodies. These findings support the concept of an intrathymic pathogenesis and argue that the hyperplastic thymus is involved in the initiation of the anti-AChR immune response in patients with thymic hyperplasia. Thymic-derived AChR subunits may serve as an antigen for the autosensitization against the AChR. Expression of MuSK on human thymic myoid cells has also been reported, suggesting that the thymus may also play a role in development of MuSK MG (MesnardRouiller et al., 2004). Neoplastic epithelial cells in thymomas express numerous self-like antigens, including AChR, titin- and ryanodine receptor-like epitopes. MG-associated thymomas are also rich in autoreactive T cells. The regulation of potentially autoreactive T cells may be impaired in thymoma due to a deficiency in the expression of the autoimmune regulator gene (AIRE), and selective loss of T regulatory cells in human thymomas (Aricha et al., 2011; Scarpino et al., 2007; Strobel et al., 2004).

Myasthenia Gravis Subtypes A number of MG subtypes (see Table 108.1) can be identified based on clinical manifestations, age at onset, autoantibody profile, and thymic pathology (Gilhus et al., 2015). These subtypes appear to have unique genetic associations, strengthening the concept of distinct clinical entities and disease mechanisms.

Ocular Myasthenia Gravis Ptosis and/or diplopia are the initial symptoms of MG in up to 85% of patients (Grob et al., 2008), and almost all patients have both symptoms within 2 years of disease onset. Myasthenic weakness that remains limited to the ocular muscles is termed ocular myasthenia

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gravis (OMG), and comprises approximately 10%–15% of all MG in Caucasian populations. If weakness remains limited to the ocular muscles after 2 years, there is a 90% likelihood that the disease will not generalize. OMG is more common in Asian populations (up to 58% of all MG patients; Zhang et al., 2007). Confirmation of the diagnosis of OMG may be a challenge as RNS studies and anti-AChR antibodies are often negative, and single-fiber electromyography (SFEMG) testing may be required.

Generalized Myasthenia Gravis Patients with GMG may be either early-onset (EOMG) or late-onset disease (LOMG), with the cutoff age usually defined as age 50 (see Table 108.1). EOMG patients are more often female, and typically have anti-AChR antibodies and enlarged hyperplastic thymus glands. LOMG patients are more often male and may have antibodies to striated muscle proteins such as titin and the ryanodine receptor in addition to anti-AChR antibodies. The presence of these anti-muscle antibodies, particularly anti-ryanodine receptor antibodies, has been associated with more severe, generalized, or predominantly oropharyngeal weakness, and frequent myasthenic crises (Romi et al., 2005a). LOMG patients without thymoma usually have a normal or atrophic thymus, but relatively few histological studies are available in this age group, as thymectomy has not traditionally been performed after age 50.

Thymomatous Myasthenia Gravis About 10%–15% of MG patients have a thymic epithelial tumor, or thymoma. Thymoma-associated MG is equally frequent in males and females and may occur at any age, with peak onset at age 50. Patients with thymomatous MG are more likely to have detectable striated muscle (e.g., titin, ryanodine receptor) antibodies.

MuSK-Antibody Myasthenia Gravis Antibodies to MuSK have been reported in up to 50% of patients with GMG who lack acetylcholine receptor antibodies (AChR-abs) (Guptill et al., 2010a) and have been rarely reported in OMG as well (Bau et al., 2006; Caress et al., 2005). The reported incidence of MuSK MG varies among geographic regions, the highest being closer to the equator and the lowest closer to the poles (Vincent et al., 2006). Genetic or environmental factors, or both, presumably play a role in these differences. MuSK MG predominantly affects females and may begin from childhood through middle age. In some patients, the clinical findings are indistinguishable from MuSK-negative MG, with fluctuating ocular, bulbar and limb weakness. However, many MuSK MG patients have predominant weakness in cranial and bulbar muscles, frequently with marked atrophy of these muscles (Fig. 108.6). Others have prominent neck, shoulder, and respiratory weakness, with little or no involvement of ocular or bulbar muscles. Electrodiagnostic abnormalities may not be as widespread as in other forms of MG and it may be necessary to examine different muscles to demonstrate abnormal NMT (Stickler et al., 2005). It is not uncommon for MuSK MG patients with proximal limb weakness and atrophy to be initially diagnosed with a myopathy, in part due to the distribution of weakness, but also as a result of needle EMG findings that are interpreted as myopathic. The more restricted distribution of physiological abnormalities also may limit the interpretation of microphysiological and histological studies in MuSK MG, inasmuch as the muscles usually biopsied for these studies may be normal. Many MuSK MG patients do not improve with cholinesterase inhibitors (ChEIs)—some actually become worse, and many have profuse fasciculations with these medications (Hatanaka et al., 2005; Punga et al., 2006, 2008; Sanders et al., 2016). Disease severity tends to be

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HLA-DR14-DQ5 (Niks et al., 2006). Different HLA associations have been reported in Asian MG patients, including an association of OMG with HLA-BW46DR9 in Chinese patients (Chen et al., 1993). NonHLA genes (PTPN22, FCGR2, CHRNA 1, CTLA4, TNFRSF11A) have also been found to be associated with MG—some are also associated with other autoimmune diseases, and thus may represent a nonspecific susceptibility to autoimmunity (Avidan et al., 2014; Klein et al., 2013; Renton et al., 2015). An exception to this is the CHRNA1 gene, which encodes the alpha subunit of the AChR and may provide pathogenetic clues specific for MG (Giraud et al., 2008) A genome-wide association study (GWAS) in European EOMG patients also found an association between PTPN22 and TNFAIP3-interacting protein 1 (TNIP1) (Gregersen et al., 2012).

Diagnostic Procedures in Myasthenia Gravis

Fig. 108.6 MuSK antibody-positive myasthenia gravis with marked upper facial muscle weakness and atrophy. At rest (upper left), there is slight bilateral lid ptosis. There is no visible (or palpable) contraction of the frontalis muscle on attempted elevation of the eyebrows (upper right) and she does not bury the eyelashes during forced eyelid closure (lower left). The tongue is markedly wasted (lower right.) (From Sanders, D.B., Massey, J.M. 2008. In Engel AG et al., Handbook of Clinical Neurology, Elsevier, figure 16, by permission.)

worse, but most improve dramatically with therapeutic PLEX or corticosteroids (Sanders et al., 2003). More immunosuppression is typically necessary, though long-term outcome is generally good (Guptill et al., 2010a). Thymic changes are absent or minimal (Lauriola et al., 2005; Vincent et al., 2005) and the role of thymectomy in MuSK MG is not yet clear (Guptill et al., 2010a; Sanders et al., 2003, 2016). Retrospective studies overwhelmingly support the benefit of rituximab (RTX) in MuSK MG (Hehir et al., 2017; Illa et al., 2008; Sanders et al., 2016). The diagnosis of MuSK MG may be elusive when the clinical features, electrodiagnostic findings, and response to ChEIs differ from typical MG.

Seronegative Myasthenia Gravis MG patients who lack both anti-AChR and anti-MuSK antibodies (“double-seronegative MG”) are clinically heterogeneous. The true frequency of “seronegative MG” may be quite low as patients may have antibodies against novel muscle antigens or low-affinity antiAChR antibodies that can only be detected using specialized assays (See Immunopathology of Myasthenia Gravis, above). The possibility of a rare adult onset congenital myasthenic syndrome must be considered, especially if there is no benefit from immunomodulatory therapy. Autoimmune seronegative MG patients are typically managed similarly to MG patients with AChR antibodies.

Genetics of Myasthenia Gravis The transmission of MG is not by classic Mendelian inheritance, but family members of patients are approximately 100 times more likely to develop the disease than is the general population (Pirskanen, 1977). In addition, 33%–45% of asymptomatic first-degree family members show jitter on SFEMG testing and anti-AChR antibodies are slightly elevated in up to 50%. These observations suggest that there is a genetically determined predisposition to develop MG. Several correlations exist between MG and the human leukocyte antigen (HLA) genes. Certain HLA types (-DR2, -DR3, -B8, -DR1) predispose to MG (see Table 108.1), whereas others may offer resistance to disease. HLA-B8-DR2 and -DR3 types occur more commonly in patients with EOMG, HLA-B7 and -DR2 in LOMG, and HLA-DR1 in OMG (see Table 108.1). MuSK MG is associated with F ECF

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The diagnosis of acquired MG is determined by demonstrating muscle weakness and one or more of the following: Elevated AChR or MuSK antibodies ter (without nerve or muscle disease sufficient to produce a decrement or increased jitter) In patients with childhood onset, congenital myasthenic syndromes (CMS) must be excluded (See Childhood Myasthenia Gravis section, below)

Edrophonium Chloride Test Edrophonium and other ChEIs impede the enzymatic breakdown of ACh by inhibiting the action of acetylcholinesterase (AChE), thus allowing ACh to diffuse more widely throughout the synaptic cleft and to have a more prolonged interaction with AChR on the postsynaptic muscle membrane. Weakness from abnormal NMT characteristically improves after administration of ChEIs; this is the basis of the diagnostic edrophonium test, which may be helpful in seronegative patients and when electrodiagnostic studies are unrevealing or unavailable. The edrophonium test is reported to be positive in 60%–95% of patients with OMG and in 72%–95% with GMG (Pascuzzi, 2003) (Video 108.4). The edrophonium test has lost favor as a diagnostic tool due to the widespread availability of autoantibody testing and it is increasingly difficult to obtain edrophonium worldwide. Details of the performance of the edrophonium test can be found in the article by Pascuzzi (2003).

Autoantibodies in Myasthenia Gravis Acetylcholine receptor antibodies. Assays measuring antibodies that react with AChR proteins are generally regarded as specific serological markers for MG. The most widely used test for MG is the AChR-ab binding assay, which tests serum for binding to purified AChR from human skeletal muscle labeled with radioiodinated α-bungarotoxin. The reported sensitivity of this assay is approximately 85% for GMG and 50% for OMG (Stålberg et al., 2010). Nearly all thymomatous MG patients have elevated AChR-abs. Finding elevated AChR-abs in a patient with compatible clinical features essentially confirms the diagnosis of MG, but absence of these antibodies does not exclude the disease. Assays for AChR-abs may be normal at symptom onset and become abnormal later in the disease; thus, repeat testing is appropriate when values obtained within 6–12 months of symptom onset were normal. AChR-ab levels tend to be lower in patients with ocular or mild generalized MG but these values vary widely among patients with similar degrees of weakness, and do not predict the severity of disease in individual patients. The AChR-ab level is not a consistent marker of overall response to therapy, and may actually rise in some patients as their symptoms improve. Although antibody levels fall in most patients after

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CHAPTER 108 Disorders of Neuromuscular Transmission Video 108.1 Ocular examination in myasthenia gravis. https:// www.kollaborate.tv/player?id=855644 Video 108.2 Pseudo-INO in myasthenia gravis. https://www.kollaborate.tv/player?id=855640 Video 108.3 “Curtain sign” https://www.kollaborate.tv/player?id =855641

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Video 108.4 Edrophonium test. https://www.kollaborate.tv/ player?id=855642 Video 108.5 Triple timed up-and-go test in Lambert-Eaton myasthenia. https://www.kollaborate.tv/player?id=855643

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IS treatment, they also fall in patients who do not improve (Sanders et al., 2014). However, if the AChR-ab level does not fall after immunotherapy, this may indicate inadequate therapy. False-positive AChR-ab tests are rare, but have been reported in autoimmune liver disease, systemic lupus, inflammatory neuropathies, amyotrophic lateral sclerosis, penicillamine-treated patients with rheumatoid arthritis, patients with thymoma but without MG, and in first-degree relatives of patients with acquired autoimmune MG. Another assay for AChR-abs measures inhibition of binding of radiolabeled α-bungarotoxin to the AChR. This technique measures antibody directed against the ACh binding site on the α-subunit of the AChR. In most patients, relatively few of the circulating antibodies recognize this site, resulting in a lower sensitivity for this assay. These blocking antibodies occur in less than 1% of MG patients who do not have measurable binding antibodies and thus have limited diagnostic value. AChR-abs cross link the AChR in the membrane and increase their rate of degradation. The AChR modulating antibody assay measures the rate of loss of labeled AChR from cultured human myotubes. About 10% of MG patients who do not have elevated binding antibodies have AChR modulating antibodies. Many patients with thymomatous MG have high levels of AChR modulating antibodies (Vernino et al., 2004). Antistriational muscle antibodies. Antistriational muscle antibodies (StrAbs), which react with contractile elements of skeletal muscle, were the first autoantibodies discovered in MG. These antibodies recognize muscle cytoplasmic proteins (titin, myosin, actin, and ryanodine receptors), and are found in 75%–85% of patients with thymomatous MG. StrAbs are not pathogenic and are also found in one-third of patients with thymoma who do not have MG and in one-third of MG patients without thymoma. They are more frequent in older MG patients and in those with more severe disease, suggesting that disease severity is related to a more vigorous humoral response against multiple muscle antigens (Romi et al., 2005b). StrAbs are only rarely elevated in MG in the absence of AChR antibodies and are therefore of limited use in confirming the diagnosis. The main clinical value of StrAbs is in predicting thymoma: 60% of patients with EOMG who have elevated StrAbs have thymoma and the combination of elevated AChR binding-abs and StrAbs has a 50% positive predictive value for thymoma in EOMG (DeCroos et al., 2013). Titin and other StrAbs are detectable in up to 50% of elderly patients with non-thymomatous MG, so these antibodies are less helpful as predictors of thymoma in patients over 60. StrAbs are also found in autoimmune liver disease, infrequently in Lambert-Eaton myasthenia (LEM), and in primary lung cancer. Anti-MuSK antibodies. Antibodies to MuSK are present in up to 50% of GMG patients who are seronegative for AChR-abs and in some patients with OMG (See MuSK-Antibody Myasthenia Gravis section, above). Anti-LRP4 antibodies. LRP4 antibodies are found in up to 5% of MG patients overall, and it up to one-third of those without AChR and MuSK antibodies (Gilhus et al., 2016). Patients with anti-LRP4 antibodies are predominantly women, usually have early-onset disease, and typically have mild ocular or generalized disease at symptom onset (Zisimopoulou et al., 2014). An exception appears to be the rare double-positive AChR/LRP4-MG and MuSK/LRP4-MG patients, who often have more severe symptoms than single-antibody-positive MG patients. About a third of LRP4 antibody MG patients have thymic hyperplasia, but not thymoma. LRP4 antibodies are predominantly of the complement-activating IgG1 and IgG2 subtypes. The clinical response of LRP4-MG patients to typical MG treatments is similar to

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patients with AChR MG. LRP4 antibodies are not specific for MG, but are also found in patients with other autoimmune disorders (Zhang et al., 2012) and in up to 23% of patients with ALS (Tzartos et al., 2014).

Electrodiagnostic Testing in Myasthenia Gravis RNS is the most commonly used electrophysiological test of NMT. Although a seemingly simple test, careful attention to proper technique is important to avoid technical errors. At low rates of stimulation (2–5 Hz) RNS depletes the store of readily releasable ACh at diseased motor endplates, causing failure of NMT. Characteristically in MG, there is a decrementing response of at least 10% to trains of 2–3 Hz stimulation (see Chapter 36). This may be present at baseline or after a period of exercise (post-activation exhaustion). RNS is reportedly abnormal in 53%–89% of patients with generalized MG and in 48%–67% of those with OMG (Bou Ali et al., 2016). RNS is more likely to be abnormal in a proximal or facial muscle and in clinically weak muscles. For maximal diagnostic yield, test several muscles, particularly those that are weak. If RNS is normal and there is a high suspicion for a NMJ disorder, jitter testing of at least one symptomatic muscle is recommended. Jitter measurement (see Chapter 36) is the most sensitive clinical test of NMT and shows increased jitter in some muscles in almost all MG patients (Sanders et al., 2019; Stålberg et al., 2010). Jitter is greatest in weak muscles but is usually abnormal even in muscles with normal strength. Sixty percent of patients with OMG show increased jitter in a limb muscle, but this does not predict the subsequent development of generalized myasthenia. In the rare patient who has weakness restricted to a few limb muscles, jitter may be abnormal only in weak muscles. This is particularly true in some patients with MuSK MG (Stickler et al., 2005) (see MuSKAntibody Myasthenia Gravis section, above). Increased jitter is a nonspecific sign of abnormal NMT and can be seen in other motor unit diseases. Therefore, when jitter is increased, perform other electrodiagnostic tests to exclude neuronopathy, neuropathy, and myopathy. Normal jitter in a weak muscle excludes abnormal NMT as the cause of weakness. Jitter is now measured with concentric needle electrodes (CNEs) in most institutions because of restrictions on the re-use of sterilized material, such as SFEMG electrodes (Stålberg et al., 2009). When jitter is measured with CNE, use electrodes with the smallest recording surface, take care to minimize signal artifacts, and use reference values specific for these electrodes (Sanders, 2013; Stålberg et al., 2016, 2017).

Ocular Cooling Myasthenic weakness typically improves with muscle cooling. This is the basis of the “ice-pack” test, in which cooling of a ptotic lid improves lid elevation (Fig. 108.7). Assess improvement in ptosis after placing an ice pack over the ptotic eyelid, usually for 2 minutes. A meta-analysis of six studies showed this test to have high sensitivity and specificity in MG, suggesting that it may be useful in patients with lid ptosis (Larner, 2004). The test may also be positive in other NMJ disorders (Alaraj et al., 2013), but a negative ice-pack test in a ptotic lid makes MG unlikely (Fakiri et al., 2013).

Comparison of Diagnostic Techniques in Myasthenia Gravis Plan diagnostic testing based on the clinical presentation and distribution of weakness. The presence of AChR or anti-MuSK antibodies virtually ensures the diagnosis of MG, but their absence does not exclude it. RNS confirms impaired NMT but is frequently normal in mild or purely ocular disease. Almost all patients with MG have increased jitter, and normal jitter in a weak muscle excludes MG as the cause of

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A

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Fig. 108.7 Ice-Pack Test In Myasthenia Gravis. Before testing (A) there is ptosis of both upper lids, more marked on the left. An ice pack is placed over the ptotic eye for 2 minutes (B). Upon removal of the ice pack, the ptosis is improved (C) and gradually returns (D).

the weakness. Neither electrodiagnostic test is specific for MG because increased jitter, even abnormal RNS, occurs in other motor unit disorders that impair NMT.

Other Diagnostic Procedures in Myasthenia Gravis Patients diagnosed with MG should have thyroid function tests and a chest imaging study (computed tomography [CT] or magnetic resonance imaging [MRI]) to assess for a possible thymoma. Thymoma is exceptionally rare in seronegative MG, but has been reported (Maggi et al., 2014; Rigamonti et al., 2014). Tuberculosis testing, either a TB skin test or QuantiFERON®-TB Gold Test, and testing for chronic viral infections (e.g., hepatitis C) should be considered if the use of immunosuppression is contemplated.

Treatment of Myasthenia Gravis The outlook for patients with MG has improved dramatically in the past 50 years, largely due to advances in intensive care medicine and the use of immunomodulating agents. In 2016, a Task Force of the MG Foundation of America published guidance statements for treating autoimmune MG based on consensus of expert opinion of an international panel of physicians experienced in the treatment of MG (Sanders et al., 2016). In addition to presenting guidance for the use of treatments for specific clinical situations, the Task Force defined the following goal of MG treatment: the patient has no symptoms or functional limitations from MG, with no more than mild side effects that require no intervention. A number of therapeutic options are available (Table 108.2), but treatment must be individualized according to the extent (ocular vs. generalized) and severity (mild to severe) of disease, and the presence or absence of concomitant disease (including, but not limited to, other autoimmune diseases and thymoma). Treatment decisions for individual patients are determined by the predicted course of disease and the predicted response to specific treatments. Successful treatment of MG requires close medical supervision and long-term follow-up. Consider the return of weakness after a period of improvement as a herald of further progression, requiring reassessment of current treatment and evaluation for underlying systemic disease or thymoma.

Symptom Management: Cholinesterase Inhibitors Pyridostigmine bromide is the most commonly used ChEI and should be part of the initial treatment in most patients with MG. The initial

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oral dose in adults is 30–60 mg every 4–8 hours (see Table 108.2). In infants and children, the initial oral dose of pyridostigmine is 1 mg/kg. Pyridostigmine is available as syrup (60 mg/5 mL) for children or for nasogastric tube administration in patients with impaired swallowing. A timed-release tablet of pyridostigmine (180 mg) is useful as a bedtime dose for patients who are too weak to swallow in the morning. Its absorption is erratic, however, leading to possible over dosage and underdosage. No fixed dosage schedule suits all patients and the dose should be adjusted to produce an optimal response in muscles causing the greatest disability. Patients with oropharyngeal weakness may require doses timed to provide optimal strength during meals. To avoid overdosage, aim for a dose that provides definite improvement in the most important muscle groups within 30–45 minutes and which wears off to some degree before the next dose. The ability to reduce or discontinue pyridostigmine can be an indicator that the patient has met treatment goals, and may guide the tapering of other therapies. Adverse effects of ChEIs result from ACh accumulation at muscarinic receptors on smooth muscle and autonomic glands and at the nicotinic receptors of skeletal muscle. Central nervous system side effects are rare with the doses used to treat MG. Common gastrointestinal complaints are queasiness, nausea, vomiting, abdominal cramps, loose stools, and diarrhea. Increased bronchial and oral secretions may be a serious problem in patients with swallowing or respiratory insufficiency. These muscarinic symptoms of overdosage may indicate that nicotinic overdose (weakness) is also occurring. Drugs that can be used to suppress the gastrointestinal side effects include glycopyrrolate, hyoscyamine sulfate, propantheline bromide, diphenoxylate hydrochloride with atropine, and loperamide hydrochloride (see Table 108.2). Be aware that some of these drugs themselves produce weakness at high dosages. Patients with MuSK MG may become worse with ChEIs (see MuSK-Antibody Myasthenia Gravis section, above). In two small studies, amifampridine produced improvement in some patients with acquired MG (Lundh et al., 1985; Sanders et al., 1993). Preliminary studies suggest that amifampridine may be effective symptomatic treatment in patients with MuSK MG (Bonanno et al., 2018), and more definitive clinical trials are in progress.

Short-Term (Rapid-Onset) Immune Therapies Plasma exchange. PLEX temporarily reduces the levels of circulating antibodies, and produces improvement in a matter of days in most patients with acquired MG. It is generally used for shortterm treatment of severe MG, myasthenic crisis, in preparation for surgery (e.g., thymectomy), or to prevent corticosteroid-induced exacerbations. A typical course of PLEX consists of 5–6 exchanges administered every other day; 2–3 liters of plasma are removed with each exchange. The total number of exchanges depends upon the clinical response and tolerability, but more than 6 exchanges may be required in some patients. Benefit from a course of PLEX typically begins to wear off after 4 weeks but may persist for as long as 3 months. Longer-lasting immune therapy maintains control of symptoms thereafter. Most patients who respond to the initial course respond again to subsequent courses. Repeated exchanges do not have a cumulative benefit and we do not use PLEX as chronic maintenance therapy unless other treatments fail or are contraindicated. Side effects during PLEX include paresthesias from citrateinduced hypocalcemia, hypotension, transitory cardiac arrhythmias, nausea, lightheadedness, chills, and pedal edema. The most serious complications relate to the use of large-bore venous access. The risks

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Therapeutic Agents Used in Myasthenia Gravis Onset of Action

Major Adverse Events

Agent

Initial Dose

Maintenance Dose

Pyridostigmine

30–60 mg tid

60–120 mg tid to 5x/ 15–30 minutes day, adjusted based on symptoms, typically not to exceed 480 mg/day

Prednisone

Hypertension, diabeOption 1: 10–20 mg/ Slow alternate day taper 2–4 weeks tes, weight gain, day, increasing daily after treatment goal bone loss, cataracts, achieved for several dose by 5 mg daily GI ulcers, glaucoma, days (see text for equivalent every neuropsychiatric details). Taper more week until treatsymptoms, growth slowly once ≤10 mg/ ment goal achieved retardation in day dose equivalent. Option 2: Start at children, hypothaContinuing a low dose 50–80 mg/day; lamic–pituitary axis long-term can help to this approach may suppression maintain the treatment require inpatient goal hospitalization (see text for details) 50 mg/day Increase by 50 mg incre- 2–10 months for Fever, abdominal pain, CBC, LFTs 1–4 times ments every 1–2 weeks initial response. nausea, vomiting, in first month, then to target of 2.5–3 mg/ Up to 24 months anorexia, leukopenia, monthly to every kg/day for maximum hepatotoxicity, skin third month. benefit rash Regular dermatological examinations if taken chronically

Azathioprine

Cyclosporine

100 mg bid

Increase slowly as needed to 3–6 mg/kg/ day on bid schedule.

1–3 months

Mycophenolate mofetil

500 mg bid

1000 to 1500 mg bid

2–12 months

Cyclophosphamide

(1) Oral: 50 mg/day (2) IV: 500 mg/m2 monthly

Oral: increase by 50 mg/ 2–6 months week to maintenance dose of 2–3 mg/kg/day

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Monitoring

Stomach cramps, nausea, vomiting, diarrhea, muscle twitching and cramps, sweating, salivation, blurred vision

Comments

Can counter muscaUse the minimal rinic adverse events amount that with anticholinergic produces clinical agents (i.e. glycopyrimprovement; this rolate, hyoscyamine is best achieved by sulfate, propantheline, using a dose that produces observable diphenoxylate HCl with atropine, or improvement after loperamide most administrations HbA1c every few Administer in single morning dose; months, blood temporary worsening pressure checks, is seen in up to 50% bone density monof patients, starting itoring, eye exam on high doses and for glaucoma and in some patients on cataracts lower doses; IVIg or PLEX may prevent steroid-induced worsening

10% of patients cannot tolerate because of flu-like reaction; major drug interaction with allopurinol; TPMT enzyme testing can be performed, if available, prior to starting treatment to identify patients at high risk of bone marrow suppression Bioequivalence differs CBC, LFTs, BUN/Cr Hirsuitism, tremor, between preparations, monthly x3, then gum hyperplasia, every 3 months; so avoid brand switchhypertension, ing when possible; monitor trough drug hepatotoxicity, nephgrapefruit juice may rotoxicity, PRES levels increase blood level; high potential for drug–drug interactions Diarrhea may resolve by Diarrhea, vomiting, CBC weekly for 4 change to tid dosing weeks, every 2 leukopenia, teratoweeks for 4 weeks, genicity (black box warning) then monthly to every 3rd month; REMS program when used in women of childbearing age IV pulse therapy may Alopecia, leukopenia, CBC, BUN/Cr, be less toxic because nausea and vomiting, electrolytes, LFTs, urinalysis every 2–4 cumulative dose is skin discoloration, weeks lower anorexia hemorrhagic cystitis, malignancy

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TABLE 108.2 Agent

1967

Therapeutic Agents Used in Myasthenia Gravis—cont’d

Initial Dose

Maintenance Dose

Tacrolimus

3–5 mg/day or 0.1 mg/kg/day

Methotrexate

5–15 mg weekly for 2 Increase by 5 mg every 2 weeks weeks to a maximum dose of 15–25 mg weekly

Intravenous 2 g/kg over 2-5 days immunoglobulin (IVIg)

Onset of Action

Increase dosing as 1–3 months needed for response following trough levels (see last column)

0.4–1 g/kg every 4 weeks; can attempt to decrease frequency over time

2–6 months

1–2 weeks

Major Adverse Events

Monitoring

Comments K+;

BUN/Cr, glucose, trough drug levels every few weeks initially, then less frequently

Insulin-dependent diabetes mellitus developed in 20% of postrenal transplant patients; trough levels of 8–9 ng/ml may be effective CBC, LFTs monthly ini- Consider folic acid Leukopenia, mouth 5 mg/day to reduce tially, then at least ulceration, nausea, toxicity. Absolutely every 3 months. diarrhea, headcontraindicated in Monitor periodically aches, hair loss, pregnancy for interstitial lung hepatotoxicity, disease, a rare pulmonary fibrosis, occurrence with rare nephrotoxicity, doses used for teratogenicity immunotherapy BUN/Cr every month, IgA level prior to starting Headache, asepdecreasing to every treatment may be tic meningitis, 3rd month over time useful to identify connephrotoxicity, genital IgA deficiency, ischemic events, fluid a contraindication overload, leukopenia, to IVIg use; avoid in thrombocytopenia patients with recent thrombotic/ischemic event. Use sucrosefree formulation for patients at risk of renal toxicity

Hyperglycemia, hypertension, headache, hyperkalemia, nephrotoxicity, diarrhea, nausea, vomiting, PRES

From Sanders DB, Wolfe GI, Benatar M, Evoli A, Gilhus NE, Illa I, et al. International consensus guidance for the management of myasthenia gravis: Executive summary. Neurology. 2016;87:419–25.

of subclavian lines, arteriovenous shunts or grafts for access include thromboses, thrombophlebitis, subacute bacterial endocarditis, as well as pneumothorax. These complications are minimized by using peripheral venous access (Guptill et al., 2013). More selective removal of circulating immunoglobulins, including anti-AChR antibodies, may be accomplished using high-affinity immunoadsorption columns (Schneider-Gold et al., 2016). These columns selectively remove immunoglobulins from separated plasma, and, unlike PLEX, patients may not need replacement fresh frozen plasma or albumin. Use of immunoadsorption to treat MG is generally limited to selected regions of the world. Intravenous immunoglobulin. Intravenous immunoglobulin (IVIg) induces rapid improvement in patients with severe disease or crisis and reduces perioperative morbidity prior to surgery. Improvement is seen in 50%–100% of MG patients after infusion of a typical course of 2 g/kg, administered over 2–5 days (see Table 108.2); improvement usually begins within 1 week and lasts for several weeks or months. Class I evidence supports the use of IVIg to treat patients with refractory exacerbations of MG (Donofrio et al., 2009). In a randomized controlled trial (RCT) of MG patients with worsening weakness, IVIg induced rapid improvement in strength; this effect was more pronounced and likely more clinically significant in patients with moderate to severe disease (Zinman et al., 2007). IVIg is also used chronically in selected refractory patients, but there is little information on the optimal dosing and duration of chronic therapy.

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IVIg may be particularly useful as an alternative to PLEX in children with limited vascular access. Although IVIg has demonstrated similar efficacy to PLEX in the treatment of MG exacerbations, it is unclear if it is as effective in MG crisis since the published comparison studies did not enroll enough patients in crisis and did not directly compare onset of improvement (Barth et al., 2011). Common side effects of IVIg include headaches, chills, and fever, which usually improve when using slow infusion rates. Serious side effects are rare, but include renal toxicity, stroke, leukopenia, and aseptic meningitis. Lyophilized forms of IVIg may be associated with more frequent adverse events (Nadeau et al., 2010). Subcutaneous administration of concentrated immunoglobulin formulations, which reduces the overall infused volume compared with IVIg, appear to be well-tolerated and may be particularly useful for patients who live in areas where home or infusion center infusions are not practical (Beecher et al., 2017; Bourque et al., 2016; Sala et al., 2018).

Long-Term Immune Therapies A number of IS medications are used in MG. While often quite beneficial, these medications require careful attention and should be tapered to the minimum effective dose in order to reduce the risk of long-term toxicity. Currently, there are no disease-related biomarkers to guide selection of specific IS agents; treatment is typically selected based on individual patient factors such as medical comorbidities and the desired timing of the clinical response.

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Corticosteroids. Corticosteroids (or other IS therapy, see below) should be used in all MG patients who have not met treatment goals after an adequate trial of pyridostigmine (Sanders et al., 2016). Prednisone produces marked improvement or complete relief of symptoms in more than 75% of MG patients and some improvement in most of the rest. Patients with recent onset of symptoms have the best responses, but those with chronic disease also may respond. The severity of disease does not predict the ultimate improvement. Patients with thymoma usually respond well to prednisone, before or after removal of the tumor. In MG patients with generalized disease prednisone is given either as an initial high dose or an incrementing dose regimen (see Table 108.2). In the former, the initial dose is 50–80 mg/day and this is continued until sustained improvement occurs, which is usually within 2–4 weeks. Then, change to alternate day administration and taper the dose over many months to the smallest amount necessary to maintain improvement, which is ideally less than 15 mg every other day. Strength typically increases, even to remission, while the dose is being tapered. The rate of dose decrease is individualized—patients who have a rapid initial response may reduce the dose on alternate days by 20 mg each month to 60 mg every other day. If the initial response is less marked, it may be preferable to change to an alternate day dose of 100–120 mg and taper this by 20 mg each month to 60 mg every other day, then taper the dose more slowly to a target dose of 10–15 mg every other day as long as improvement persists. If weakness returns during the taper, the dose should be increased, another IS agent should be added, or both, to prevent further worsening. Discontinuing prednisone altogether almost invariably leads to return of weakness, but a very low dose (5–15 mg every other day) may be sufficient to maintain good improvement in many patients (Abuzinadah et al., 2018). Transitory worsening occurs in approximately one-third to onehalf of patients treated with high-dose daily prednisone (Pascuzzi et al., 1984). This usually begins within the first 7–10 days and lasts for several days. In mild cases, ChEIs usually manage this worsening. We recommend that patients with significant oropharyngeal or respiratory symptoms be hospitalized or receive PLEX or IVIg to minimize the steroid-induced worsening. The incrementing dose regimen favored by some begins with prednisone 20 mg/day, increasing by 10 mg every 1–2 weeks until improvement begins. The ultimate dose is maintained until improvement is maximum, and then tapered as above. Exacerbations still may occur with this regimen, but the onset of such worsening and the therapeutic response are less predictable. A similar incrementing dose regimen is commonly used in OMG (see Ocular Myasthenia, in this chapter). Prednisone is inexpensive, has a rapid onset of response, and has an established track record in MG; its use is limited by numerous and frequent side effects (Table 108.3), the severity and frequency of which increase when high doses are given for more than 1 month. Most side effects improve with dose reduction and become minimal when the dose is less than 20 mg every other day. A low-fat, low-sodium diet and exercise will minimize weight gain. Use supplemental calcium and vitamin D with bisphosphonate to counter osteopenia, particularly in postmenopausal women. Treat patients with peptic ulcer disease or symptoms of gastritis accordingly. Prednisone is contraindicated in patients with untreated tuberculosis. Prednisone given with azathioprine (AZA), cyclosporine or mycophenolate mofetil (MMF) produces more benefit than either drug alone (see next section, Immunosuppressant drugs). Immunosuppressant drugs. A nonsteroidal IS agent should be used alone when steroids are contraindicated or refused (Sanders et al., 2016). AZA is a purine antimetabolite that interferes with T- and B-cell proliferation; expert consensus and some evidence from RCTs support

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TABLE 108.3

Corticosteroids

Common Side Effects of

Side Effect

Treatment/Prevention

Weight gain/fluid retention

Low-calorie, low-fat, sodium-restricted diet; exercise Glucose intolerance Monitor blood glucose/treat Osteopenia/osteoporosis/avascular Calcium and vitamin D supplementation, necrosis bisphosphonates Hypertension Monitor/treat Cataracts/glaucoma At least yearly ophthalmological evaluation Steroid myopathy Exercise/high protein diet Peptic ulcer disease Proton pump inhibitors, H2 blockers

its use as a first-line IS agent in MG (Palace et al., 1998). AZA improves weakness in most MG patients, but benefit may not be apparent for at least 6–12 months. The initial dose is 50 mg/day, which is increased by 50 mg/day every 7 days to a total of 150–200 mg/day (2–3 mg/kg/ day). After maximum benefit has been achieved and maintained for many months, reduce the dose by 50 mg/day no more often than every 3 months to the minimal effective dose, which may be as low as 50 mg/day. Patients may respond better and more rapidly if prednisone is given concurrently. AZA allows steroid sparing during long-term therapy, which is especially beneficial in older patients (Evoli et al., 2000; Hart et al., 2007; Slesak et al., 1998). An idiosyncratic reaction, with “flu-like” symptoms, occurs within 10–14 days after starting AZA in 15%–20% of patients—this reaction requires discontinuing the drug. The use of divided doses after meals or dose reduction minimizes gastrointestinal irritation. Leukopenia and even pancytopenia can occur at any time during treatment but are not common. Liver toxicity may also occur and is heralded by elevated serum transaminase. Monitor complete blood counts and liver enzymes every week during the first month, every 1–3 months for a year, and every 3–6 months thereafter. Reduce the dose if the peripheral white blood cell (WBC) count falls below 3500 cells/mm3, then gradually increase the dose after the WBC count rises. Discontinue the drug immediately if the count falls below 1000 WBC/mm3. Also discontinue treatment if the serum transaminase level exceeds twice the upper limit of normal, and restart at lower doses after values normalize. There are rare reports of AZA-induced pancreatitis, but the cost-effectiveness of monitoring serum amylase concentrations is not established. About 80% of patients treated with AZA have an increase in erythrocyte mean corpuscular volume (MCV), which is seen more often and is greater in responders than in nonresponders. Thus, a normal MCV in a patient with an incomplete AZA response suggests a higher dose may be needed. There does not appear to be an increased risk of cancer when AZA is given for less than 10 years (Confavreux et al., 1996). Lymphoma, myelodysplastic syndromes, and serious opportunistic infections have rarely been observed in MG patients receiving AZA (Herrlinger et al., 2000; Hohlfeld et al., 1988). Data from the nephrology field indicate an increased incidence of cutaneous hyperkeratosis and skin cancer in patients taking AZA, which is attributed to the increased ultraviolet photosensitivity. Regular dermatological examinations and protection of sun-exposed areas are therefore recommended for MG patients receiving AZA chronically. Myasthenic symptoms recur if AZA is withdrawn abruptly, even up to myasthenic crisis (Hohlfeld et al., 1985; Michels et al., 1988). In 10%–20% of MG patients, satisfactory improvement is not achieved

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CHAPTER 108 Disorders of Neuromuscular Transmission with AZA in combination with corticosteroids, requiring the use of other IS agents. MMF selectively blocks purine synthesis, thereby suppressing both T- and B-cell proliferation. Pilot studies and retrospective reports indicate efficacy in MG (Hehir et al., 2010; Meriggioli et al., 2003). However, data from an RCT failed to show additional benefit of MMF over 20 mg daily prednisone as initial immunotherapy of MG (Muscle Study Group, 2008) and another RCT did not show a significant steroid-sparing effect (Sanders et al., 2008a). Despite the lack of RCT evidence supporting its use in MG, MMF is widely used as monotherapy or as a steroid-sparing agent, and is recommended in several national MG treatment guidelines (Murai, 2015; Sussman et al., 2015) and in the Consensus Guidance statement for MG treatment (Sanders et al., 2016). The usual MMF dose is 1000 mg twice daily, but doses up to 3000 mg a day have been used. In general, side effects are relatively mild and most commonly consist of diarrhea, nausea, and abdominal pain. MMF is contraindicated during pregnancy because of a high rate of malformations and spontaneous abortions (US Food and Drug Administration, 2007) and should be discontinued at least 4 months before planned pregnancies. In nonscheduled pregnancies, MMF must be discontinued immediately and sonographic examination with expert consultation initiated. Progressive multifocal leukoencephalopathy has been observed in rare heavily immunosuppressed patients receiving MMF, and isolated cases of primary CNS lymphoma and a T-cell proliferative disorder have been reported in MG patients treated with MMF (Dubal et al., 2009; Vernino et al., 2005). Cyclosporine (CYA) is a potent IS agent that binds to the cytosolic protein cyclophilin of immunocompetent lymphocytes, especially T lymphocytes. This complex of CYA and cyclophilin inhibits calcineurin, which activates transcription of interleukin-2 (IL-2). It also inhibits lymphokine production and interleukin release and leads to reduced function of effector T cells. Evidence from RCTs (Tindall et al., 1993) and retrospective reviews (Ciafaloni et al., 2000) support the use of CYA in MG, but potential serious side effects and drug interactions limit its use. We use this agent in MG only when other IS agents are contraindicated or ineffective. Tacrolimus is a calcineurin inhibitor similar to CYA that selectively inhibits the transcription of proinflammatory cytokines and IL-2 in T lymphocytes. Several RCTs suggest benefit of tacrolimus in MG (Cruz et al., 2015); it is approved for the treatment of MG in Japan and recommended in several national MG treatment guidelines (Fuhr et al., 2012; Murai, 2015; Sussman et al., 2015). Tacrolimus appears to be less nephrotoxic than CYA at doses used in published MG reports, but hyperglycemia due to inhibition of insulin is relatively common in transplant patients receiving tacrolimus. Increased potassium levels often occur and there are interactions with other drugs and food, particularly grapefruit juice. Pending further study, tacrolimus should be considered as adjunctive therapy in refractory MG, as a steroid-sparing agent in patients intolerant or unresponsive to AZA and MMF, or as an alternative to prednisone in patients with contraindications when a relatively rapid clinical response is desired. Cyclophosphamide (CP) is an alkylating cytotoxic agent that has been used after failure of standard therapy in severe, refractory GMG (de Feo et al., 2002; Drachman et al., 2003). In an RCT, patients with refractory MG had improved muscle strength and required lower steroid doses after pulsed doses of intravenous CP (500 mg/m2). There are also reports of improvement in refractory MG after a one-time, high-dose (50 mg/kg) course of CP for 4 days followed by rescue therapy. Side effects of CP are common and potentially serious, including myelosuppression, hemorrhagic cystitis, and an increased risk of

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infection and malignancy. For this reason, CP should be reserved for patients with truly refractory, severe disease, and its use should be limited to experienced centers. The cumulative dose and duration of therapy should be monitored because of the increasing risk of infertility in both sexes after age 30 and late effects, including malignancies (about 1%, increasing in frequency with increasing dose and duration of therapy). A single-blind prospective study provided class III evidence that methotrexate (MTX) is an effective steroid-sparing agent in generalized MG (Heckmann et al., 2011), but a subsequent RCT found no steroid-sparing effect over 12 months of treatment (Pasnoor et al., 2016). Despite the absence of high-quality data to support its use in MG, MTX has been used as a reserve treatment in the way it is used in rheumatoid arthritis—a dose of 5–15 mg oral/IV is administered once a week (Hilton-Jones, 2007). MTX is known to be teratogenic and cannot be used by males or females planning reproduction (HiltonJones, 2007). RTX is a chimeric monoclonal antibody directed against the B-cell surface marker CD20. Recent studies indicate that RTX should be considered as a second-line treatment in MuSK MG patients who do not improve adequately on prednisone (Cortés-Vicente et al., 2018; DiazManera et al., 2012; Guptill et al., 2010a; Iorio et al., 2015; Keung et al., 2013; Meriggioli et al., 2009)(Sanders et al., 2016). RTX may also be effective in “refractory” MG (Iorio et al., 2015; Sanders et al., 2016), but a recent RCT did not demonstrate a steroid-sparing effect of RTX in AChR MG (clinicaltrials.gov: NCT02110706). Relapses are common and may improve with repeated treatment cycles. The treatment protocol is empirical, but most patients reported receiving 4 courses of 375 mg/m2. Eculizumab is a monoclonal antibody that inhibits the cleavage of C5 into C5a and C5b, which results in blockade of terminal complement activation. Complement deposition at the NMJ is thought to play a prominent role in MG pathogenesis (Engel et al., 1987), and it is presumed that eculizumab reduces complement-mediated damage to the postsynaptic muscle membrane. In the United States, eculizumab is approved for the treatment of generalized AChR MG, and in Europe and Japan the therapy is approved only for refractory generalized AChR MG. The approval of eculizumab is based on a phase III RCT of patients with refractory AChR GMG (Howard et al., 2017). Eculizumab is not appropriate for patients with MuSK MG because complement is not thought to play a major role in the pathogenesis of MuSK MG. Eculizumab requires biweekly infusions following an induction phase. All patients must receive vaccination against Neisseria meningitis prior to treatment.

Summary In a review of 1000 MG patients who received IS agents for at least 1 year, all forms of MG benefited from immunosuppression: the rate of remission or minimal manifestations ranged from 85% in OMG to 47% in thymoma-associated disease (Sanders et al., 2010). Prednisone was used in the great majority of these patients and AZA was the firstchoice nonsteroidal immunosuppressant; MMF and CYA were used as second-choice agents. Treatment was ultimately discontinued in nearly 20% of AChR-ab positive EOMG patients, but in only 7% of patients with thymoma. The risk of complications was related to drug dosage, treatment duration, and patient characteristics, the highest rate of serious side effects (20%) occurring in LOMG and the lowest (4%) in early-onset disease. The goal of minimal manifestations or better is often obtained, but few patients maintain improvement unless IS therapy is continued at effective doses indefinitely. The long-term risk of malignancy is not established, so use the minimal maintenance dose of IS agents

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necessary to keep the MG in control. Reduce medication dosage slowly after several years of stable improvement. Avoid abrupt withdrawal of immunosuppression, as this may lead to recurrent symptoms, even myasthenic crisis (Hohlfeld et al., 1985; Witte et al., 1984). Anecdotal evidence suggests that some patients may not achieve previous levels of improvement after withdrawal and exacerbation. Opportunistic infections, lymphomas, and other serious treatment-related morbidities may occur with increasing duration of immunosuppression. Monitoring and adjustment of therapy is best done in a specialized clinic.

Thymectomy In an international single-blinded RCT of thymectomy in non-thymomatous generalized AChR MG, at the end of 3 years patients who underwent extended thymectomy while taking prednisone had lower Quantitative Myasthenia Gravis (QMG) scores and required less prednisone than those who took prednisone alone (Wolfe et al., 2016). A follow-up extension study showed that these benefits from thymectomy persisted at the end of 5 years (Wolfe et al., 2019). The response to thymectomy is gradual and often continues for months or years after surgery. Clinical experience suggests that the best responses are likely in young people, especially women, early in the disease, but improvement can occur even after many years of symptoms. In non-thymomatous MG, thymectomy is performed to potentially reduce exposure to IS agents, or if immunotherapy has been ineffective or produced intolerable side effects (Sanders et al., 2016). Thymectomy is always an elective procedure and should be performed when the patient is stable and deemed safe to undergo the procedure. Thymectomy is generally not recommended for ocular MG, but may be an option if drug therapy is inadequate (Liu et al., 2011; Mineo et al., 2013; Roberts et al., 2001; Sanders et al., 2016; Schumm et al., 1985). The preferred surgical approach has traditionally been a transthoracic, sternal-splitting procedure that allows wide exploration of the anterior mediastinum. Transcervical and endoscopic approaches have less postoperative morbidity and shorter recovery times, and large case series of video-assisted thoracoscopic thymectomy (VAT-T) report therapeutic results similar to the transsternal procedure (Masaoka et al., 1981; Meyer et al., 2009). Robotic video-assisted thorascopic thymectomy (VATS) combines the advantages of minimally invasive techniques with added maneuverability and enhanced visualization, which reportedly permits an extended thymectomy similar to that using a transsternal approach. Without a prospective study comparing different techniques, the value of different surgical approaches remains unclear. The transsternal approach is often performed in thymoma to assure complete tumor removal. Thymectomy has usually been limited to AChR MG patients, although some reports suggest that MG patients without AChR antibodies may benefit as well (Guptill et al., 2010b; Lavrnic et al., 2005; Yuan et al., 2007); one study reported a 21% complete remission rate in both AChR-antibody negative and AChR MG patients after thymectomy (Guillermo et al., 2004). In non-thymomatous MG, we recommend thymectomy in virtually all early-onset AChR MG patients, and as an option in AChR MG patients with onset between ages 50 and 60; others also recommend thymectomy for older patients. We do not base the decision to recommend thymectomy on the presence of AChR antibodies alone. The role of thymectomy in MuSK MG has not yet been determined, but the majority of evidence to date suggests it is not beneficial in most patients (Sanders et al., 2016). However, we, and others, have noted stable drug-free remission in some MuSK MG patients after thymectomy (Lavrnic et al., 2005; Ponseti et al., 2009; Witoonpanich et al., 2013). Further studies are

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needed to assess the value of thymectomy in other groups besides AChR MG. We consider repeat thymectomy when relapse follows a good response to the initial surgery or when there is concern that thymic tissue removal had been incomplete. MRI with appropriate cardiac gating may be useful in identifying residual thymus tissue, although many authors believe that the clinical suspicion should be the basis upon which repeat surgery is considered (Jaretzki, 2003). Virtually all patients with thymoma should have surgical resection regardless of age and any residual normal thymus tissue should also be resected. Elderly and multimorbid patients with small tumors may be followed with periodic imaging; palliative radiation therapy may be adequate when there is little tumor spread and slow tumor progression. Stage II and WHO type B2 and B3 and all III and IV stage tumors should have radiation therapy and be treated with an interdisciplinary approach.

Evolving Treatments Autologous stem-cell transplantation has been performed in refractory MG patients (Pringle et al., 2005), but the role of this procedure for MG and other autoimmune disorders is unclear at this time. Other therapies in clinical development for MG include anti-neonatal Fc receptor monoclonal antibodies targeting IgG recycling (clinicaltrials.gov: NCT03052751, NCT03772587, NCT02965573), additional complement inhibitors (clinicaltrials.gov: NCT03920293, NCT03315130), a vaccine for AChR MG (clinicaltrials.gov: NCT02609022), and amifampridine for treatment of MuSK MG (clinicaltrials.gov: NCT03304054).

Treatment Plan for Myasthenia Gravis Individualize the treatment of MG according to the clinical presentation/subtype; this requires a comprehensive assessment of the patient’s functional impairment and its effect on daily life. ChEIs may be sufficient in some patients with OMG or mild generalized disease (before or after thymectomy), but most will ultimately require immunotherapy. The therapeutic goal is to return the patient to normal function as rapidly as possible while minimizing side effects of therapy. In the long-term management of patients treated with immunotherapies, the lowest effective dose should always be used. As noted, long-term risks of infections and malignancy, while not clearly defined, have been associated with the immunosuppressants commonly used in MG.

Association of Myasthenia Gravis With Other Diseases MG is often associated with other immune-mediated diseases, especially hyperthyroidism and rheumatoid arthritis (Nakata et al., 2013; Ramanujam et al., 2011). Population-based studies have also shown associations with Guillain-Barré syndrome, pemphigus, and dermatomyositis (Eaton et al., 2007). Seizures occur with increased frequency in children with MG. One-fifth of our MG patients have another disease: 7% had diabetes mellitus before corticosteroid treatment, 6% have thyroid disease, 3% have an extrathymic neoplasm and fewer than 2% have rheumatoid arthritis. Extrathymic malignancies have been reported to be common in MG patients, especially in the older age group, possibly due to a common background of immune dysregulation (Levin et al., 2005).

Treatment of Associated Diseases and Medications to Avoid It is important to recognize the effect of concomitant diseases and their treatments on myasthenic symptoms. Thyroid disease requires vigorous treatment—both hypo- and hyperthyroidism adversely affect myasthenic weakness. Intercurrent infections require immediate attention because they exacerbate MG and can be life-threatening in immunosuppressed patients.

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BOX 108.2

1971

Drugs to Avoid or Use with Caution in Myasthenia Gravis*

Many drugs are associated with worsening of MG. However, reported associations do not necessarily mean these medications should never be prescribed in MG. Reports are often rare or represent a coincidental association. Clinical judgment and the risk-to-benefit ratio of the drug should be considered when it is deemed important for a patient’s treatment. Listed below are medications that have the strongest evidence for worsening MG. Telithromycin: antibiotic for community-acquired pneumonia. Not available in the US, but may be available in other countries. Should not be used in MG. Fluoroquinolones (e.g., ciprofloxacin, moxifloxacin, and levofloxacin): commonly prescribed broad-spectrum antibiotics that are associated with worsening MG. The US FDA has designated a “black box” warning for these agents in MG. Use cautiously, if at all. Botulinum toxin: avoid. D-penicillamine: used for Wilson disease and rarely for rheumatoid arthritis. Strongly associated with causing MG. Avoid. Quinine: occasionally used for leg cramps. Use prohibited except in malaria in the United States. Magnesium: potentially dangerous if given intravenously, i.e., for eclampsia during late pregnancy or for hypomagnesemia. Use only if absolutely necessary and observe for worsening. Macrolide antibiotics (e.g., erythromycin, azithromycin, clarithromycin): commonly prescribed antibiotics for gram-positive bacterial infections. May worsen MG. Use cautiously, if at all. Aminoglycoside antibiotics (e.g., gentamycin, neomycin, tobramycin): used for gram-negative bacterial infections. May worsen MG. Use cautiously if no alternative treatment available. Corticosteroids: A standard treatment for MG but may cause transient worsening within the first 2 weeks. Monitor carefully for this possibility (see Table 108.3).

Procainamide: used for irregular heart rhythm. May worsen MG. Use with caution. Desferrioxamine: Chelating agent used for hemochromatosis. May worsen MG. Beta-blockers: commonly prescribed for hypertension, heart disease, and migraine but potentially dangerous in MG. May worsen MG. Use cautiously. Statins (e.g., atorvastatin, pravastatin, rosuvastatin, simvastatin): used to reduce serum cholesterol. May worsen or precipitate MG. Use cautiously if indicated and at lowest dose needed. Iodinated radiological contrast agents: older reports document increased MG weakness, but modern contrast agents appear safer. Use cautiously and observe for worsening. Chloroquine (Aralen): used for malaria and amoeba infections. May worsen or precipitate MG. Use with caution. Hydroxychloroquine (Plaquenil): used for malaria, rheumatoid arthritis, and lupus. May worsen or precipitate MG. Use with caution. Immune checkpoint inhibitors (ICIs): used as immunotherapy for many types of cancer. May cause MG or worsen myasthenic weakness in previously existing MG. Patients with MG and cancer who are considering ICI therapy should discuss this possible side effect with their oncologist and neurologist. Doctors evaluating new-onset weakness in cancer patients should consider MG. MG patients who have worsening weakness following ICI treatment should contact their neurologist and oncologist immediately. Examples of ICIs: Pembrolizumab (Keytruda) Nivolumab (Opdivo) Atezolizumab (Tecentriq) Avelumab ((Bavencio) Durvalumab (Imfinzi) Ipilimumab (Yervoy)

* See also http://myasthenia.org/What-is-MG/MG-Management/Cautionary-Drugs FDA, Food and Drug Administration; MG, myasthenia gravis.

Use drugs that adversely affect NMT (Box 108.2) with caution. Many antibiotics fall into this category, particularly aminoglycosides, fluoroquinolones, and macrolides. Ophthalmic preparations of β-blockers and aminoglycoside antibiotics may cause worsening of ocular symptoms. When using corticosteroids to treat concomitant illness, anticipate and explain the potential adverse and beneficial effects to the patient. MG may develop in patients during interferon α-2b treatment for malignancy and chronic active hepatitis C. In some, MG has presented with myasthenic crisis. The mechanism is unknown, but the expression of interferon-γ at motor endplates of transgenic mice results in weakness and abnormal NMJ function that improve with ChEIs. This suggests an autoimmune humoral response, similar to that in human MG. The administration of botulinum toxin injections to patients with neuromuscular disease such as MG risks systemic side effects, including dysphagia and respiratory compromise. Administer only with great caution. We recommend annual vaccination against influenza (including H1N1) for most patients with MG and the recombinant shingles vaccine in older patients. Vaccination against pneumococcus is a recommendation for at-risk patients before starting prednisone or other IS drugs. Never give live attenuated vaccines to immunosuppressed patients due to the risk of viral reactivation. The Centers for Disease Control and Prevention report that those taking less than 2 mg/kg per day of prednisone or every-other-day prednisone are not at risk. Patients with prior thymectomy should not receive the yellow fever vaccine.

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Checkpoint Inhibitor-Induced Myasthenia Gravis Immune checkpoint inhibitor (ICI) drugs have revolutionized the treatment of advanced cancers. These drugs promote immune system activation to attack cancer cells by targeting CTLA-4 and PD-1 or PD-1 ligands. Neurological complications from ICIs, including MG, occur rarely and result from a loss of immune regulatory mechanisms (Pardoll, 2012). Patients may present with isolated ocular symptoms or severe MG with dysphagia and respiratory crisis (Alnahhas et al., 2016; Gonzalez et al., 2017; Kao et al., 2017). MG will often overlap with myositis and it may be difficult to distinguish between muscle and NMJ involvement on clinical grounds alone (Kimura et al., 2016; Konoeda et al., 2017). It is therefore important to perform a comprehensive evaluation, including electrodiagnostic testing and MG and myositis laboratory testing, to determine whether myositis and MG are coexisting. Biopsy of an affected muscle may also be warranted. Evidence-based treatment recommendations are lacking but we use standard MG treatments, including pyridostigmine for mild ocular symptoms, and steroids and PLEX or IVIg for severe disease. After the development of MG, if other treatment options are available or the MG disease severity was severe, avoid reinstituting an ICI. However, since many patients are receiving ICIs for advanced stage cancer with a limited life expectancy otherwise, treatment options may be limited, and restarting ICI therapy may be considered. The best candidates for restarting this class of drug may be patients with mild disease that can be controlled without aggressive interventions. Coordination with the oncology team is important at all stages of managing checkpoint inhibitor induced MG.

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Special Situations

Morning

Myasthenic Crisis

Myasthenic crisis is respiratory failure from myasthenic weakness. An identifiable precipitating event, such as infection, aspiration, surgery, or medication change, precedes most episodes of crisis. Cholinergic crisis is respiratory failure from overdose of ChEIs and was more common before the introduction of IS therapy, when using very large dosages of ChEIs. In MG patients with progressive respiratory symptoms, no single factor determines the need for ventilatory support. The safest approach is to admit the patient to an intensive care unit and observe closely for impending respiratory insufficiency. Serial measurements of negative inspiratory force (NIF) provide the best measure of deteriorating respiratory function in MG. Noninvasive mechanical ventilation using bilevel positive pressure ventilation (BiPAP) may avoid the need for intubation in patients in crisis without hypercapnia (Rabinstein et al., 2002). Retrospective studies suggest that PLEX and IVIg are equally effective in stabilizing patients in crisis (Murthy et al., 2005). Others suggest that PLEX is superior, producing more rapid respiratory improvement (Qureshi et al., 1999). We use PLEX in the treatment of crisis except when there is hemodynamic instability, sepsis, coagulopathy, or during the first trimester of pregnancy. Once ventilated, discontinuing ChEIs is safe and recommended to eliminate the possibility of cholinergic overdose and permit determination of disease severity. After addressing the precipitating factors causing crisis, add ChEIs in low doses and titrate to the optimal dose. Consider extubation when the patient has a NIF greater than −20 cm H2O and an expiratory pressure greater than 35–40 cm H2O. If the patient complains of fatigue or shortness of breath, defer extubation even if these values and blood gas measurements are normal. Prevention and aggressive treatment of medical complications offer the best opportunity to improve the outcome of myasthenic crisis.

Anesthetic Management in Myasthenia Gravis The stress of surgery and some drugs used perioperatively may worsen myasthenic weakness. As a rule, local or spinal anesthesia is preferred over inhalation anesthesia. Avoid the use of neuromuscular blocking agents or use them sparingly; inhalation anesthetic agents alone usually provide adequate muscle relaxation. The required dose of depolarizing blocking agents may be greater than that needed in non-myasthenic patients, whereas low doses of nondepolarizing agents cause pronounced and long-lasting blockade that may require extended postoperative assisted respiration.

Ocular Myasthenia While ChEIs may control symptoms adequately in some OMG patients, the benefit is usually partial and not protracted, while prednisone is often quite effective. The decision to initiate steroid therapy will depend upon the risk-benefit assessment, which is different in patients considering treatment for purely cosmetic reasons versus those in whom ocular symptoms have a profound effect on their livelihood (pilots, surgeons, etc.). Prednisone treatment may delay or reduce the frequency of progression of OMG to generalized disease (Kupersmith et al., 2003). Start prednisone at an initial dose of 10–20 mg/day with gradual increases every 3–5 days until achieving a clinical response (see Table 108.2). Alternatively, begin prednisone at a dose of 20-60mg–60 mg; the risk of steroid-induced exacerbation is less in OMG. Aim to use a maintenance dosage of prednisone that causes few major systemic adverse effects. Consider a steroid-sparing IS agent if this cannot be achieved. In general, OMG is not an indication for thymectomy,

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C Fig. 108.8 Twins, Age 2, Both With Acetylcholine Receptor Myasthenia Gravis (A, B). In the morning, one (B) has mild bilateral lid ptosis, slightly worse on the right; ptosis is worse or has become apparent in the evening in both boys (C).

though this may be effective in some patients. (See Thymectomy section, above.)

Childhood Myasthenia Gravis The onset of immune-mediated MG before age 18 is referred to as juvenile MG (JMG) (Andrews et al., 2002; Barraud et al., 2018; Castro et al., 2013; Finnis et al., 2011; Jastrzębska et al., 2019) (Fig. 108.8). Twenty percent of JMG and almost 50% of those with onset before puberty are seronegative, which makes the distinction from CMS challenging (see Congenital Myasthenic Syndromes section, later in this chapter). Electrodiagnostic studies demonstrate abnormal NMT but features that distinguish CMS from autoimmune MG are present in only a few forms of CMS. Improvement after PLEX or IVIg may help to establish an autoimmune etiology, but failure to improve does not exclude an autoimmune etiology. Many children who are initially seronegative later develop AChR-abs. Thymomas are rare in this age group. Treatment decisions in children with autoimmune MG should recognize that the rate of spontaneous remission is high in these patients. We recommend ChEIs alone in prepubertal children not disabled by weakness. For patients who remain symptomatic despite optimal dosing of ChEIs, prednisone is efficacious and cost-effective although the chronic side effects potentially have a long-term impact in children (growth stunting, weight gain, mood alteration, hyperglycemia, hypertension, etc.). A suggested starting dose is 0.5 mg/kg/day, with a maximum starting dose in older children of 30 mg/day. Use steroid-sparing IS drugs in more severe or refractory cases as in adult MG. PLEX and IVIg are effective short-term therapies in JMG.

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CHAPTER 108 Disorders of Neuromuscular Transmission Favorable results have been reported for thymectomy in JMG, even in patients less than 5 years of age, although the high rates of spontaneous remission make the assessment of benefit difficult. There are no reported adverse effects on the immune system from removing the thymus after 1 year of age (Ashraf et al., 2006; Hermes et al., 2011; Herrmann et al., 1998; Sauce et al., 2009; Tracy et al., 2009). The value of thymectomy in the treatment of prepubertal patients with MG is unclear, but the international consensus guidance for MG management recommends thymectomy in children with generalized AChR MG if the response to pyridostigmine and IS therapy is unsatisfactory, or to avoid potential complications of IS therapy (Sanders et al., 2016).

Pregnancy Myasthenia may improve, worsen, or remain unchanged during pregnancy. It is common for the first symptoms of MG to begin during pregnancy or postpartum. First-trimester worsening is more common in first pregnancies, whereas third-trimester worsening and postpartum exacerbations are more common in subsequent pregnancies. Complete remission may occur late in pregnancy. The clinical status at onset of pregnancy does not reliably predict the course during pregnancy. Pregnancy is more difficult to manage at the beginning of MG and women with MG should delay pregnancy until after the disease is stable. Therapeutic abortion is rarely, if ever, needed because of MG, and the frequency of spontaneous abortion is not increased. Oral ChEIs are the first-line treatment during pregnancy. Intravenous ChEIs may produce uterine contractions and are contraindicated. Prednisone is the IS agent of choice. Whenever possible we do not use other IS drugs during pregnancy because of theoretical potential mutagenic effects, although others feel that AZA and even CYA can be used safely during pregnancy (Ferrero et al., 2005). Increased risk of fetal malformation has been reported when men used AZA prior to conception (Norgard et al., 2004). MMF can cause birth defects and is contraindicated during pregnancy. PLEX or IVIg are useful when an immediate, albeit temporary, improvement is required during pregnancy, but avoid PLEX during the first trimester. Thymectomy should be postponed until after delivery as benefit is unlikely to occur during pregnancy. Magnesium sulfate has neuromuscular blocking effects and is not recommended to manage pre-eclampsia; barbiturates usually provide adequate treatment. Labor and delivery are usually normal. Cesarean section is recommended only for obstetrical indications. Regional anesthesia is preferred for delivery or cesarean section. MG does not affect uterine smooth muscle and therefore does not compromise the first stage of labor. In the second stage, voluntary muscles are at risk for easy fatigue and outlet forceps or vacuum extraction may be necessary. In our experience, breast-feeding is not a problem for myasthenic mothers, despite the theoretical risk of passing maternal AChR-abs in breast milk to the newborn.

Transient Neonatal Myasthenia Gravis A temporary form of MG affects 10%–20% of newborns whose mothers have immune-mediated MG. The severity of symptoms in the newborn does not correlate with the severity of symptoms in the mother. Transient neonatal myasthenia gravis (TNMG) also occurs in MuSK MG (Niks et al., 2008b) and rarely in infants of seronegative mothers. Weakness may manifest in utero, particularly when maternal antibodies are directed against the fetal AChR, and may lead to arthrogryposis multiplex congenita (Barnes et al., 1995). Consider decreased fetal movement as a possible indication for PLEX or IVIg. Birth of a child with arthrogryposis should also prompt a search for MG in the mother. An affected mother who delivers an infant with TNMG is likely to have

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similarly affected, subsequent infants. Consider prophylactic treatment with PLEX and/or steroids in a woman with a previously affected child, as the risk of recurrent TNMG is high. Affected newborns are typically hypotonic and feed poorly during the first 3 days. In some newborns, symptoms may be delayed for 1–2 days. Symptoms usually last less than 2 weeks but may persist for as long as 12 weeks, which correlates with the half-life of neonatal antibodies. It is not clear why some newborns develop weakness and others, with equally high antibody levels, do not. Some mothers with antibodies directed specifically against fetal AChR might themselves be asymptomatic, which makes diagnosing TNMG more difficult. Examine all infants born of myasthenic mothers carefully at birth for evidence of myasthenic weakness. Detection of AChR or MuSK antibodies in the child provides strong evidence for the diagnosis, although seronegative mothers have delivered affected seronegative infants. Improvement following injection of 0.1 mg/kg edrophonium supports the diagnosis of TNMG, but it may be difficult to assess the response in an intubated and ventilated neonate. Improvement after edrophonium does not distinguish TNMG from some CMS. A decrementing response to RNS confirms abnormal NMT, but also does not distinguish TNMG from most CMS. Affected newborns require symptomatic treatment with ChEIs if swallowing or breathing is impaired. Consider exchange transfusion if respiratory weakness is severe.

CONGENITAL MYASTHENIC SYNDROMES The CMS are a group of NMJ diseases caused by genetic defects of muscle endplate molecules involved in NMT (Engel, 2008; Finlayson et al., 2013; Finsterer, 2019). Mutations in 32 genes involved in presynaptic (8), postsynaptic (15), synaptic (4), and glycosylation (5) proteins have been identified, and most have autosomal recessive inheritance (Finsterer, 2019). Symptoms are present at birth in most forms, but may go unrecognized until adolescence or adulthood, particularly when progression is gradual and clinical manifestations are mild. The most common and clinically important CMS are discussed below. Overall, there is a 2:1 male predominance. Ophthalmoparesis and ptosis are present in most cases during infancy; mild facial paresis may be present as well. Ophthalmoplegia is often incomplete at onset but progresses to complete paralysis during infancy or childhood. Some children develop generalized fatigue and weakness, but limb weakness is usually mild compared to ophthalmoplegia. Skeletal deformities such as high-arched palate, facial dysmorphism, arthrogryposis and scoliosis are common. Muscles may be small and underdeveloped. Episodic respiratory crises may occur with any form of congenital myasthenia but are particularly common in choline acetylcholinesterase (ChAT) deficiency (see below). The diagnosis of CMS is suggested by the clinical features and the response to ChEIs, or findings on standard electrodiagnostic studies. Determination of the specific genetic or physiological defect requires genetic studies or specialized morphological and electrophysiological studies on muscle tissue. The specific diagnosis is important since many CMS patients respond to drugs that increase the availability of ACh at the muscle endplate or alter the kinetics of the AChR. ChEIs, sometimes in very high doses, improve limb muscle weakness in some forms but worsen it in others. The weakness in some forms responds to amifampridine (Harper et al., 2000). Thymectomy and immunosuppression are not effective.

Acetylcholine Receptor Deficiency This is a genetically heterogeneous group with patients having various AChR subunit or rapsyn mutations. Most commonly, an ε-subunit mutation results in continued expression of the fetal γ-subunit. The

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age of symptom onset ranges from infancy to adulthood. Clinical manifestations include hypotonia, respiratory insufficiency, weakness of ocular and bulbar muscles, and skeletal deformities. Electrodiagnostic findings are variable and depend on the severity and distribution of weakness. RNS studies usually demonstrate a decrement but the decrement may be absent or restricted to facial muscles in mild cases. Jitter is increased in all reported cases. These disorders respond variably to symptomatic therapy with pyridostigmine or amifampridine. Ephedrine produces benefit in some cases. Immunotherapy has no effect.

Fast-Channel Syndrome

Choline Acetyl Transferase Deficiency

Rapsyn Mutations

This condition, previously called congenital myasthenic syndrome with episodic apnea or familial infantile myasthenia, is caused by mutations in the CHAT gene, which codes for endplate ChAT, the rate-limiting enzyme in the resynthesis of acetylcholine within the nerve terminal. Generalized hypotonia, ptosis, and feeding difficulties are present at birth, and the early course of the disease is punctuated by sudden episodes of severe bulbar and generalized weakness with life-threatening apnea triggered by infections or stress. Arthrogryposis may be present. Within weeks after birth, the child becomes stronger and ultimately breathes unassisted. However, episodes of life-threatening apnea occur repeatedly throughout infancy and childhood, even into adult life, and there may be a history of sudden infant death syndrome in siblings. A decrementing response to RNS is usually present in weak muscles but may only be seen after prolonged exercise or continuous repetitive stimulation (Stålberg et al., 2010). Jitter and blocking also become progressively greater during continuous nerve stimulation (Stålberg et al., 2010), ChEIs improve strength in most children with ChAT deficiency. Symptoms tend to lessen in adolescence and adulthood when the disease resembles mild autoimmune MG or a congenital myopathy.

Rapsyn is a postsynaptic protein involved in clustering AChR at the muscle endplate. Rapsyn mutations produce a CMS in which respiratory distress, hypotonia, and poor feeding are usually present at birth. There is generalized weakness and ptosis but ophthalmoplegia is uncommon. Patients have a high-arched palate and may have arthrogryposis. Respiratory crises are common until about 7 years of age in the setting of stress, such as infections, and then become less frequent. The response to ChEIs and amifampridine is good and the overall prognosis is relatively favorable, many patients being able to discontinue treatment as adults. A milder form of the disease can occur that may not be noticed during childhood and should be considered in suspected autoimmune MG that is refractory to treatment.

Congenital Acetylcholinesterase Deficiency Endplate AChE deficiency results from a recessive mutation of COLQ, the gene coding for the collagenous tail of the heteromeric AChE molecule at the muscle endplate (Ohno et al., 1999). Presentation is usually in infancy or early childhood. The symptoms are usually severe, consisting of generalized weakness, ptosis, ophthalmoparesis, bulbar and limb weakness, underdevelopment of muscles and slowed pupillary responses to light. Skeletal deformities include lordosis or scoliosis that worsens with prolonged standing. Single-nerve stimuli characteristically produce repetitive discharges and ChEIs typically make symptoms worse. Pyridostigmine is ineffective or even detrimental. Some patients respond to ephedrine (Yeung et al., 2010) or salbutamol (Padmanabha et al., 2017).

Slow-Channel Congenital Myasthenic Syndrome Variable expression results in a wide spectrum of clinical manifestations and severity in slow-channel congenital myasthenic syndrome (SCCMS), which has autosomal dominant inheritance. Mutations in an AChR subunit (CHRNE, CHRNA, CHRNB or CHRND genes) results in prolonged open time of the ACh channel. Severe cases present in infancy or early childhood, but mild cases may present in adulthood, as late as the seventh decade. In SCCMS neck and distal upper limb muscles; the intrinsic hand muscles and digit extensors are particularly weak and atrophic. Ptosis, ophthalmoparesis, dysarthria, dysphagia, proximal limb weakness, and respiratory insufficiency also occur in some cases. RNS shows a decrementing response. Single-nerve stimuli produce repetitive muscle discharges similar to those seen in ChEI toxicity or congenital deficiency of endplate AChE (see above). ChEIs worsen the weakness. Quinidine sulfate and fluoxetine, which reduce AChR channel open time, may improve strength (Harper et al., 2003).

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Fast-channel syndrome is a very severe form of CMS. It results from AChR subunit mutations (CHRNE, CHRNA, or CHRND genes) that cause abnormally brief opening of the AChR ion channel. Symptoms are usually present at birth and there is severe ptosis and ophthalmoplegia. Patients have a weak cry and poor feeding, severe acral weakness, and frequent respiratory crises. Treatment is primarily supportive with ventilator support, often from birth, and gastrostomy for feeding. Patients respond to ChEIs and amifampridine but the improvement from ChEIs may wane over time.

DOK-7 Mutations DOK-7 is a muscle protein that activates MuSK and is critical in endplate development and AChR aggregation. The clinical manifestations and electrodiagnostic findings of CMS associated with DOK-7 mutations may be indistinguishable from those of AChR deficiency (Selcen et al., 2008), including reduced fetal movements in utero and static and fatigable weakness of cranial, respiratory and limb muscles. A presentation with nonfluctuating limb girdle distribution weakness may mistakenly lead to a diagnosis of a muscular dystrophy. Ephedrine, salbutamol, or albuterol is the first choice of treatment; amifampridine may provide additional benefit. ChEIs should be avoided (Witting et al., 2014).

GFPT1 and DPAGT1 Mutations These mutations affect enzymes in glycosylation pathways and produce slowly progressive limb girdle weakness beginning in childhood or early teens (Belaya et al., 2012; Guergueltcheva et al., 2012). Some patients with the GFPT1 mutation were initially called “familial limb-girdle myasthenia” (McQuillen, 1966). Ocular muscles are not involved and bulbar muscles are only minimally affected. EMG shows myopathic features, as well as abnormal NMT. Muscle biopsy may show tubular aggregates. ChEIs and amifampridine benefit most patients. Albuterol and ephedrine may also help.

LAMBERT-EATON MYASTHENIA LEM results from an immune-mediated attack against the P/Q type voltage-gated calcium channels (VGCCs) on presynaptic cholinergic nerve terminals at the NMJ and in autonomic ganglia, thereby inhibiting release of ACh (Fig. 108.9). First described in patients with lung cancer (CA-LEM), LEM also occurs as an organ-specific autoimmune disorder in the absence of cancer (NCA-LEM). LEM is usually clinically quite distinct from MG. Most patients report gradual onset of lower extremity weakness, sometimes with muscle tenderness. Dry mouth is a common symptom of autonomic dysfunction; others are erectile dysfunction, postural hypotension, constipation, and dry eyes. Ocular and bulbar symptoms are generally not prominent

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(CMAPs) with low amplitude, which increases during 20–50 Hz nerve stimulation and after brief maximum voluntary muscle activation. Low-frequency RNS produces a decrementing response in a hand or foot muscle in almost all patients and almost all have small CMAPs in some distal muscle (Tim et al., 2000). The characteristic increase in CMAP size after activation is more prominent in distal muscles but it may be necessary to examine several muscles to demonstrate this important finding. Immunoprecipitation assay demonstrates VGCC antibodies in almost all patients with CA-LEM and in more than 90% with NCALEM (Harper., 2002). Low titers of VGCC antibodies have also been reported in systemic lupus erythematosus and rheumatoid arthritis (Lang et al., 1993). These antibodies may not be detectable early in the disease, in which case repeat antibody testing may be useful. Antibodies to SOX1, a transcription factor involved in neural development, were found in 64% of CA-LEM patients with SCLC and in none with NCA-LEM (Sabater et al., 2008); thus SOX1 antibodies are a marker for underlying cancer in LEM patients.

Immunopathology of Lambert-Eaton Myasthenia

Fig. 108.9 Freeze-Fracture Electron Micrographs Of Presynaptic Membrane P-Faces. Top: control muscle. Active zones tend to be aligned along an arc (arrow). Some zones display fewer than four rows of particles (arrowhead). x98,000. Bottom: LEM muscle. Membrane leaflet shows active zones (arrows) and clusters of large intramembrane particles (arrowheads). x59,800. (From Fukunaga, H., Engel, A.G., Osame, M., Lambert, E.H., 1982. Paucity and disorganization of presynaptic membrane active zones in the Lambert-Eaton myasthenic syndrome. Muscle Nerve 5, 686–697, figures 2A and 4, by permission.)

(O’Neill et al., 1988; Tim et al., 2000; Wirtz et al., 2002), but are reported in some patients, in a pattern suggesting MG (Burns et al., 2003; Titulaer et al., 2008). Prolonged apnea and ventilator dependence may follow use of neuromuscular blocking agents for surgery (Anderson et al., 1953) but respiratory failure is otherwise uncommon in the absence of primary pulmonary disease (Barr et al., 1993; Smith et al., 1996). Symptoms usually begin after age 40, but LEM can occur in children. Males and females are equally affected. Approximately one-half the patients have an underlying malignancy—in 80% this is small-cell lung cancer (SCLC)—which may be discovered years before or years after the onset of LEM symptoms. Examination usually demonstrates less weakness than the symptoms suggest. Tendon reflexes are almost always absent or diminished. Strength (and tendon reflexes) may facilitate briefly after exercise and then weaken with sustained activity, but this is not a universal finding. The response to edrophonium is not as robust or consistent as in MG. The weakness in LEM is not usually life-threatening and more closely resembles cachexia, polymyositis, or a paraneoplastic neuromuscular disease.

Diagnostic Procedures in Lambert-Eaton Myasthenia The following characteristic electrodiagnostic findings confirm the diagnosis (see Chapter 36): compound muscle action potentials

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P/Q VGCCs are the target of disease-causing antibodies in LEM. The number of active zone particles in the motor nerve terminal, which represent the VGCC, is reduced (see Fig. 108.9). Similar changes occur in mice injected with IgG from LEM patients. The mechanism is probably from cross-linking of the VGCC by antibodies that downregulate VGCC expression by antigenic modulation. SCLC cells are of neuroectodermal origin and contain high concentrations of VGCC. In CA-LEM, these antigens induce production of VGCC antibodies. In NCA-LEM, as in other primary autoimmune disorders, altered self-tolerance presumably induces production of VGCC antibodies as part of a more general immune-mediated state. VGCC antibody titers do not correlate with disease severity but the antibody levels may fall as the disease improves in patients receiving immunosuppression.

Treatment of Lambert-Eaton Myasthenia Once the diagnosis of LEM is established, an extensive search for underlying malignancy, especially SCLC, is mandatory. Chronic smokers should undergo bronchoscopy and/or positron emission tomography (PET) scan if chest-imaging studies are normal. The target of initial treatment is any underlying malignancy. Weakness may improve after effective cancer therapy and some patients require no further treatment. Repeat the search for occult malignancy periodically, especially during the first 2 years after symptom onset. Determine the frequency of re-evaluation by the patient’s cancer risk factors. Tailor therapy to the individual, based on the severity of weakness, underlying disease, life expectancy, and response to previous treatment. RCTs have shown that amifampridine and IVIg improve muscle strength scores and CMAP amplitudes in patients with LEM (Bain et al., 1996; Keogh et al., 2011; Maddison et al., 2005; McEvoy et al., 1989; Oh et al., 2009; Oh et al., 2016; Wirtz et al., 2009; Sanders et al., 2000; Sanders et al., 2018b). Other treatments, such as PLEX (Newsom-Davis et al., 1984), corticosteroids, and IS agents, including RTX (Maddison et al., 2011), may be of benefit in some patients but have not been tested in controlled trials. A quick clinical test that is particularly helpful to monitor therapeutic responses in LEM is the triple-timed up-and-go test (Video 108.5) (Raja et al., 2019; Sanders et al., 2018a). This validated test is sensitive to changes in clinical status and assesses the proximal lower extremity weakness and gait difficulty characteristic of LEM. The following treatment plan for LEM is a general guide that should be modified to suit specific situations.

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ChEIs improve strength in occasional LEM patients. Try pyridostigmine, 30–60 mg every 6 hours, for several days. In some patients, the major benefit is relief of dry mouth. Amifampridine facilitates release of ACh from motor nerve terminals and produces clinically significant improvement of strength and autonomic symptoms in most LEM patients. Therapeutic responses occur with doses of 5–25 mg three to four times a day; seizures may occur at doses higher than 100 mg/day. Concomitant use of pyridostigmine, 30–60 mg, three or four times a day often enhances the response. Side effects usually are negligible: transitory perioral and digital paresthesias occur with doses greater than 10–15 mg. Cramps and diarrhea may occur when amifampridine is given with pyridostigmine and can be minimized by reducing the dose of pyridostigmine. Amifampridine has been approved for treatment of LEM at doses up to 80 mg/day. Both PLEX and IVIg provide short-term improvement in some patients with LEM (Keogh et al., 2011). If these treatments are not effective, determine if weakness is sufficiently severe to warrant immunotherapy with prednisone, AZA, CYA, or RTX. In patients with severe weakness, use PLEX or IVIg first and add prednisone and AZA after improvement begins. It may be necessary to administer repeated courses of treatment in order to maintain improvement. In LEM patients with cancer, the response to cancer therapy determines the prognosis. In patients without cancer who are not well treated with amifampridine, immunosuppression produces improvement in many patients, but most require substantial and continuing doses of IS medications (Abenroth et al., 2017; Maddison et al., 2001).

Myasthenia Gravis/Lambert-Eaton Myasthenia Overlap Syndrome The clinical presentations of MG and LEM are usually quite distinct but in some patients the clinical and electrodiagnostic findings may be similar and the correct diagnosis may not obvious. Features that favor MG include prominent ocular muscle weakness, limb weakness that predominates in the arms, and normal muscle stretch reflexes (Wirtz et al., 2002). Features that favor LEM include weakness that predominates in the hip girdle muscles, hypoactive or absent reflexes, and autonomic symptoms, especially dry mouth. Numerous reports of patients with various overlapping features of MG and LEM have been published. These include patients with (1) clinical features of MG but facilitation on manual muscle testing or EMG, typical of LEM; and (2) clinical and EMG patterns typical of one condition initially that change to the other later; or EMG patterns typical of MG in one muscle and of LEM in another. A few reported patients appear to have a true MG/LEM overlap syndrome, with antibodies to both the AChR and VGCC (Kanzato et al., 1999; Katz et al., 1998; Newsom-Davis et al., 1991; Oh et al., 2005); we have seen one such case among 1300 patients with acquired MG and 115 with LEM. The ultimate diagnosis in patients with mixed features of MG and LEM may be moot because most treatments are the same for both conditions. Exceptions are that we do not search for cancer other than thymoma in MG, and thymectomy is not a treatment for LEM.

BOTULISM Botulism is caused by a toxin produced by the anaerobic bacterium Clostridium botulinum, which blocks the release of ACh from the motor nerve terminal (Cherington, 2007) and produces a long-lasting, severe muscle paralysis. Botulism usually follows ingestion of inadequately sterilized contaminated foods. Of eight types of botulinum toxins (A, B, Cα, Cβ, D, E, F and G), types A and B cause most cases of botulism in the United States. All toxin types block ACh release from the presynaptic motor nerve terminal and the parasympathetic and

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sympathetic nerve ganglia. Neuromuscular symptoms usually begin 12–36 hours after ingestion of contaminated food and are preceded by nausea and vomiting. Not all people who ingest the contaminated food become symptomatic.

Clinical Features of Botulism The major initial symptoms of botulism are blurred vision, dysphagia, and dysarthria. Pupillary responses to light are impaired and tendon reflexes are variably reduced. Weakness progresses for several days and then reaches a plateau. Severe respiratory paralysis may occur rapidly. Blocking of ACh release in the autonomic system produces blurring of vision from ophthalmoparesis, pupillary abnormalities, dry mouth, postural hypotension, and urinary retention. Electrophysiological findings aid the diagnosis (see below). Bioassay of the toxin by injecting serum or stool from an affected patient into mice is positive if paralysis and death of the animals follows. Polymerase chain reaction (PCR) assays are available to rapidly detect the bacteria. Infantile botulism results from the growth of C. botulinum in the immature gastrointestinal tract and the elaboration of small quantities of toxin over a prolonged period (Jones, 2002). Honey is commonly incriminated as a vehicle carrying the C. botulinum spores that produce infantile botulism. Symptoms of constipation, lethargy, poor suck, and weak cry usually begin at approximately 4 months of age. Examination reveals weakness of the limb and oropharyngeal muscles, poorly reactive pupils, and hypoactive tendon reflexes. Most patients require ventilatory support. Demonstrating botulinum toxin in the stool or isolation of C. botulinum from stool culture confirms the diagnosis. Wound botulism occurs predominantly in drug abusers after subcutaneous injection of heroin: Clostridium bacteria colonize the injection site and release toxin that produces local and patchy systemic weakness.

Electromyographic Findings in Botulism Electrophysiological abnormalities in botulism tend to evolve with time and may not be present early in the disease (Padua et al., 1999). The EMG findings in botulism include: lation post-activation exhaustion affected muscles. Not all patients with botulism have all these electrophysiological findings. The diagnosis is unlikely if none of these features are present. SFEMG demonstrates markedly increased jitter and blocking in virtually every case (Padua et al., 1999). Jitter and blocking may decrease as the firing rate increases but this is not a consistent finding. Botulinum toxin injections used in the treatment of focal dystonia and other conditions may produce focal or regional weakness, including diplopia, dysphagia, urinary incontinence, and brachial plexopathy, and may unmask or exacerbate other neuromuscular diseases, such as MG, LEM, and motor neuron disease. Jitter may be increased in muscles remote from the site of injection, and may persist for many months (Sanders et al., 1986).

Treatment of Botulism Treatment consists of administration of bivalent (type A and B) or trivalent (A, B, and E) antitoxin. Antibiotic therapy is not effective since the cause of symptoms (in all but infantile and wound botulism) is the ingestion of toxin rather than organisms. In infantile botulism, IV human botulism immune globulin (BIG-IV) neutralizes the toxin

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CHAPTER 108 Disorders of Neuromuscular Transmission for several days after illness onset, shortens the length and cost of the hospital stay, and reduces the severity of illness (Arnon et al., 2006). Otherwise, treatment is supportive. ChEIs are usually not beneficial. With improvements in intensive care, the mortality rate has declined to about 20%. Depending on initial severity, recovery may be quite prolonged; many patients still have symptoms a year or more after the onset of illness.

OTHER CAUSES OF ABNORMAL NEUROMUSCULAR TRANSMISSION Envenomation by animal toxins is the most common cause of NMJ toxicity worldwide. Muscles of eye movement or the eyelids are most often involved, along with muscles of neck flexion and the pectoral and pelvic girdles. In more severe envenomation, bulbar and respiratory muscles are also involved. Cognition and sensation are intact and muscle stretch reflexes are often preserved or only minimally diminished, particularly early in the illness. Arthropod venoms that affect the NMJ include those of the funnel web and black widow spiders, which produce marked acute neurotransmitter release by depolarizing the presynaptic nerve terminal and increasing calcium influx into the nerve terminal. Tick paralysis results from a neurotoxin that blocks AChR function postsynaptically. Envenomation by snakebite occurs primarily from the Elapidae and Hydrophiodae species. Snake NMJ toxins act either presynaptically or postsynaptically. Presynaptic β-neurotoxins (β-bungarotoxin, notexin, and taipoxin) impair ACh release—often there is an initial augmentation of ACh release, followed by depletion of neurotransmitter. Presynaptic toxins tend to be more potent than those that act postsynaptically. Postsynaptic α-neurotoxins produce a curare-like, nondepolarizing neuromuscular block that is variably reversible. Most

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venoms contain both pre- and postsynaptic neurotoxins, although one type may predominate. Marine neurotoxins affecting the NMJ are rare and come primarily from poisonous fish (stonustoxin), a few mollusks (conotoxins), and dinoflagellates. Most marine intoxications result from ingestion. With some marine toxins, there is an increase in the concentration of toxin through successive predatory transvection up the food chain. Heavy-metal intoxication is a rare cause of neuromuscular toxicity. Ingestion of bread made from grain contaminated with methylmercury fungicide produces weakness with characteristic decrementing responses to RNS and partial reversal by ChEIs. Organophosphates impair NMT by irreversibly inhibiting AChE, producing a depolarizing neuromuscular block. Abnormal NMT may be a cause of weakness in critically ill patients, and is often due to administration of drugs such as antibiotics, antiarrhythmics, and nondepolarizing neuromuscular blocking agents (Gorson, 2005). Prolonged use of these agents may result in weakness due to persistent neuromuscular blockade even hours or days after discontinuation. NMT may also be impaired in motor unit diseases that do not primarily affect the NMJ. For example, patients with ALS may have fluctuating weakness that responds to ChEIs, a decrementing response to RNS, and increased jitter and blocking. Jitter is increased in most patients with mitochondrial disease that predominantly affects the extraocular muscles (progressive external ophthalmoplegia, PEO) (Krendel et al., 1987; Ukachoke et al., 2015), which also has clinical findings similar to MG. Features attributable to abnormal NMT have also been reported in syringomyelia, poliomyelitis, peripheral neuropathy, and inflammatory myopathy. The complete reference list is available online at https://expertconsult. inkling.com/.

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109 Disorders of Skeletal Muscle Christopher T. Doughty, Anthony A. Amato

OUTLINE Muscle Histology, 1978 Changes of Denervation, 1979 Myopathic Changes, 1979 Other Changes, 1980 Immunohistochemistry and Immunoblot, 1981 Specific Disorders, 1982 Muscular Dystrophies, 1982 Ion Channelopathies, 2001

Metabolic Myopathies, 2004 Mitochondrial Myopathies, 2008 Congenital Myopathies, 2010 Inflammatory Myopathies, 2012 Toxic Myopathies, 2018 Inflammatory Myopathy, 2019 Endocrine Myopathies, 2020 Rhabdomyolysis, 2021

Disorders of skeletal muscle encompass a variety of illnesses that cause weakness, pain, and fatigue in any combination. They vary from the protean symptoms of muscle pain and fatigue that often defy any explanation to the muscular dystrophies, which one recognizes instantly on clinical grounds. Motor neuron disease (e.g., spinal muscular atrophies), neuromuscular junction disorders (myasthenia gravis, Lambert-Eaton syndrome, and congenital myasthenia), and certain polyneuropathies (e.g., chronic inflammatory demyelinating polyneuropathy) can cause similar symptoms and may be difficult to differentiate from muscle disorders on clinical grounds. Some definitions are worth reviewing. Myopathy simply refers to an abnormality of the muscle and has no other connotation. Muscular dystrophies are genetic myopathies usually caused by a disturbance of a structural protein or enzyme, resulting in necrosis of muscle fibers and replacement by adipose and connective tissue. Congenital myopathies are a group of illnesses that usually present in young children; many are relatively nonprogressive. However, rare “congenital myopathies” may manifest initially in adults (e.g., central nuclear myopathy, nemaline myopathy) and can be progressive. With the advent of molecular genetics, we recognize that many are allelic to what others have reported as dystrophies, further blurring their distinction as a separate category from muscular dystrophy. Myositis implies an autoimmune or infectious disorder in which the muscle histology shows an inflammatory response. The myotonias are diseases in which the occurrence of involuntary persistent muscle activity accompanied by abnormal repetitive electrical discharges distorts the normal contractile process. This occurs after percussion or voluntary contraction. Metabolic myopathies refer mainly to disorders of glycogen or lipid metabolism leading to impaired synthesis of adenosine triphosphate (ATP) or cause abnormal accumulation of material in the cell. The term endocrine myopathy refers to myopathies associated with disorders of the thyroid and parathyroid glands and to myopathies associated with corticosteroids. Within muscle fibers chemical energy is converted into mechanical energy. The component processes include (1) excitation and

contraction occurring in the muscle membranes, (2) the contractile mechanism itself, (3) various structural supporting elements that allow the muscle to withstand the mechanical stresses, and (4) the energy system that supports the activity and integrity of the other three systems. The logical categorization of myopathies is according to the part of the system involved. Abnormalities in the membrane ion channels (channelopathies) involved in muscle excitation cause various forms of myotonia and periodic paralysis (see Chapter 98). The complex of proteins that include dystrophin, the sarcoglycans, and α-laminin constitute a vital structural mechanism linking the contractile proteins with the extracellular supporting structures. Defects in these proteins are the basis of many forms of muscular dystrophy. Although knowledge remains incomplete, it seems reasonable to modify the classic description of the myopathies to incorporate the new information. For this reason, in the sections that follow, disease descriptions are under the heading of their known molecular defect where possible; the classic appellation appears parenthetically. Before describing the illnesses themselves, we first review the techniques used in the clinical evaluation of patients.

MUSCLE HISTOLOGY The technique of muscle biopsy is not difficult. Under local anesthesia, a small incision made over the muscle allows, with careful dissection, removal of a small strip of muscle. Needle biopsies are useful in some situations. Histochemical studies of frozen sections are essential for proper interpretation. A transverse section of normal muscle shows fibers that are roughly of equal size and average approximately 60 mm in transverse diameter (Fig. 109.1). The muscle fibers of infants and young children are proportionately smaller. Each fiber consists of hundreds of myofibrils separated by an intermyofibrillar network containing aqueous sarcoplasm, mitochondria, and the sarcoplasmic reticulum with the associated transverse tubular system. Surrounding each muscle fiber is a thin layer of connective tissue (the endomysium).

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Fig. 109.1 Normal Muscle Biopsy. The fibers are roughly equal in size, the nuclei are peripherally situated, and the fibers are tightly apposed to each other with no fibrous tissue separating them (Verhoeff-van Gieson stain).

Strands of connective tissue group muscle fibers into a fascicle, separated from each other by the perimysium. Groups of fascicles are collected into muscle bellies surrounded by epimysium. Situated at the periphery within muscle fibers are the sarcolemmal nuclei. The fibers are of different types. The simplest division is into type 1 and type 2 fibers, best demonstrated with the histochemical reaction for myosin adenosine triphosphatase (ATPase; Fig. 109.2). The type 1 and type 2 fibers are roughly synonymous with slow and fast fibers or with oxidative and glycolytic fibers in human muscle. Type 2 fibers can be further subdivided based on both staining properties and resistance to fatigue. The best demonstration of the intermyofibrillar network pattern is with the histochemical reactions for oxidative enzymes, such as reduced nicotinamide adenine dinucleotide dehydrogenase (NADH). A regular network extends across the whole fiber. In addition to the routine stains with hematoxylin and eosin, modified Gomori trichrome, myosin ATPase, and NADH, the use of other special stains demonstrates fat (Sudan black or oil red O), complex carbohydrates (periodic acid–Schiff), amyloid (Congo red), or specific enzymes (e.g., phosphorylase, succinic dehydrogenase, cytochrome oxidase [COX]). Immunocytochemical techniques demonstrate the location and integrity of structural proteins such as dystrophin. They also characterize cell types in biopsy samples with inflammatory changes.

Changes of Denervation When muscle loses its nerve supply, muscle fibers atrophy, often resulting in fiber squeezing into the spaces between normal fibers and assuming an angulated appearance (Fig. 109.3). Scattered angulated fibers appear early in denervation. Sometimes, picturesque changes in the intermyofibrillar network occur, as in the “target fiber,” which characterizes denervation and reinnervation. This is a three-zone fiber on which the intermediate zone stains more darkly, and the central “bull’s eye” stains much lighter than normal tissue (Fig. 109.4). Often a neighboring nerve twig reinnervates a denervated fiber. This results in the same anterior horn cell supplying two or more contiguous fibers. If

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Fig. 109.2 Normal Muscle Biopsy. Myosin adenosine triphosphatase stain at pH 9.4 demonstrates relative proportions in size of type 1 (light) and type 2 (dark) fibers. Muscle fibers belonging to one motor unit innervated by the same anterior horn cell are uniform in type, implying there are fast and slow anterior horn cells. Subsets of fiber types are types 2A, 2B, and 2C. Metabolism of type 2A fibers is more oxidative than that of type 2B. The type 2C fiber is present in fetal muscle.

that nerve twig then undergoes degeneration, instead of only one small angulated fiber being produced, a small group of atrophic fibers develops. Group atrophy suggests denervation (Fig. 109.5). As the process continues, large groups of geographical atrophy occur in which entire fascicles are atrophic. In addition to the change in size, a redistribution of the fiber types occurs as well. Normally a random distribution of type 1 and 2 muscle fiber types exists, sometimes incorrectly called a checkerboard or mosaic pattern. The same process of denervation and reinnervation results in larger and larger groups of contiguous fibers supplied by the same nerve twig. Because all fibers supplied by the same nerve twig are of the same fiber type, groups of type 1 fibers next to groups of type 2 fibers replace the normal random pattern. This fiber type grouping is pathognomonic of reinnervation (Fig. 109.6). When long-standing denervation is present, the atrophic muscle fibers almost disappear, leaving small clumps of pyknotic nuclei in their place.

Myopathic Changes Myopathies are typically associated with greater variation in pathological changes than those that occur with denervation. The type of change depends on the type of muscle disease. The normal peripherally placed nuclei may migrate toward the center of the fiber. Internalized nuclei may be seen in normal muscle (up to 2% of fibers), but when they are numerous, they usually indicate a myopathic process. Numerous internal nuclei are a feature of the myotonic dystrophies and the limb– girdle muscular dystrophies (LGMDs). Occasionally, internal nuclei are seen in certain chronic denervating conditions (e.g., juvenile spinal muscular atrophy). Necrosis of muscle fibers, in which the fiber appears liquefied and later presents as a focus of phagocytosis, occurs in many of the myopathies. These changes usually represent an active degenerative process. They often are a feature of myoglobinuria, toxic myopathies, inflammatory myopathies, and metabolic myopathies,

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Fig. 109.3 Denervation. Notice the small, dark, angulated fibers demonstrated with this oxidative enzyme reaction (nicotinamide adenine dinucleotide dehydrogenase stain).

Degeneration and regeneration of fibers characterize many illnesses. When this occurs, the regenerating fibers often become basophilic, and myonuclei enlarge because of the accumulation of ribonucleic acid (RNA) needed for protein synthesis. Fiber basophilia is a sign of an active myopathy. Cellular responses include frank inflammatory reactions around blood vessels, which characterize the collagen vascular diseases and dermatomyositis (DM). Endomysial inflammation with invasion of non-necrotic muscle fibers occurs in inclusion body myositis (IBM) and polymyositis (PM). Importantly, pronounced inflammatory cellular responses may occur in dystrophies, particularly facioscapulohumeral dystrophy (FSHD) and dysferlinopathies. Even the so-called congenital inflammatory myopathies actually represent forms of congenital muscular dystrophy. Fibrosis is another reactive change in muscle. Normally a very thin layer of connective tissue separates the muscle fibers. In dystrophic conditions, this layer thickens, and muscle fibrosis may be quite pronounced. In the inflammatory myopathies, there may be a loose edematous separation of fibers, but fibrosis is not usually characteristic in early phases of the disease except when associated with systemic sclerosis or in IBM. Changes in the intermyofibrillar network pattern are common in myopathic disorders. There is often a moth-eaten, whorled change to the intermyofibrillar network in LGMD and FSHD (Fig. 109.7); the intermyofibrillar network loses its orderly arrangement and swirls, resembling the current in an eddying stream. These changes may be seen in several diseases but tend to be much more common in the myopathies.

Other Changes

Fig. 109.4 Denervation. Target fibers (nicotinamide adenine dinucleotide dehydrogenase stain).

but can also be seen in dystrophies. Fiber-size variation may occur in primary diseases of muscle, with large fibers and small fibers intermingling in a random pattern. This is sometimes the only indication of a pathological process. Fiber splitting often accompanies muscle fiber hypertrophy. In transverse section, recognition of split fibers is by a thin fibrous septum, often associated with a nucleus that crosses partway but not all the way across the fiber. A detailed study of serial transverse sections may reveal more split fibers than in a single section. Fiber splitting is particularly visible in dystrophic conditions such as LGMD.

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Selective changes in fiber types can occur. Type 2 fiber atrophy is one of the most common abnormalities seen in muscle (Fig. 109.8). Type 2 atrophy, particularly if limited to type 2B fibers, is nonspecific and indicates muscle disuse. If a limb is casted and the muscle examined some weeks later, selective atrophy of type 2 fibers is noted. Any chronic systemic illness tends to produce type 2 atrophy. It occurs in rheumatoid arthritis, nonspecific collagen vascular diseases, cancer (hence the name cachectic atrophy), intellectual disability in children, and pyramidal tract disease. Type 2B fiber atrophy can also result from chronic corticosteroid administration. Therefore type 2 fiber atrophy should probably be regarded as a nonspecific result of anything less than robust good health. Type 1 fiber atrophy is more specific. It occurs in some of the congenital myopathies and dystrophies, congenital myasthenia, and is characteristic of myotonic dystrophy type 1 (Video 109.1). Changes in the proportion of fiber types are quite separate from changes in the fiber size. The name fiber type predominance refers to a change in the relative numbers of a particular fiber type. Type 1 fiber predominance is a normal finding in the gastrocnemius and deltoid muscles. When widespread, it is also the hallmark of congenital myopathies and many of the early dystrophies. Type 2 fiber predominance is seen in the lateral head of the quadriceps muscle. Type 2 predominance occurs occasionally in juvenile spinal muscular atrophy and motor neuron disease but is not firmly associated with any particular disease condition. Some changes in muscle biopsy results are pathognomonic of a particular disease. Perifascicular atrophy, in which the atrophic fibers are more numerous around the edge of muscle fascicles, is the hallmark of DM. The presence of lipid vacuoles or abnormal pockets of glycogen characterizes the metabolic myopathies. Enzyme defects including myophosphorylase deficiency and phosphofructokinase (PFK) deficiency are detectable with appropriate histochemical stains. Interpretation of a muscle biopsy usually includes the description of a constellation of changes and the subsequent association of these

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References Video 109.1 Myotonic Dystrophy. Myotonic discharges are seen in a muscle at rest on needle electromyography in a patient with type 1 myotonic dystrophy. https://www.kollaborate.tv/player?id=855455

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CHAPTER 109 Disorders of Skeletal Muscle

Fig. 109.5 Denervation. Small groups of atrophic fibers are scattered throughout the biopsy (modified Gomori trichrome stain).

Fig. 109.6 Chronic Denervation and Reinnervation. Instead of the usual mosaic pattern of the two fiber types, fibers clump together, groups of one type appearing next to groups of the other type (myosin adenosine triphosphatase stain, pH 9.4).

1981

Fig. 109.7 Myopathy. Moth-eaten whorled fibers. Intermyofibrillar network pattern is distorted, and some areas lack proper stain (nicotinamide adenine dinucleotide dehydrogenase stain).

Fig. 109.8 Type 2 fiber atrophy is a common change of disuse atrophy or steroid myopathy (myosin adenosine triphosphatase stain).

Immunohistochemistry and Immunoblot changes with a particular diagnosis when possible. Illnesses that have characteristic biopsies include infantile spinal muscular atrophy, DM, IBM, the congenital myopathies, lipid storage myopathies, and glycogen storage diseases (e.g., Pompe disease, myophosphorylase deficiency). Immunocytochemical staining can also distinguish many forms of muscular dystrophy from each other. Although not disease specific, characteristic biopsy changes differentiate chronic denervation from acute simple denervation.

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The use of biopsy material to identify missing proteins is increasing with the greater availability of commercial antibodies to the proteins of interest. Although genetic testing is becoming easier, cheaper, and more commonly utilized, immunohistochemical testing remains useful. Identification of an absent muscle protein may allow for diagnosis when genetic testing is either unremarkable or reveals a variant of uncertain significance in a gene of interest. Immunohistochemical findings may also allow narrowing of the panel of genetic tests to be sent. For example, if a patient with suspected Duchenne muscular

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dystrophy (DMD) undergoes genetic testing but no pathogenic mutation is discovered, confirmation of the diagnosis may rest on demonstrating absent or abnormal dystrophin in the muscle tissue. All the sarcoglycans are demonstrated using similar techniques. Deficiency of any of the sarcoglycans causes a muscular dystrophy, and because they comprise a complex, when one is missing, all or some of the others may be absent in the biopsy. The α-sarcoglycan is particularly prone to be missing, which makes it a suitable and economical screening tool. Absence or reduction of laminin-α2 chain (merosin) or α-dystroglycan occurs in some forms of congenital muscular dystrophy. The lack of nuclear membrane staining with anti-emerin antibodies occurs in X-linked Emery-Dreifuss muscular dystrophy (EDMD). Immunohistochemical techniques may give information about the type of inflammatory cell present via affinity for various markers such as CD68 (macrophages and dendritic cells), CD20 (B cells), CD3 (activated T cells), CD8 (cytotoxic T cells), and CD4 (T-helper and dendritic cells). These identify cells involved in cytotoxic, humoral, and innate immune mechanisms. Antibodies to the major histocompatibility antigen 1 (MHC1) are used to demonstrate overexpression on muscle fibers in inflammatory myopathy, while membrane attack complex (MAC) deposits may be found on the capillary endothelium in DM. Immunohistochemistry can be used to demonstrate inclusions (e.g., p62, TDP43) within muscle fibers to assist in diagnosis of IBM. Immunoblot or Western blot of muscle biopsy is more sensitive than immunohistochemistry, particularly when dealing with an enzyme deficiency or nonstructural protein in evaluation of dystrophies. Patients with Becker muscular dystrophy may have normal-appearing immunostaining for dystrophin, because the commercial antibodies may react to that part of the dystrophin protein that is normally made. However, immunoblot reveals abnormal size or amount of dystrophin in such cases. Immunoblotting is valuable in assessing for calpainopathy (LGMD2A), dysferlinopathy (LGMD2B), and in the secondary α-dystroglycanopathies. Reductions of proteins in these disorders may be secondary, so a primary deficiency must be confirmed by genetic testing.

SPECIFIC DISORDERS

membrane. This large protein (427 kD) is coded by a gene on the short arm of the X chromosome. Dystrophin consists of two ends separated by a long, flexible rod-like region. The amino terminus binds to actin, and the carboxyl terminus links dystrophin to a complex of glycoproteins in the sarcolemma. Two of these, the dystroglycans, form a direct link between dystrophin and laminin, a protein within the basal lamina. α-Dystroglycan is located extracellularly and connects to laminin. The α2 chain of laminin (also called merosin) provides the anchor into the extracellular matrix because it provides the attachment for α-dystroglycan. β-Dystroglycan spans the sarcolemmal membrane, linking dystrophin and α-dystroglycan. Merosin also binds to α7β1D integrin, a protein complex located on the sarcolemma membrane. The sarcoglycan complex, composed of α-, β-, γ-, and δ-sarcoglycans, also spans the sarcolemmal membrane and link to the dystrophin-dystroglycan complex. Dystrophin, the sarcoglycans, the dystroglycans, and merosin appear to function as a unit in stabilizing the muscle membrane. Together these proteins make up the dystrophin-glycoprotein complex. Other sarcolemmal proteins not directly linked to the dystrophin-glycoprotein complex are affected in other forms of muscular dystrophies (e.g., dysferlin, caveolin-3). Sarcomeric proteins (e.g., myosin, actin, tropomyosin, myotilin, Z-band alternatively spliced PDZ motif-containing protein [ZASP], filamin-c, desmin, titin, and telethonin, etc.), important in stabilizing the contractile apparatus, are mutated in certain dystrophies and congenital myopathies, highlighting the pathophysiological overlap of these historically clinically defined classifications. Mutations of the muscle-specific calcium-dependent protease, calpain-3 gene, are responsible for the majority of nondystrophin-related LGMDs in patients of Italian and Spanish ancestry. In addition, secretory enzymes (e.g., O-mannose-β-1,2-Nacetylglucosaminyl transferase, fukutin, and fukutin-related protein [FKRP]), which probably play a role in glucosylation of α-dystroglycan and other import proteins, are responsible for some forms of congenital muscular dystrophy, but may be associated with milder LGMD. Furthermore, mutations encoding for the nuclear envelope proteins, emerin, lamin A/C, and nesprin 1 and 2 cause EDMD.

Muscular Dystrophies

Dystrophin Deficiency (Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, and Atypical Forms)

The muscular dystrophies are a group of hereditary muscle disorders that occur at all ages and with varying degrees of severity. The traditional classification is on clinical grounds. Increasing information about the molecular basis of these disorders provides both reassurance and puzzlement to clinicians (Table 109.1). Different dystrophies are due to distinct molecular abnormalities; however, patients with similar molecular defects may show a wide variability in phenotype not always easily explained. Disorders traditionally classified as congenital myopathies on clinical grounds have been found to result from mutations in myofiber structural proteins, similar to those affected in muscular dystrophies. For the most part, the underlying molecular abnormalities in the dystrophies involve structural proteins. Therefore it is useful to review these proteins as they occur in normal muscle. The contractile proteins, actin and myosin, are arrayed with other proteins such as troponin to form the familiar thick and thin filaments of the sarcomere. The reaction between actin and myosin results in realignment between the two molecules. In the sliding filament model, the thick and thin filaments form an array that slides back and forth. The contractile proteins connect to the “outside” of the cell by means of a complex of proteins that ultimately links up with the basal lamina of the extracellular matrix. The first step in this connection is the protein dystrophin, located on the cytoplasmic face of the muscle

An absence or deficiency of dystrophin is responsible for two disorders that cause progressive destruction of muscle. Absence of dystrophin impairs the integrity of the sarcolemmal membrane, rendering the membrane susceptible to mechanical damage. Molecules such as calcium can gain access to the fiber, initiating a chain of destructive processes ultimately leading to necrosis of the muscle fiber. Eventually, this process leads to severe loss of muscle and replacement of the muscle fibers with fibrous tissue. The responsible gene is located on the short arm of the X chromosome at locus Xp21. The gene is extremely large, comprising more than 2.5 million base pairs and 79 exons or coding regions. Approximately 65%–75% of cases are associated with a deletion or duplication of one or more exons in the gene. Genetic testing assays designed to detect deletions and duplications should be used first, such as multiplex ligation-dependent probe amplification (MLPA) and microarray-based comparative genomic hybridization (CGH) (Hegde MR et al., 2008; Sansovic et al., 2013). “Hot spots” for these gene deletions exist, notably between exons 43 and 52 and particularly 44 and 49 (Nobile et al., 1997). The remaining 25%–35% of cases are due to point mutations (many of which introduce a premature stop codon), smaller deletions, or small insertions or duplications, which are best detected using next-generation sequencing. Whether a deletion is in frame or out of frame (see Chapter 48) determines whether dystrophin is absent

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TABLE 109.1

1983

Molecular Defects of Muscular Dystrophies

Disease

Inheritance

Chromosome

Affected Protein

X-Linked Dystrophies Duchenne/Becker Emery-Dreifuss Scapuloperoneal/reducing body myopathy

XR XR XR

Xp21 Xq28 Xq26.3

Dystrophin Emerin Four-and-a-half LIM domain 1 (FHL1) protein

Limb-Girdle Muscular Dystrophies (LGMD) (Classical Classification/Proposed New Classification Where Appropriate) LGMD1A/myofibrillar myopathy AD 5q22.3-31.3 Myotilin LGMD1B/EDMD AD 1q11-21 Lamin A and C LGMD1C/rippling muscle disease AD 3p25 Caveolin-3 LGMD1D/LGMD D1 AD 6q23 DNAJB6 LGMD1E/myofibrillar myopathy AD 2q35 Desmin LGMD1F/LGMD D2 AD 7q32 Transportin 3 LGMD1G/LGMD D3 AD HNRNPDL LGMD1I/LGMD D4 AD 15q15.1-21.1 15q15.1-21.1 Calpain-3 Calpain-3 LGMD2A/LGMD R1 AR 15q15.1-21.1 Calpain-3 LGMD2B/LGMD R2* AR 2p13 Dysferlin LGMD2C/LGMD R5 AR 13q12 γ-Sarcoglycan LGMD2D/LGMD R3 AR 17q12-21.3 α-Sarcoglycan LGMD2E/LGMD R4 AR 4q12 β-Sarcoglycan LGMD2F/LGMD R6 AR 5q33-34 δ-Sarcoglycan LGMD2G/LGMD R7 AR 17q11-12 Telethonin LGMD2H/LGMD R8 AR 9q31-33 E3-ubiquitin-ligase (TRIM 32) LGMD2I/LGMD R9 AR 19q13 Fukutin-related protein (FKRP) LGMD2J/LGMD R10 AR 2q31 Titin LGMD2K/LGMD R11 AR 9q31 POMT1 LGMD2L/LGMD R12 AR 11p14.3 Anoctamin 5 LGMD2M/LGMD R13 AR 9q31-33 Fukutin LGMD2N/LGMD R14 AR 14q24 POMT2 LGMD2O/LGMD R15 AR 1p32 POMGnT1 LGMD2P/LGMD R16 AR 3p21 α-Dystroglycan LGMD2Q/LGMD R17 AR 8q24 Plectin 1 LGMD2R/myofibrillar myopathy AR 2q35 Desmin LGMD2S/LGMD R18 AR 4q35.1 TRAPPC11 LGMD2T/LGMD R19 AR 3p11 GDP-mannose pyrophosphorylase B LGMD2U/LGMD R20 AR 7p21 Isoprenoid synthase domain containing protein LGMD2V AR 17q25.31 α-1,4-Glucosidase LGMD2W AR 2p14 LIM and senescent cell antigen like domains 2 LGMD2X AR 6q21 Popeye domain-containing protein 1 LGMD2Y AR 1q25.1 Torsin-A interacting protein 1 or lamin-associated protein 1 LGMD2Z/LGMD R21 AR 3q13.33 Protein O-glucosyltransferase 1 LGMD R23 AR 6q22-23 Laminin-α2 LGMD R24 AR 3p22.1 POMGNT2 Congenital Muscular Dystrophies (MDC) Bethlem myopathy/LGMD R22 AR Bethlem myopathy/LGMD D5 AD MDC1A AR α7-Integrin-related MDC AR MDC1C AR Fukuyama AR WWS AR MEB disease AR Rigid spine syndrome AR Ullrich AR

21q22.3 and 2q37 21q22.3 and 2q37 6q22-23 12q13 19q13 9q31-33 9q31 1p32 1p35-36 21q22.3 and 2q37

Collagens 6A1, 6A2, and 6A3 Collagens 6A1, 6A2, and 6A3 Laminin-α2 α7-Integrin Fukutin-related protein (FKRP) Fukutin POMT1 POMGnT1 Selenoprotein N1 Collagens 6A1, 6A2, and 6A3 Continued

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Molecular Defects of Muscular Dystrophies—cont’d

Disease

Inheritance

Distal Dystrophies/Myopathies Welander AD Udd AD Markesbery-Griggs AD Nonaka or hIBM/GNE myopathy AR Miyoshi 1* AR Miyoshi 2 AR Laing (MPD1) AD Williams AD Distal myopathy with vocal cord and AD pharyngeal weakness (VCPDM or MPD2)

Chromosome

Affected Protein

2p13 2q31 10q22.3-23.2 9p1-q1 2p13 11p14.3 14q11 7q32 5q31

TIA1 Titin ZASP GNE Dysferlin Anoctamin 5 MyHC 7 Filamin C Matrin 3

Deletion in D4Z4 region with secondary increase in DUX4 SMCHD1 with secondary increase in DUX4 DNMT3B (DNA methyltransferase 3B) Desmin MyHC 7 Four-and-a-half LIM domain 1 (FHL1) protein Nesprin-1 Nesprin-2 TMEM43 PABP2 DMPK ZNF9 Myotilin ZASP Filamin-c αB-crystallin Desmin Selenoprotein N1 BAG-3 Titin

Other Dystrophies Facioscapulohumeral type 1

AD

4q35

Facioscapulohumeral type 2

AD

18p11.32

Facioscapulohumeral type 3 Scapuloperoneal dystrophy

AD AD AD XR

20q11.21 2q35 14q11 Xq26.3

Emery-Dreifuss type 3 Emery-Dreifuss type 4 Emery-Dreifuss type 5 Oculopharyngeal Myotonic dystrophy 1 Myotonic dystrophy 2 Myofibrillar myopathy

AD AD AD AD AD AD AD AD AD AD AD/AR AR AD AD

6q24 14q23 3p25.1 14q11.2-13 19q13.3 3q21 5q22.3-31.3 10q22.3-23.2 7q32.1 11q21-23 2q35 1p36 10q25-26 2q31

Hereditary Inclusion Body Myopathies AR hIBM AR hIBM with FTD and Paget disease AD hIBM 3 AD

GNE VCP MyHC IIa

FRG1, FSHD region gene 1; FTD, frontotemporal dementia; GNE, UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase; hIBM, hereditary inclusion body myopathy; MEB, muscle-eye-brain; MyHC, myosin heavy chain; POMGnT1, O-mannose-β-1,2-N-acetylglucosaminyl transferase; POMT1, O-mannosyltransferase gene; VCP, valosin-containing protein; WSS, Walker-Warburg syndrome; ZASP, Z-band alternatively spliced PDZ motif-containing protein. *LGMD 2B and Miyoshi distal dystrophy are the same condition. Modified with permission from Amato, A.A., Russell, J., 2016. Neuromuscular Disease, second edition. McGraw-Hill, New York.

from the muscle or present in a reduced altered form. This has clinical significance because the former is usually associated with the severe DMD, whereas the latter may cause the milder Becker variant (BMD). In BMD, the abnormal dystrophin preserves enough function to slow down the progress of the illness. Reading of the DNA code is triplet by triplet. Maintenance of this reading frame throughout the length of the gene is required for dystrophin production. If a deletion removes a multiple of three base pairs, the reading frame may be intact upstream and downstream and may make limited sense, as if the sentence “You F ECF

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cannot eat the cat” were changed to “You not eat the cat,” and some modified dystrophin may be formed. This is often the situation in the mild form of dystrophin deficiency (BMD). In the severe form, the reading frame is destroyed, as if a deletion resulted in the sentence “Yoc ann ote att hec at.” Exceptions to this rule exist, as frameshift deletions have been associated with the milder form of the disease, particularly at the 5′ end of the gene in exons 3–7. The prevalence of DMD in the general population is approximately 3 per 100,000, and the incidence among live-born males is 1 per 3500. BMD is approximately one-tenth 02 .4.(1( 4 (

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Age Fig. 109.10 Duchenne muscular dystrophy: change in serum creatine kinase (CK) level with age. This is a scattergram of serum CK levels in individual patients. Lines represent the 5th, 25th, 50th, 75th, and 95th percentiles.

Fig. 109.9 Duchenne Muscular Dystrophy. Calf and thigh hypertrophy in an ambulatory 8-year-old patient.

as common. Although the inheritance is clearly X-linked recessive, almost a third of cases are sporadic. Presumably this is due to a spontaneous mutation occurring either in the child or in the mother’s ova. Duchenne muscular dystrophy. Affected children are typically normal at birth. After affected boys begin walking, however, the clumsiness seen in all toddlers persists. Progressive leg weakness, proximal greater than distal, develops through early childhood. Affected boys must place one hand on the knee to assume an upright position when rising from the floor (Gower maneuver). Parents notice that the child runs improperly and is unable to jump clear of the floor with both feet. Toe-walking and a waddling gait are common. Often at this stage, the calf muscles are rather firm and rubbery (pseudohypertrophy) (Fig. 109.9). In the absence of therapy, tightness across several joints in the legs develops. The iliotibial bands and the heel cords are usually the first to tighten. This is particularly noticeable in boys who habitually walk on their toes. Apparent improvement may occur between ages 2 and 6 as the child gains motor skills. This is illusory because it simply represents the child’s natural development, which muscle weakness has not yet outpaced. By 5 or 6 years of age, climbing upstairs becomes difficult, requiring the use of the railing. By the age of 6 or 7, the boys often complain of sudden spontaneous falls. At first, these falls occur when the child is in a hurry or knocked off balance by playmates. The fall is quite spectacular to the onlooker; the knees collapse abruptly, and the child drops like a stone to the ground. At approximately 8–10 years of age, affected children cease to be able to climb stairs or stand up from the floor, and upper limb weakness becomes more apparent. This is typically when they begin using a wheelchair for locomotion. Earlier studies suggested that the ability to walk was lost at about age 9, but with appropriate bracing, reconstructive surgery, and physiotherapy, confinement to a wheelchair is about 12 years of age. With the increasing use of

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corticosteroids, many affected boys maintain ambulation even beyond 12 (Kohler et al., 2009). Contractures of the hips, knees, and ankles become severe when the relatively untreated child spends much of the day in a wheelchair. The hips and knees lock at 90 degrees, and the feet turn downward and inward in an exaggerated position of equinovarus. It is very difficult to get normal shoes to fit them, and it is impossible for them to sleep, except in one position: usually with the knees propped up with pillows and slightly turned on one side. Handling the children at this stage becomes very difficult, and back pain and limb pain almost inevitably accompany this severe stage of muscular dystrophy. Development of a severe scoliosis compromises respiratory function. Cardiac muscle is also affected, and clinically evident cardiomyopathy develops in one-third of patients by age 14 and virtually all patients over age 18. Screening with an electrocardiogram (ECG) and either echocardiogram or cardiac Magnetic Resonance Imaging (MRI) should be performed at diagnosis, then annually while patients are asymptomatic. Co-management with a cardiologist is essential to aid in surveillance and initiation of heart failure therapies. Progressive ventilatory muscle weakness is also uniform. Respiratory screening with once-yearly measurement of forced vital capacity (FVC) should be performed annually while boys are still ambulatory. Affected boys usually die of either cardiac or respiratory complications. The serum concentration of creatine kinase (CK) is typically markedly elevated; levels greater than 10,000 mU/mL are common (Fig. 109.10). Electromyography (EMG) shows myopathic changes (see Chapter 36). Genetic testing has largely replaced muscle biopsy to diagnose DMD as it is less invasive and has become more widely available, but a biopsy is essential if genetic testing is unrevealing. A diagnosis may be made when immunohistochemistry reveals reduction of dystrophin on the sarcolemma or when Western blot demonstrates absent or marked reduced quantity and size of dystrophin. Three antibodies are available against the ends (Dys-2 for the carboxyl terminus and Dys-3 for the amino terminus) and the rod region (Dys1) of the molecule. In DMD, immunostaining is absent or the stain is irregular and fragmented. Absence of the amino terminus, the end that binds with actin, appears to be associated with more severe symptoms. Variation in myofiber size, fibrosis, groups of basophilic fibers,

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Fig. 109.11 Duchenne Muscular Dystrophy: Muscle Biopsy. Fibers are of variable size and separated by connective tissue. Large heavily stained opaque fibers are noted (Verhoeff-Van Gieson stain).

Fig. 109.12 Duchenne Muscular Dystrophy. Groups of small basophilic (darkly staining) fibers are scattered in the biopsy (hematoxylin and eosin stain).

and opaque or hypercontracted fibers (hyaline fibers) are typically seen (Figs. 109.11 and 109.12).

Treatment of Duchenne muscular dystrophy Physical therapy. The primary aim of physical therapy is to keep the joints as loose as possible, avoiding contractures. Early on, the iliotibial bands and the heel cords give the greatest problems. Late in the course, elbow, wrist, and finger contractures add to functional disability. Physical therapy generally commences at 3–4 years of age, when parents learn to stretch the child’s heel cords, hip flexors, and iliotibial bands daily. Passive stretching of joints is directed not at

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increasing the range of motion but rather at preventing any further development of contractures. This requires careful explanation to parents because they can be disheartened to see no improvement in the tightness even after many months of therapy. Night splints molded around the lower part of the legs to maintain the feet at right angles to the legs should be used starting at an early age. Ankle contractures rarely occur in patients who use these splints conscientiously. Unfortunately, some patients, particularly those 6 or 7 years or older, cannot tolerate the splints. Parents often ask about an active exercise program; such a program is largely unnecessary in a young child who runs around to the best of his ability anyway. By the time a child is having difficulty walking or is in a wheelchair, muscle weakness is severe, and exercise does not increase muscle strength. Bracing. The appropriate use of bracing may delay the child’s progression to a wheelchair by approximately 2 years. A major factor responsible for inability to stand or walk is weakness of the quadriceps. Such weakness causes the knee to collapse when even slightly flexed; the only stable position is in hyperextension. The addition of a long-leg brace (knee-foot orthosis) can help solve this problem. Such a device stabilizes the knee and prevents the knee from flexing. The children walk stiff legged but do not have the same problem with falling they had previously. Generally, children are ready for bracing when they have ceased to climb stairs, are having great difficulty arising from the floor, and are having frequent daily falls. On examination, inability to straighten the knee against gravity is also an indication for bracing. Because the brace functions as a pendulum, slight elevation of the hip is sufficient to bring the leg forward so the weight of the brace is rarely a problem. There may be some advantage to a lightweight plastic kneefoot orthosis, but it may be more difficult to keep the leg straight with such a device. Surgery. Reconstructive surgery of the leg often accompanies bracing. The purpose of leg surgery is to keep the leg extended and prevent contractures of the iliotibial bands and hip flexors. Contractures of the iliotibial bands are associated with a stance in which the boy’s legs are widely abducted. As noted before, the long-leg brace acts like a pendulum. If the leg is widely abducted, the child cannot swing the leg forward. Lifting the hip causes the leg to try to swing inward toward the midline, but resistance from the iliotibial band contractures renders this impossible. A simple way to maintain function in the leg is to perform percutaneous tenotomies of the iliotibial bands, knee flexors, hip flexors, and Achilles tendons. This procedure often allows a child who is becoming increasingly dependent on a wheelchair to resume walking with the aid of bracing. Spinal stabilization is also an important option for DMD patients. Because of the extreme discomfort of severe scoliosis and the respiratory problems associated with it, spinal surgery is an acceptable procedure for managing the late stages of the disease. It is considered in patients with 35 degrees or more of scoliosis and significant discomfort. To reduce the risks associated with surgery, FVC ideally should be greater than 35% of predicted. Pharmacological treatment. Accumulating evidence suggests that corticosteroids not only improve muscle strength and pulmonary function but also delay time to disease progression milestones such as loss of ambulation (Gloss et al., Neurology 2016; Koeks et al., 2017). There is a possible but less proven beneficial effect for the associated scoliosis and cardiomyopathy, as well. Prednisone 0.75 mg/kg/daily CTD is typically initiated by the age of 5—after motor function plateaus and before substantial decline has begun; 10 mg/kg/weekend CTD is an alternative for those with side effects. The synthetic steroid deflazacort has a similar therapeutic effect and may be associated with less weight gain (Griggs et al., 2016). The usual dosing is 0.9 mg/kg/ daily CTD.

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CHAPTER 109 Disorders of Skeletal Muscle Improved cardiorespiratory intervention has extended median survival dramatically from the late teens into the late 20s and early 30s (Ishikawa et al., 2011). Consensus recommendations suggest initiating an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker by the age of 10. Additional treatments such as beta-blockers are used for symptomatic heart failure. Assisted ventilatory support is typically required by the age of 18. Therapies currently in development aim to circumvent deficient dystrophin protein production. Eteplirsen is a phosphorodiamidate morpholino oligomer that binds to dystrophin gene pre-mRNA and induces exon 51 skipping (Mendell et al., 2016). Skipping this exon restores the open reading frame that is disrupted by certain dystrophin mutations. Although this actually increases the size of the deletion, it preserves translatable mRNA after the deletion, leading to production of a dystrophin protein more similar to what is seen in BMD mutations rather than DMD mutations. Thus the treatment is not curative but instead aims to convert DMD into a BMD phenotype. Approximately 13% of DMD boys are amenable to exon 51 skipping, based on which specific mutation they harbor. Eteplirsen was granted accelerated approval by the US Food and Drug Administration (FDA) in 2016 based primarily on small trials demonstrating increased dystrophin protein production in the muscle on biopsy specimens. The FDA mandated an additional clinical trial to ensure the efficacy of the drug, which is ongoing. Eteplirsen is not yet approved in Europe. Additional exon skipping therapies are in development. Ataluren, by contrast, was recently approved by the European Commission but is not yet available in the United States. Despite promising early trials, a phase III placebo-controlled trial showed no benefit for its primary endpoint, change in the 6-minute walk test (McDonald et al., 2017). It targets the estimated 11% of boys with a nonsense mutation, promoting ribosomal read-through of the stop codon. Becker muscular dystrophy. BMD shares the clinical characteristics of DMD but has a milder course (Narayanaswami et al., 2014). The disease usually begins in the first decade, although parents may notice the first signs of weakness later because of the milder symptoms. Occasionally, symptom onset is delayed until the fourth decade or later. The muscular hypertrophy, contractures, and pattern of weakness are similar to those seen in DMD. These boys, however, continue to walk independently past the age of 15 years and may not use a wheelchair until they are in their 20s or even later (Bushby et al., 1993). Teenagers with BMD often complain of leg cramps and muscle pain, often associated with exercise and often more severe than in DMD. A significant proportion of these patients have a cardiomyopathy that can be more disabling than the weakness. Cardiac transplantation has been successful in some patients with this form of the illness. As with DMD, serum CK levels are elevated but typically not as high. EMG demonstrates myopathic features. Diagnosis requires demonstration of a mutation in the dystrophin gene or reduced quantity or size of dystrophin on muscle biopsy. In BMD, staining may be reduced but can be normal appearing. Therefore immunoblotting is required to show a decreased amount of dystrophin. Because boys do not have much trouble in the first few years, there is a reduced need for aggressive physiotherapy, surgical reconstruction, and night splints. Patients with BMD are less prone to develop kyphoscoliosis, perhaps because they lack wheelchair confinement until after the spine has become fully mature. We have used corticosteroids only occasionally in patients with BMD. The stabilizing effect of steroids is less noticeable when the disease is already slowly progressive. In every other respect, including bracing and genetic counseling, disease treatment is the same as that for the severe form.

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Other phenotypes associated with dystrophinopathy. With the development of genetic testing and dystrophin analysis, it is becoming clear that dystrophin deficiency is not always associated with the BMD or DMD phenotype. Some patients have only symptoms of exercise intolerance, muscle pain, and myoglobinuria (Narayanaswami et al., 2014). Others manifest only a cardiomyopathy or are asymptomatic despite elevated serum concentrations of CK. Most female carriers of dystrophin gene mutations are asymptomatic, but approximately 8% manifest weakness and have a clinical phenotype similar to BMD or LGMD. Manifesting carriers will usually have an elevated serum CK level and myopathic EMG. Muscle biopsy will usually demonstrate a mosaic pattern or patchy staining of dystrophin on the sarcolemma. It is impractical to perform genetic testing on all patients with neuromuscular complaints. However, the presence of muscle pain, mild weakness, an elevated serum CK, and muscle hypertrophy warrants consideration of analyzing dystrophin. Attempts to correlate the genetic abnormality with the clinical picture are inexact, but abnormalities in the amino terminus and at the carboxyl terminal domains of dystrophin are associated with the more severe form of disease. Alterations in the rod domain are more variable and may be associated with a mild phenotype. In-frame deletions and insertions are associated with a much milder phenotype than out-of-frame alterations. Genetic counseling. Because DMD and BMD are X-linked recessive disorders, we recommend testing the carrier state of all women related to an affected person by maternal linkage. Routine laboratory testing (i.e., CK elevation) and muscle biopsy are insensitive, so genetic testing is required. Up to 30% of cases may be sporadic and due to new mutations or deletions. In the experience of many clinicians, an even higher percentage of new patients arriving in the clinic are sporadic cases, perhaps because genetic counseling is widely available and the women who carry the abnormal gene decide not to have children. Genetic analysis of all potential carriers is advisable. In a family in which the disease is associated with a deletion, there is little problem in determining whether the woman is carrying the affected X chromosome, using techniques that are presently available. Genetics laboratories can identify the presence of a mutant gene over the background contributed by the normal allele through analysis of the gene “dosage.” Two normal alleles that have a double dose are compared against a deleted allele and a normal allele that have a single dose (VoskovaGoldman et al., 1997). Unfortunately, situations exist in which a mutation is identified in a boy with “sporadic” DMD but not in the mother, and yet the mother is still a carrier. This occurrence is secondary to germline mosaicism in which the mutation in the mother lies only in a percentage of her oocytes. The estimated recurrence rate of DMD is as high as 14% even in such cases. If desired, prenatal diagnosis using amniotic cells or chorionic villus biopsies can identify whether or not the fetus is affected.

Limb–Girdle Muscular Dystrophies There is a broad diversity in the clinical presentations of patients with forms of LGMD (Narayanaswami et al., 2014). The traditional diagnosis and classification of LGMDs was accordingly challenging. Many patients present predominantly with proximal weakness, but in others the pattern of weakness is more disparate. In some, hip weakness is greater than shoulder weakness, others the reverse. Some cases are dominantly inherited, others recessively. Onset may be late in life with mild symptoms, but in others severe and early in life. Beginning with the discovery that a defect in one of the sarcoglycans caused a severe form of LGMD occurring in North Africa, the delineation of several other entities characterized by defects in structural proteins or enzymes followed. These include the sarcoglycans, the α2-chain of laminin (merosin), calcium-activated protease, calpain-3,

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and others. Those forms with autosomal dominant inheritance have been designated type 1, and those with autosomal recessive inheritance type 2. Subclassification with an alphabetical letter has traditionally characterized distinct genetic forms of LGMD1 and LGMD2 (see Table 109.1; Bushby, 1995). As more and more novel disease genes have been identified, however, this classification scheme has run out of letters for LGMD2. An updated classification schema was recently proposed which replaces 1 and 2 with A and R and the alphabetical letter with a number designating order of gene discovery as well as the gene itself. As an example, LGMD2A would be reclassified as LGMD R1 calpain-3–related (Straub et al., 2018). In this text, we will refer to both the traditional and newly proposed nomenclature. Certain forms of LGMD have been shown to be associated with respiratory muscle weakness and/or cardiomyopathy, so identification of a specific gene can be very helpful in guiding management and informing prognosis. For some culprit genes, certain mutations have been shown to result in a LGMD phenotype while others result in other phenotypes historically classified as distinct from LGMD, such as forms of distal myopathy or congenital muscular dystrophy, autosomal dominant EDMD, exercise intolerance, or even asymptomatic hyperCKemia. Adding to the confusion, a limb–girdle pattern of weakness can also be seen in disorders not strictly classified as a form of LGMD. The following sections outline the known genetic abnormalities and then comment on the more amorphous forms of LGMD. The prevalence of these diseases as a group ranges from 1 to 2.27/100,000 (Norwood et al., 2009; van der Kooi et al., 1996). The autosomal recessive LGMDs are more common than the autosomal dominant LGMDs. Although there is heterogeneity between patients and specific disorders, as a general rule the autosomal recessive LGMDs are also more severe.

Autosomal dominant limb–girdle muscular dystrophies

LGMD1A or myofibrillar myopathy (myotilin deficiency). Patients with LGMD1A can present with proximal arm and leg weakness in their teens to late adult life or with distal leg weakness (e.g., foot drop) later in life. Some patients have early pharyngeal weakness as well (Narayanaswami et al., 2014). Serum CK concentrations can be normal or moderately elevated. Muscle biopsies may demonstrate rimmed vacuoles within muscle fibers and features of myofibrillar myopathy (MFM). LGMD1A is allelic to one subtype of MFM and is caused by mutations in the myotilin gene located on chromosome 5q22.3-31.3 (Selcen and Engel, 2004). Myotilin is a sarcomeric protein that is present at the Z-disk. The protein is likely important in myofibrillogenesis and stabilization of the Z-disk and sarcomere.

LGMD1B or Emery-Dreifuss muscular dystrophy (lamin A/C deficiency). This myopathy is as also known as autosomal dominant EDMD (Bonne et al., 2000; Narayanaswami et al., 2014; van der Kooi et al., 1996). Some patients manifest with a limb–girdle pattern of weakness, while others present with a humeral-peroneal weakness. Cardiomyopathy with severe conduction defects and arrhythmias may also occur, with or without skeletal muscle involvement. Sudden death secondary to fatal arrhythmias is common, so early diagnosis is desirable and pacemaker insertion and/or implantable cardiac defibrillator (ICD) is often necessary (Kayvanpour et al., 2017). Early elbow and ankle contractures as well as spine rigidity are features seen in some patients, but not universal. Serum CK levels may be normal or elevated up to 25-fold. Muscle biopsies demonstrate dystrophic features with the rare occurrence of rimmed vacuoles. LGMD1B is localized to mutations in the lamin A/C gene located on chromosome 1q11-21 (Bonne et al., 1999; van der Kooi et al., 1997). Alternative splicing of the lamin A/C messenger (m)RNA transcript produces lamins A and C. Lamin A/C is an intermediate-size filament located on the nucleoplasmic surface of the inner nuclear membrane,

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where it interacts with various lamin-associated proteins including emerin, the abnormal protein associated with X-linked EDMD. Lamin A/C may also bind to heterochromatin. Immunostaining of the nuclear membrane with anti-emerin antibodies is normal, helping distinguish this myopathy from X-linked EDMD. Electron microscopy reveals alterations in myonuclei, including the loss of peripheral heterochromatin, altered interchromatin texture, and fewer than normal nuclear pores (Sabatelli et al., 2001).

LGMD1C or rippling muscle disease (caveolin-3 deficiency). This rare myopathy usually presents in childhood with proximal leg weakness greater than arm weakness and exertional myalgias (Carbone et al., 2000; Minetti et al., 1998; Narayanaswami et al., 2014). Progression of weakness is variable. The clinical phenotype associated with caveolin-3 mutations is quite heterogeneous. Some patients manifest with mainly distal weakness, involving thenar, hypothenar, and intrinsic hand muscles predominantly. Others have familial hypertrophic cardiomyopathy or autosomal dominant rippling muscle disease (Aboumousa et al., 2008; Betz et al., 2001). Serum CK levels are increased 3–25 times normal. In fact, some patients manifest with asymptomatic hyperCKemia. LGMD1C is caused by mutations in the gene encoding for caveolin-3 on chromosome 3p25 (Carbone et al., 2000; Minetti et al., 1998). Caveolins are scaffolding proteins that interact with lipids and other proteins in caveoli, which are flask-shaped invaginations of the sarcolemmal membrane. Immunostaining of muscle biopsies demonstrates a reduction of caveolin-3 along the sarcolemma. Electron microscopy EM reveals a decreased density of caveoli on the muscle membrane as well. LGMD1D or LGMD D1 DNAJB6-related. This recently described myopathy presents in the second to sixth decade with proximal muscle or distal weakness greater in the lower extremities (Hackman et al., 2011; Harms et al., 2012; Narayanaswami et al., 2014; Sarparanta et al., 2012). Cardiorespiratory involvement was notably absent. Serum CK levels are typically slightly elevated. Muscle biopsy reveal rimmed vacuoles and features suggestive of a MFM.

LGMD1E or myofibrillar myopathy (desmin deficiency). This is described in the section on MFM (Greenberg et al., 2012). LGMD1F or LGMD D2 TNP03-related. This recently described myopathy presents in the first to sixth decade with proximal greater than distal weakness, legs more than arms (Melià et al., 2013). Anticipation may be seen, with increasing severity in subsequent generations. CK level is normal to moderately elevated. Muscle biopsy can show rimmed vacuoles and features of MFM. It is caused by mutation in the transportin 3 (TNP03) gene, which encodes a nuclear import receptor for precursor-mRNA splicing factors. LGMD1G or LGMD D3 HNRPDL-related. This myopathy was initially described in two kindreds, one Brazilian and one Uruguayan (Viera et al., 2014). Onset of weakness is in the second to sixth decade, with proximal lower limb weakness usually preceding upper limb weakness. Finger flexion and toe flexion weakness are typical, and early-onset cataracts may occur. It is caused by mutations in the HNRPDL gene, which encodes a ribonucleoprotein important in mRNA biogenesis and metabolism, mediating alternative splicing. Bethlem myopathy or LGMD D5 collagen 6–related. Bethlem myopathy is allelic to the more severe Ullrich congenital muscular dystrophy (UCMD, see below) (Camacho-Vanegas et al., 2001; Bertini and Pepe 2002). Both are due to mutations encoding collagen VI (COL6A1, COL6A2, COL6A3). Onset is typically by early childhood. Joint laxity, especially distally, is common early in this disorder (Fig. 109.13). Contractures are also very common, especially at the elbows and ankles, and can lead to confusion with EDMD. Contractures can involve the wrists and fingers over time. Restrictive ventilatory deficits can be seen, presumably from a combination of weakness and

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Fig. 109.13 Bethlem Myopathy. Joint laxity in the thumb and finger.

contractures. Some patients, however, have a limb–girdle pattern of weakness without any contractures.

LGMD2A or LGMD R1 calpain-3–related or LGMD D4 calpain-3–related. LGMD2A was first reported in an inbred population on Reunion Island in the Indian Ocean (Fardeau et al., 1996). It is caused by mutations in the gene for muscle-specific calcium-activated neutral protease (CANP-3 or calpain-3) (Spencer et al., 1997). Since the initial description, the disorder has shown a worldwide distribution and is the most common LGMD (Lostal et al., 2018; Vissing et al., 2016). The underlying pathophysiology of the illness is uncertain. CANP-3 is not a structural protein but an enzyme. It has been suggested that the enzyme has a regulatory role in the modulation and control of transcription factors and thus of gene expression. CANP-3 also binds to titin and can cleave filamin-C; thus it may have a role in stabilizing the sarcomere. Although most commonly autosomal recessive inheritance is seen, autosomal dominant inheritance has recently been reported in a series of 37 patients with a single 21-base-pair, in-frame deletion. These patients had a similar phenotype to traditional LGMD2A, but with milder weakness (Vissing et al., 2016). The disease is progressive and typically begins in early adolescence but can begin in early or middle adulthood for some. Most cases have been mild to moderately progressive, with loss of ambulation in adult life. Severe forms occur. Weakness occurs in the hips first and then in the shoulders. Facial strength is preserved, and the neck flexors and extensors are strong. Scapular winging occurs, different from that seen in FSHD, with the whole of the medial scapular border jutting backward. Posterior thigh muscles and adductors are more severely affected than the knee extensors. The rectus abdominis muscles are affected early which can lead to abdominal hernias. Early contractures may develop. Mild to moderate respiratory muscle weakness can develop, commensurate with the severity of skeletal muscle weakness, but cardiac muscle is spared. The serum concentration of CK is markedly elevated early in the course and then decreases to normal concentrations later in the illness. Muscle biopsies may demonstrate endomysial inflammatory cell infiltrate with prominent eosinophils that may lead to misdiagnosis as eosinophilic myositis (Brown and Amato, 2006; Krahn et al., 2006).

LGMD2B or LGMD R2 dysferlin-related (dysferlin deficiency). Mutations in the gene encoding for dysferlin, located on chromosome 2p13, lead to clinically heterogeneous myopathies. Some

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patients show a limb–girdle pattern of weakness (LGMD2B), while others present with weakness and atrophy of the calf muscles (Miyoshi myopathy) (Harris et al., 2016). In both cases, early preferential involvement of the gastrocnemius and thigh adductors is common (Paradas et al., 2010). Dysferlinopathies account for only about 1% of LGMDs but about 60% of distal myopathies (Fanin et al., 2001). Looking at this another way, 80% of patients with dysferlinopathy manifest a distal myopathy, 8% have an LGMD pattern of weakness, and 6% have asymptomatic elevation of serum CK. Less common presentations include progressive foot drop, axial muscle weakness with bent spine syndrome/camptocormia, and rigid spine syndrome (Illa et al., 2001; Nagashima et al., 2004; Seror et al., 2008; Vilchez et al., 2005). The dysferlinopathies typically present in adolescence or early adult life. Progression is usually slow, but some patients lose ambulation in their 20s while others can walk late in life. Interestingly, intrafamilial variability exists in the pattern of weakness and disease progression. Serum CK concentrations are markedly elevated, usually 35–200 times normal. Muscle biopsies demonstrate dystrophic features in severely affected muscles but nonspecific myopathic features in less affected muscles. Occasionally a striking endomysial or perivascular inflammatory process is appreciated, leading to an incorrect diagnosis of PM. However, unlike PM, the inflammatory cells usually do not invade non-necrotic muscle fibers. Amyloid deposition may also be evident in some cases (Spuler et al., 2008). Immunostaining and immunoblot confirm the diagnosis. Dysferlin localizes to the sarcolemmal membrane but does not directly interact with dystrophin or the sarcoglycans. Dysferlin is thought important in membrane repair (Bansal et al., 2003; Cenacchi et al., 2005; Glover and Brown, 2007). LGMD2C, 2D, 2E, and 2F (sarcoglycan deficiencies). Four known sarcoglycans expressed in muscle are associated with different forms of autosomal recessive LGMD2. The genetic abnormality underlying LGMD2C, 2D, 2E, and 2F are mutations in the genes for γ-sarcoglycan, α-sarcoglycan, β-sarcoglycan, and δ-sarcoglycan, respectively. The sarcoglycans are a tightly knit family, and when one is absent, the others may also be missing. This is particularly true of α-sarcoglycan, making it both a useful screening tool and a misleading one on occasion. An absence of α-sarcoglycan is an indication to search for the abnormal gene, be it an α-, β-, γ-, or δ-sarcoglycanopathy.

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Sarcoglycanopathies may account for more than 10% of patients with a limb–girdle pattern and normal dystrophin (Duggan et al., 1997; Marsolier et al., 2017). Of these, α-sarcoglycanopathies (LGMD2D) are most common, accounting for approximately 6% of cases. The most common type varies considerably between geographic areas. Sarcoglycanopathies may account for up to 50% of patients with muscular dystrophy in North Africa. The four sarcoglycanopathies are very similar clinically and may be confused with DMD; the lack of cognitive impairment can help distinguish. Childhood-onset is common, with trunk and proximal leg weakness and a serum CK concentration of 1000 units and higher (Narayanaswami et al., 2014). Facial weakness is absent, but scapular winging and calf hypertrophy occur. Weakness is progressive and many patients require a wheelchair. Many patients experience respiratory muscle weakness and assisted ventilation may be required (Fayssoil et al., 2016). Cardiac dysfunction occurs in a minority of affected patients, more commonly in those with LGMD2C and 2E. LGMD2G or LGMD R7 telethonin-related. Patients with this dystrophy may have either proximal or distal weakness (Moreira et al., 1997; Narayanaswami et al., 2014). Mean age of onset is approximately 12.5 years. Legs are affected more than arms; the quadriceps and anterior tibial muscles are affected early. Some may have a cardiomyopathy. Serum CK levels are 3–17 times normal. Muscle pathology shows dystrophic features in addition to the frequent occurrence of rimmed vacuoles within muscle fibers. LGMD2G links to mutations in the gene that encodes for telethonin on chromosome 17q11-12 (Moreira et al., 2000). Telethonin is one of the most abundant muscle proteins, where it localizes to the sarcomere. Telethonin may interact with the large sarcomeric proteins, titin and myosin. Abnormal telethonin may disrupt normal myofibrillogenesis. LGMD2H or LGMD R8 TRIM 32-related. This LGMD was initially reported in families of Manitoba Hutterite origin (Weiler et al., 1998) and is allelic with sarcotubular myopathy. Most affected individuals have a mild limb–girdle pattern of weakness, with onset from birth to the seventh decade (Narayanaswami et al., 2014). Patients may note exertional myalgias; scapular winging and facial weakness may be variably noted. Serum CKs range from 250 to over 3000 IU/L, and EMGs reveal myopathic features. Muscle biopsy features demonstrate small vacuoles that represent focal dilations of the sarcoplasmic reticulum. This myopathy is caused by mutation in the gene that encodes for E3-ubiquitin ligase (also known as TRIM 32) (Frosk et al., 2002). This ligase may be important for ubiquinating proteins targeted for destruction by the proteasomes (Kramerova et al., 2007). TRIM32 mutations may lead to dysregulation of myofibrillar protein turnover. LGMD2I or LGMD R9 FKRP-related. This dystrophy was initially reported in a large consanguineous Tunisian family (Driss et al., 2000). Subsequently the dystrophy has shown a worldwide distribution and is the most common type of LGMD in patients of northern European ancestry (Narayanaswami et al., 2014). The clinical phenotype is variable, with age of onset from the first to the sixth decade. The course resembles a dystrophinopathy in some, including calf hypertrophy (Mercuri et al., 2003). Difficulty running, difficulty climbing stairs, and cramps/myalgias are all common presenting symptoms. A severe cardiomyopathy can develop, and respiratory muscle weakness occurs as the disease progresses. Serum CKs are elevated 10–30 times normal in some affected younger patients but are normal in some older individuals (Brockington et al., 2001, 2002; Mercuri et al., 2003; Willis et al., 2014). LGMD2I is caused by mutations in the gene that encodes for FKRP, a glycosyltransferase, and its deficiency is associated with abnormal glycosylation of α-dystroglycan (Brockington et al.,

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2002). It is unique among secondary α-dystroglycanopathies in that it more commonly causes an adult-onset LGMD rather than a form of congenital muscular dystrophy, but mutations in FKRP do also cause congenital muscular dystrophy with normal merosin (MDC1C). LGMD2J or LGMD R10 titin-related. TTN is an enormous gene, producing the largest protein in humans. Titin is a protein that spans the entire sarcomere and serves as a ligand for calpain-3. Numerous clinical phenotypes have been described in relation to mutations throughout the gene, with varying forms of skeletal muscle involvement and/or cardiomyopathy. Autosomal dominant disorders include hereditary myopathy with early respiratory failure (HMERF), Udd distal myopathy (discussed in the Distal Myopathies section), and isolated dilated cardiomyopathy; autosomal recessive disorders include LGMD2J, adult-onset distal myopathy, proximal adult-onset rimmed vacuolar myopathy, and a congenital titinopathy (discussed in the Congenital Myopathies section) (Narayanaswami et al., 2014; Oates et al., 2018; Savarese et al., 2018). Because of its massive size, it is common to uncover novel or rare variants of uncertain significance (VUS) in the TTN gene when genetic testing is pursued; many of these will not be related to the patient’s condition. By converse, pathogenic mutations can also be missed due to the gene’s large size and complex structure. LGMD2J is characterized by childhood-onset weakness that is more severe in the proximal muscles of the arms and legs, with distal weakness often present but mild (Udd et al., 2005). Some patients develop a cardiomyopathy. CKs are usually mildly elevated. Muscle biopsies reveal dystrophic features, and rimmed vacuoles are usually absent or rare. As the name implies, proximal adult-onset rimmed vacuolar myopathy includes rimmed vacuoles on biopsy, with a unique pattern of weakness affecting the quadriceps and soleus but sparing the tibialis anterior. HMERF resembles Udd distal myopathy; it is autosomal dominant and associated with progressive foot drop (Narayanaswami et al., 2014; Ohlsson et al., 2012; Pénisson-Besnier et al., 2010; Pfeffer et al., 2012). However, it tends to affect patients earlier in adulthood, may also affect the proximal muscles (legs greater than arms), and is associated with early respiratory failure. Muscle biopsies reveal rimmed vacuoles and features of MFM. LGMD2L or LGMD R12 anoctamin 5-related. This disorder was initially described in 14 French Canadian patients from eight different families, but has since been shown to be among the most common LGMDs in Northern Europe (Jarry et al., 2007). Subsequently, patients have been reported with a Miyoshi myopathy-like phenotype with involvement of the calves in the second decade of life, exertional myalgias, hyperCKemia, or calf hypertrophy (Bolduc et al., 2010; Mahjneh et al., 2010; Narayanaswami et al., 2014; Schessl et al., 2012). Females are more likely than males to have mild phenotypes without weakness (Penttila et al., 2012). Symptoms may begin from age 20 to 70. Those with the LGMD phenotype usually have associated quadriceps atrophy and myalgias, and weakness may be asymmetric. There is usually no cardiac or respiratory muscle involvement. Serum CK concentrations can be markedly increased. Muscle biopsies demonstrate nonspecific dystrophic features with increased endomysial connective tissue associated with basal lamina duplication and collagen disorganization infiltration. The disorder is caused by mutations in the ANO5 gene that encodes for anoctamin 5, a transmembrane protein that may be a calcium-activated chloride channel.

LGMD2K, LGMD2M, LGMD2N, LGMD2O, LGMD2T, and LGMD2U. These are all secondary α-dystroglycanopathies, which usually present in infancy or early childhood as congenital muscular dystrophies (discussed in detail in the Congenital Muscular Dystrophy

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CHAPTER 109 Disorders of Skeletal Muscle section) (Iannaccone and Castro, 2013). Rarely they present later in childhood or early adult life with a limb–girdle pattern of weakness with or without CNS involvement (Narayanaswami et al., 2014). LGMD2K, or LGMD R11 POMT1-related, is caused by mutations in protein O-mannosyltransferase 1 (POMT1). This is usually associated with Walker-Warburg syndrome, but can also cause childhood onset of a milder LGMD phenotype associated with severe cognitive impairment (Godfrey et al., 2007). LGMD2M, or LGMD R13 fukutin-related, is caused by mutations in the gene that encodes for fukutin, which usually causes Fukuyama congenital muscular dystrophy (FCMD). However, mutations in the fukutin gene have also been associated with a milder adult-onset myopathy (LGMD2M), particularly outside of Japan (Puckett et al., 2009; Vuillaumier-Barrot et al., 2009). Affected individuals can have normal intelligence and brain structure, have a mild limb–girdle weakness, present with only a cardiomyopathy, or have asymptomatic elevation of serum CK concentrations. Some patients have remarkable steroid responsiveness (Godfrey et al., 2006). LGMD2N, or LGMD R13 POMT2-related, is caused by mutations in the gene encoding protein O-mannosyltransferase 2 (POMT2). Mutations in this gene can also cause Walker-Warburg syndrome and rarely are associated with a milder limb–girdle syndrome affecting hamstrings, gluteal, and paraspinal muscles with universal cognitive impairment (Østergaard et al., 2018). LGMD2O, or LGMD R15 POMGnT1-related, is caused by mutations in POMGnT1, which encodes protein O-mannose-β-1,2-Nacetylglucosaminyl transferase. Mutations in this enzyme also cause muscle-eye-brain (MEB) disease. Mutations in POMGnT1 can be associated with milder allelic variants of muscular dystrophy and normal intelligence (LGMD2N) (Clement et al., 2008; Godfrey et al., 2007). LGMD2T, or LGMD R19 GMPPB-related, is caused by mutations in GMPPB, encoding guanosine diphosphate mannose pyrophosphorylase B. Those with a LGMD phenotype present from very early childhood to the fourth decade; cognitive impairment, seizures, and cataracts are common with early-onset cases (Carss et al., 2013; Cabrera-Serrano et al., 2015). LGMD2U, or LGMD R20 ISPD-related, is caused by mutations in a gene encoding isoprenoid synthetase domain-containing protein (ISPD), more commonly associated with Walker-Warburg syndrome. A childhood-onset LGMD phenotype with normal intelligence has been recently reported (Cirak et al., 2013). LGMD2P or LGMD R16 α-dystroglycan-related. This is a newly reported rare dystrophy that has presented with onset in the first decade, severe cognitive impairment, and with reduced α-dystroglycan expression on muscle biopsy (Dinçer et al., 2003; Hara et al., 2011; Narayanaswami et al., 2014). This dystrophy caused by a mutation in the gene encoding for α-dystroglycan. LGMD2Q or LGMD R17 plectin-related. LGMD2Q has also been considered a form of congenital myasthenia and is associated with epidermolysis bullosa, in which patients develop blistering of the skin and mucous membranes, typically in infancy or early childhood (Narayanaswami et al., 2014). Affected individuals may present with congenital hypotonia or slowly progressive, proximal weakness in late childhood or adulthood. Ptosis and ophthalmoplegia may be evident. CK levels are usually elevated.

LGMD2R or myofibrillar myopathy (desmin deficiency). Unlike most cases of primary desminopathy, this recently reported LGMD is inherited in an autosomal recessive as opposed to autosomal dominant fashion (Cetin et al., 2013; Henderson et al., 2013). It may present in early childhood or adulthood with slowly progressive, predominantly proximal muscle fatigue and weakness and ventilatory failure. CK levels are mildly elevated. Unlike the more common

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autosomal dominant primary desminopathies (e.g., LGMD1E), biopsies in the reported cases did not reveal features of MFM. LGMD2S or LGMD R18 TRAPPC11-related. This is another recently reported LGMD in Syrians and Hutterites (Bögershausen et al., 2013) that is characterized by an infantile onset of choreiform, athetoid or dystonic movements, seizures, truncal ataxia, and mental intellectual disability. Proximal weakness is apparent in childhood along with scoliosis and hip dysplasia; CK is mild to moderately elevated. It is caused by mutations in the transport (trafficking) protein particle complex, subunit 11 (TRAPPC11), which is important in trafficking proteins between endoplasmic reticulum and the Golgi complex.

Recently described limb–girdle muscular dystrophies. LGMD2W, attributed to a mutation in LIMS2 (also called PINCH2), was recently reported in two Northern European siblings, both of whom developed proximal weakness, calf hypertrophy, and an enlarged triangular tongue in early childhood and later developed cardiomyopathy (Chardon et al., 2015). LGMD2X, attributed to a mutation in BVES, was reported in three members of an Albanian family. Those affected had second-degree heart block and an elevated CK, with the grandfather developing proximal muscle weakness in his 40s (Schindler et al., 2016). LGMD2Y, attributed to a mutation in TOR1AIP1, was recently reported in three patients from a consanguineous Turkish family. Weakness began in the first or second decade, along with joint contractures and rigid spine (Kayman-Kurecki et al., 2014). LGMD2Z, or LGMD R21, is attributed to mutation in POGLUT1 and was recently reported in four patients from a consanguineous Spanish family. Proximal leg weakness began in the third decade, progressing to include upper limb weakness and loss of ambulation (Servan-Morilla et al., 2016). Myofibrillar myopathy. MFM likely results from disruption of the Z-disc. The characteristic pathological finding in MFM is myofibrillary disruption on EM and excessive sarcoplasmic accumulation of desmin and other proteins on immunostains (Amato et al., 1998; Dalakas et al., 2000; De Bleecker et al., 1996; Nakano et al., 1996, 1997; Narayanaswami et al., 2014). Desmin is a cytoskeletal protein linking the Z-disc to the sarcolemma and nucleus. This myopathy has been reported as desmin storage myopathy, desmin myopathy, familial desminopathy, spheroid body myopathy, cytoplasmic body myopathy, Mallory body myopathy, reducing body myopathy, familial cardiomyopathy with subsarcolemmal vermiform deposits, myopathy with intrasarcoplasmic accumulation of dense granulofilamentous material, Markesbery-Griggs myopathy, and hereditary inclusion body myopathy (hIBM) with early respiratory failure (Amato et al., 1998). The original classification of many such disorders was as forms of congenital myopathy, but it is now clear that MFM is a muscular dystrophy and many are allelic with forms of LGMD and distal muscular dystrophy/myopathy (Narayanaswami et al., 2014). There is a spectrum of clinical phenotypes associated with MFM (Amato et al., 1998; Narayanaswami et al., 2014). Most patients develop weakness between 25 and 45 years of age, but onset can occur from infancy to late adulthood. Either cardiac or skeletal muscles can be involved and dominate the clinical picture. Limb weakness can be predominantly distal and affect either the arms or the legs, but in others, proximal muscles are involved more than distal muscles. Facial and pharyngeal muscles are also affected. Some patients have a facioscapulohumeral or scapuloperoneal distribution of weakness. The cardiomyopathy may manifest as arrhythmias or conduction defects as well as congestive heart failure. Pacemaker insertion or cardiac transplantation may be required. Severe respiratory muscle weakness can also complicate MFM. In addition, there are rare reports of smooth muscle involvement leading to intestinal pseudo-obstruction.

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Muscle histology demonstrates variability in fiber size, increased central nuclei, and occasionally type 1 fiber predominance (Amato et al., 1998; De Bleecker et al., 1996; Nakano et al., 1996, 1997; Narayanaswami et al., 2014). Muscle fibers with rimmed vacuoles may also be evident. Two major types of lesions are evident on light and electron microscopy: hyaline structures and nonhyaline lesions. The hyaline structures are cytoplasmic granular inclusions that are typically eosinophilic on hematoxylin and eosin, and dark blue-green or occasionally red on modified Gomori trichrome stains. They appear as cytoplasmic bodies, spheroid bodies, or Mallory bodies on EM. The nonhyaline lesions appear as dark green areas of amorphous material on Gomori trichrome stains. On EM, these nonhyaline lesions correspond to foci of myofibrillar destruction and consist of disrupted myofilaments, Z-disk–derived bodies, dappled dense structures of Z-disk origin, and streaming of the Z-disk. Immunohistochemistry reveals that both the hyaline and nonhyaline lesions contain desmin, myotilin, and numerous other proteins (Amato et al., 1998; De Bleecker et al., 1996; Nakano et al., 1996, 1997). Interestingly, abnormal muscle fibers also abnormally express several cyclin-dependent kinases in the cytoplasm, including CDC2, CDK2, CDK4, and CDK7 (Amato et al., 1998). The pathogenesis of MFM is multifactorial (Narayanaswami et al., 2014; Selcen et al., 2004). As alluded to previously, MFM can be caused by mutations in the desmin gene, allelic with LGMD1E, and mutations in the myotilin gene, allelic with LGMD1A; the recently proposed updated classification schema of LGMDs, in fact, characterizes both disorders simply as myofibrillar myopathies and not LGMDs at all (Straub et al., 2018). Markesbery-Griggs distal myopathy, caused by mutations in the ZASP gene, also demonstrates MFM on pathology (Selcen and Engel, 2005). Less common mutations have been identified in the FLNC, CRYAB, BAG3, FHL1, TTN, PLEC, ACTA1, HSPB8, and DNAJB6 genes, many of which encode proteins important in the formation and stabilization of the Z-disk (Kley et al., 2016). Autosomal dominant inheritance is most common, but autosomal recessive and X-linked inheritance have been reported.

Congenital Muscular Dystrophies The congenital muscular dystrophies, abbreviated MDC by convention, are a group of diseases typically evident at birth or soon thereafter with hypotonia and severe trunk and limb weakness (Iannaccone and Castro, 2013). All are typically autosomal recessive in their inheritance and are distinguished in part by greater or lesser central nervous system (CNS) and eye involvement (Kang, 2015). Contractures of the joints are prominent, particularly at the ankles, knees, and hips. Intellectual disability may be present, and MRI of the head shows strikingly increased white matter signal in many patients. Several distinct forms of MDC are recognizable by clinical and genetic feature, and can be stratified based on the defective protein responsible. MDCs related to genes encoding structural proteins of the basal lamina and sarcolemma include MDC type 1 and UCMD. MDCs related to impaired glycosylation of α-dystroglycan are referred to as dystroglycanopathies (DG). Finally, mutations in selenoprotein N1 produce a unique phenotype of rigid spine syndrome. MDC type 1. MDC type 1 is the most common type of MDC in the Western Hemisphere. It is genetically heterogeneous, with approximately 50% of cases associated with primary merosin or α2laminin deficiency (MDC1A). Laminin-α2, also known as merosin, is one of a large family of glycosylated proteins found in the basement membrane and attaches to the dystroglycan complex. The hallmark of merosinopathy includes severe weakness of the trunk and limbs and hypotonia at birth, sparing the extraocular muscles and face (Iannaccone and Castro, 2013). Prominent contractures of the feet and

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Fig. 109.14 Congenital Muscular Dystrophy (Classic Type). This boy also had weakness and contractures of the limbs. His illness was relatively static.

hips are present. Although intelligence is often normal, the incidence of epilepsy is 12% to 20%. MRI and computed tomography (CT) of the brain often reveal white-matter abnormalities. For the most part, these children are severely disabled, and many remain dependent on their caregivers for their whole lives. In milder forms of the disease, caused by partial merosin deficiency, delayed onset of symptoms and mild weakness occur (Tan et al., 1997). This situation is similar to dystrophin deficiency. CK concentrations are elevated. EMG, in addition to demonstrating abnormalities in the muscle, shows slowed nerve conduction velocities; laminin-α2 is also expressed in nerve tissue. Diagnosis is established by identifying a mutation in the laminin-α2 gene. Demonstration of altered merosin in muscle can be helpful to guide this testing (Sewry et al., 1997). As in dystrophin deficiency, it may be advantageous to use at least two different antibodies. Skin biopsy may also reveal merosin deficiency. There are patients with identical symptoms who do not have a mutation in the laminin-α2 gene (Fig. 109.14). MDC1B, for example, is caused by mutations in the gene encoding for the α7 subunit of α7β1D integrin, a sarcolemmal protein that binds to merosin (Hayashi et al., 1998). Frequently the muscle symptoms are milder and progress more slowly; children may gain function as they grow older and may walk independently. Despite a shortened life span, many survive to adulthood. Certain α-dystroglycanopathies produce an identical clinical phenotype, most importantly MDC1C, which results from mutations in FKRP (Brockington et al., 2002).

Ullrich congenital muscular dystrophy/Bethlem myopathy.

UCMD, also known as atonic-sclerotic dystrophy and recently reclassified as LGMD R22 collagen 6-related, is associated with neonatal weakness, multiple contractures, and distal hyperlaxity (Bertini E, 2002). Affected children often have marked protrusion of the calcanei in their feet. The clinical course is static or slowly progressive. Serum CKs are normal or only slightly elevated. Mutations in subunits of collagen type VI cause

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Fig. 109.15 Congenital Muscular Dystrophy (Fukuyama Type). This severely intellectually disabled girl had many seizures and marked contractures of the limbs. She was too weak to support her own weight. The disease was nonprogressive. Her two brothers had the same illness.

Fig. 109.16 Biopsy from Fukuyama-type congenital muscular dystrophy. In addition to variability in fiber size and type 1 fiber predominance with fibrosis, note nonrandom distribution of atrophy. Fascicle in lower part of picture contains fibers larger than those in upper part (myosin adenosine triphosphatase stain, pH 9.4).

the disorder. UCMD is allelic to the more benign Bethlem myopathy, or LGMD D5 (see above) (Camacho-Vanegas et al., 2001). Skeletal muscle MRI scans may reveal early involvement of the thigh muscles that preferentially involve the periphery of each muscle and relatively spare the central regions along with a peculiar involvement of the rectus femoris with a central area of abnormal signal within the muscle (Mercuri et al., 2005; ten Dam et al., 2012). α-Dystroglycanopathies. At least 18 distinct genes have now been associated with forms of DG with autosomal recessive inheritance, and the resulting spectrum of disease is broad (Liewluck et al., 2018). As already described, an adult-onset LGMD2 phenotype can result in many of these patients. Most, however, result in varying severities of congenital muscular dystrophies, many of which include CNS and eye involvement. Described syndromes include MDC1C, Fukuyama congenial muscular dystrophy, Walker-Warburg syndrome, and MEB disease. A phenomenon of profound, transient weakness occurring in the setting of febrile illness has been described in patients with DG association with mutations in FKRP, FKTN, POMT1, POMT2, and POMGNT1. This typically occurs in children younger than 7, and often precedes the diagnosis of a muscular dystrophy (Carlson et al., 2017). Fukuyama-type muscular dystrophy is caused by mutations in the fukutin gene (Kobayashi et al., 1998). This disease is more common in Japanese and Korean populations due to founder mutations (Kang, 2015). The glycoprotein-dystrophin complex is also expressed in the CNS, which probably accounts for the severe CNS manifestations associated with Fukuyama-type muscular dystrophy. Affected children are usually normal at birth, but some are floppy. Joint contractures are present in 70% by the age of 3 months, with the hip, knee, and ankle commonly involved. Children are often severely intellectually disabled, sometimes to the extent that speech is never developed, and either major motor or absence seizures are common (Fig. 109.15). Another curious finding is asymmetry of the skull. Weakness is diffuse, including the face and neck, and often disabling so that the child never learns to walk. The muscle disease is moderately or slowly progressive, and

survival into early adult life is common. These children are completely dependent on their parents, however. The Fukuyama variant does not resemble DMD, and the only real difficulty is in differentiating it from other forms of congenital dystrophy. Serum CK concentration is usually markedly elevated. A muscle biopsy can easily distinguish this disorder from congenital nonprogressive myopathies, as dystrophic changes with variability in fiber size and fibrosis are common. Internal nuclei are also common. The changes in fiber size may not be random, and some fascicles contain much smaller fibers than others. This nonrandom change differs from denervation atrophy, in which there is a wide random variability in fiber size within individual fascicles (Fig. 109.16). MRI and CT scans of the brain show a variety of abnormalities, but the most striking is the presence of lucencies, particularly in the frontal area (Fig. 109.17). These changes seldom extend to the genu of the corpus callosum and spare the medial subependymal regions along the trigones and occipital horns. As the children grow older, these lucencies disappear in sequence from the occipital to the frontal region in a fashion resembling the progression of normal myelination. Occasionally, marked pallor of the myelin in the centrum semiovale, together with mild gliosis or edema, is noted. Postmortem examination reveals numerous brain malformations including agyria, pachygyria, and microgyria. The cortex may have a cobblestone appearance, absence of gray-matter lamination, and other abnormal cytoarchitectural features. Heterotopias are present in the brainstem and basal meninges, as is micropolygyria of the cerebellum. Ventricular dilatation, enlarged sulci, and aqueductal stenosis are other associated features. In short, there are marked abnormalities in the architecture of the brain. The combination of muscular dystrophy, lissencephaly, cerebellar malformations, and severe retinal and eye malformations characterizes Walker-Warburg syndrome and the related muscle-eye-brain disease (Haltia et al., 1997). Both are associated with more severe eye abnormalities than Fukuyama-type muscular dystrophy. WalkerWarburg syndrome is the more catastrophic disease, with death often

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Other Regional Forms of Muscular Dystrophies

Fig. 109.17 Computed tomographic scan of head of patient with Fukuyama congenital muscular dystrophy demonstrates lucencies in white matter, particularly toward frontal poles.

occurring within the first 2 years; eye changes include microphthalmia, colobomas, congenital cataracts and glaucoma, corneal opacities, retinal dysplasia and nonattachment, hypoplastic vitreous, and optic atrophy. MEB disease is milder and characterized by high myopia and possibly a preretinal membrane or gliosis, but severe structural abnormalities of the eye are not present. The CNS findings are also different. MRI may be a useful technique to separate the entities (van der Knaap et al., 1997). The changes in Walker-Warburg syndrome are more severe, with various combinations of hydrocephalus, aqueductal stenosis, cerebellar and pontine hypoplasia with a small posterior vermis, Dandy-Walker malformations, and an agyric or pachygyric cobblestone cortex. T1-weighted images show diffuse decreased white-matter signal; T2-weighted images show an increased signal compatible with a defect in myelination. In MEB disease, white-matter changes are focal and the cortical changes milder. In Walker-Warburg syndrome, mutations in POMT1 account for 20% of cases; POMT2, fukutin, and FKRP are also frequent but still account for only a minority of cases (Beltran-Valero de Bernabe et al., 2002; Cormand et al., 2001; Diesen et al., 2004; van Reeuwijk et al., 2005). Some cases of muscle-eye-brain disease are caused by mutations in the gene that encodes for O-mannose β-1,2-N-acetylglucosaminyl transferase (POMGnT1) located on chromosome 1p3 (Yoshida et al., 2001).

Congenital muscular dystrophies with rigid spine syndrome.

This disorder presents in infancy with hypotonia, weakness, and delayed motor milestones. Reduced mobility of the spine is marked, and many children also develop scoliosis and contractures at the knees and elbows. Serum CK concentrations are normal to moderately elevated. Muscle biopsies may reveal type 1 predominance, increased internal nuclei, and other nonspecific myopathic features. In some kinships, the myopathy links to mutations in the selenoprotein N1 gene located on chromosome 1p3 (Moghadaszadeh et al., 2001). Other myopathic disorders (e.g., EDMD), however, can also be associated with rigid spine syndrome.

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Emery-Dreifuss dystrophy (emerin deficiency). EDMD is characterized by the triad of scapuloperoneal weakness, early contractures, and cardiac involvement. Wasting and weakness of the upper arms, shoulders, and anterior compartment muscles in the legs are typical (Narayanaswami et al., 2014). This weakness is associated with early contractures, particularly in the elbows, posterior neck, paraspinal muscles, and Achilles tendon. Elbow contractures are characteristic and are severe. As the arm extends, sudden resistance is met, which feels more like bone than the pressure of a tight tendon. EDMD can produce a rigid spine syndrome. Contractures typically develop by the teenage years. The disorder is slowly progressive and often spreads to involve other muscle groups such as those of the hip. Cardiac complications are frequent. Conduction block may explain the sometimes sudden unexpected death of these patients. Atrial paralysis occurs in which the atria are electrically inexcitable, and the heart responds only to ventricular pacing. Other cardiac problems include ventricular myocardial disease with ventricular failure. Female carriers may develop the cardiac abnormalities at a later age, and sudden death occurs. The severity of the cardiopathy in both men and women increases with age. The most common form of EDMD exhibits X-linked inheritance and is caused by mutations in the gene (STA) that encodes for emerin. Emerin localizes to the inner nuclear membrane, from which it projects into the nucleoplasm (Manilal et al., 1996). Emerin belongs to a family of lamina-associated structural proteins and is important in nuclear membrane organization and its attachment to heterochromatin. EDMD-X2 is also an X-linked myopathy that can have either an “EDMD” pattern of weakness or a scapuloperoneal pattern and is caused by mutations in the FHL1 gene that encodes for four-and-onehalf LIM1 protein. Autosomal dominant EDMD can be caused by mutations in lamin A/C, as discussed in the section on LGMD1B (Narayanaswami et al., 2014). Rare causes of autosomal dominant EDMD link to mutations in the SYNE1 and SYNE2 genes that encode for the nuclear proteins, nesprin-1 and nesprin-2, as well as in transmembrane protein 43 (TMEM43) or LUMA. The clinical phenotype is essentially identical to that seen with emerin and lamin A/C mutations. Genetic testing is done to confirm the diagnosis. Because emerin is present in many tissues, skin biopsy showing that the protein is absent from nuclei in the skin confirms the diagnosis. Muscle biopsy and EMG reveal nonspecific myopathic features. The CK level is usually only slightly elevated. Every patient with the syndrome should have an ECG repeated at regular intervals, and regular ECG in other family members is recommended as isolated cardiac involvement occurs (Narayanaswami et al., 2014). Analysis and treatment of the cardiac problems are the most pertinent parts of therapy. Most patients with EDMD need a cardiac pacemaker or intracardiac defibrillator (Narayanaswami et al., 2014) because fatal arrhythmias can be sudden, unpredictable, and fatal; it is wise to implant a pacemaker or even a defibrillator when the diagnosis is first established. It is important to realize that cardiac devices do not retard development of a cardiomyopathy and only protect the patient against the complications of conduction block. Female carriers should be screened with ECG after age 35. Facioscapulohumeral dystrophy. FSHD is an autosomal dominant disorder; however, approximately 30% of cases arise as a result of an apparently sporadic mutation (Tawil, 2015). The estimated prevalence is 1/15,000–20,000, making it the third most common muscular dystrophy. The genetic underpinnings of the disorder are complex. The disease is thought to arise from expression of a

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CHAPTER 109 Disorders of Skeletal Muscle normally silenced gene, DUX4 (double homeobox 4), which resides on chromosome 4q35. The gene is typically epigenetically repressed via methylation of a large, repetitive 3.3 kilobase sequence of DNA near the gene known as D4Z4. Normal copies of the region contain greater than 10 D4Z4 repeats. Greater than 95% of FSHD cases are caused by a deletion in the D4Z4 sequence, leading to only 1–10 repeats; this is termed FSHD1 (Tawil and Van Der Maarel, 2006). The resulting contracted D4Z4 region is hypomethylated, creating an open reading frame permissive of transcription into mRNA (de Greef et al., 2009). The situation is more complex, however, in that two allelic variants distal to the repeats (A and B) exist; only the A allele contains the polyadenylation sequence required to result in stable messenger RNA once transcribed. Both contraction of the D4Z4 repeats and a permissive A allele are required for the disease state. The other 5% of patients with FSHD do not have a deletion of this region, but the D4Z4 region is hypomethylated nonetheless. About 85% of these patients have mutations in the structural maintenance of chromosome’s flexible hinge domain containing 1 (SMCHD1) gene that encodes a chromatin modifier of D4Z4, known as FSHD2 (Lemmers et al., 2012; Saconi et al., 2013). FSHD2 also requires at least one copy of DUX4 to contain the permissive A allele. Finally, heterozygous mutations in DNA methyltransferase 3B (DNMT3B) have recently been described as an alternative cause of D4Z4 hypomethylation and FSHD (van den Boogard, 2016). FSHD can often be reasonably suspected clinically due to the specific pattern of weakness typical in the disorder—facial, periscapular, and humeral muscles are weak early, with sparing of the deltoid. Asymmetry of the weakness is almost the rule, often leading the clinician to doubt the diagnosis of muscular dystrophy and seek a superimposed peripheral nerve lesion where none exists. Age of onset is commonly in the second decade, but can vary from infancy to well into adulthood. Facial weakness expresses itself as difficulty blowing up balloons or drinking through a straw. The child sleeps with the sclera of the eyes showing through partially opened lids. Facial expression is relatively preserved, but the smile is often flattened and transverse as opposed to the upward curve of the usual smile. When the patient attempts to whistle, the lips move awkwardly and have a peculiar pucker (Fig. 109.18). The mouth also may have a pouting quality called bouche de tapir. Weakness of the shoulder muscles particularly affects fixation of the scapula. Scapular winging is expected; with the arms outstretched in front, the scapulae jut backward, with the inferomedial corner pointing backward. The deltoid muscle, by contrast, is usually bulky and its strength preserved late in the illness. The axillary folds may become horizontal and exaggerated owing to pectoral weakness and atrophy. The biceps and triceps muscles are often weak but the forearm muscles less involved, leading to the characteristic “Popeye arm” appearance. A discrepancy between the stronger wrist flexors and weaker wrist extensors as the disease progresses often supports the diagnosis. Abdominal and paraspinal muscle weakness is very common. Exaggerated lumbar lordosis or camptocormia may occur and the abdomen may be protuberant. Preferential involvement of the lower (or less commonly the upper) abdominal muscles leads to the Beevor sign—asking the patient to lie supine and lift the head off the bed leads to displacement of the umbilicus upward or downward, away from the weaker abdominal muscles. Despite the name, leg weakness is also common. Often the ankle dorsiflexors are involved very early in the illness and foot drop may even be the presenting complaint, creating overlap with the scapuloperineal syndromes. Hip flexor and quadriceps weakness are common, but ankle plantarflexion strength is often preserved. Rare patients present with symmetrical proximal leg weakness greater than arm

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Fig. 109.18 Facioscapulohumeral Dystrophy. Note characteristic appearance of shoulders, downward-sloping clavicles, and bulge in trapezius muscle region due to scapula being displaced upward on attempted elevation of arms. Patient also is attempting to purse his lips.

weakness with sparing of facial muscles, such that they resemble an LGMD. Even in severe cases, ptosis, dysphagia, cardiomyopathy, and prominent contractures are not seen and thus should suggest an alternative diagnosis. With FSHD1, the severity of the illness bears a relationship to the size of the deletion: the smallest fragments (1–3 repeats) tend to be associated with severe illness. Another phenomenon exhibited by these families is anticipation of the illness, where cases occur with more severity and at a younger age with successive generations (Tawil and Van Der Maarel, 2006). This suggests the mutation is a dynamic one that may become increasingly severe with each generation, as is the case with myotonic dystrophy. That said, FSHD varies in severity even within the same family. Some patients may have mild facial weakness that can go unnoticed throughout life. The most severe form of FSHD, however, begins in infancy. Affected infants may have no movement at all in the face, which remains passive and expressionless. Weakness of the limbs, although it conforms to the general pattern of FSHD, is so severe that such children may lose the ability to walk by 9 or 10 years of age. Genetic testing is available to confirm the diagnosis of FSHD1 or FSHD2, but may be unnecessary in cases with prototypical weakness and a consistent family history. The serum CK concentration usually is elevated several-fold above normal. Muscle biopsy may show general dystrophic features or tiny fibers scattered throughout the biopsy sample that suggest neuropathic change, or scattered inflammatory cellular foci associated with muscle fibers and in the interstitial tissue in patients with more severe disease (Fig. 109.19). EMG shows myopathic potentials. Management of FSHD is supportive and includes screening for complications of the disease. The American Academy of Neurology (AAN) produced an evidence-based guideline summary in 2015 to aid clinicians in proper care (Tawil, 2015). Respiratory insufficiency occurs in an estimated 1.25% to 13% of patients, especially in those with spinal deformity or those who are wheelchair bound. Affected patients may not complain of dyspnea, as commonly respiratory insufficiency begins only during sleep—excessive daytime somnolence may be the only clue. Baseline pulmonary function testing is thus recommended at diagnosis and then annually in those with proximal leg weakness.

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Fig. 109.19 Facioscapulohumeral Dystrophy. Cellular responses occur in biopsy samples from many patients with this illness. These are more often associated with necrotic fibers than with blood vessels (hematoxylin and eosin stain).

In severe cases, there is an association with Coats disease, an oxidative vascular degeneration of the retina. While this affects less than 1% of patients, 25% will have asymptomatic retinal abnormalities evident on examination. A baseline retinal examination is recommended; those with a low repeat number should also be followed longitudinally. Finally, sensorineural hearing loss occurs in severe cases, so affected children should be screened for hearing loss. Management also includes offering interventions to reduce morbidity and improve functional status. Stretching and range of motion exercises are important. Physical and occupational therapy should be involved early to assist with these, as well as to assess for the need for assist devices. An ankle-foot orthosis may be beneficial for patients with foot drop. If patients have severe weakness of the anterior tibial group, overactivity of the posterior tibial muscle may be seen in an attempt to dorsiflex the foot and allow the toes to clear the ground. This results in marked inversion of the foot while walking and may lead to an equinovarus contracture. It also may make the use of an ankle-foot orthosis impossible. If lack of scapular fixation renders the patient unable to raise the arms above the head, surgical stabilization of the scapula may improve shoulder abduction and forward flexion (Twyman et al., 1996). This is particularly true in the majority of patients with preserved deltoid function. Manual fixation of the scapula at the bedside can be used to assess the potential for benefit prior to surgery. FSHD does not typically affect the life span, but 20% of those above age 50 will be wheelchair dependent. Scapuloperoneal syndromes. Weakness of the muscles of the shoulder and the anterior compartment of the lower leg is the early symptom of scapuloperoneal syndromes. Some forms of scapuloperoneal dystrophy may relate to FSHD, but most cases show no linkage to the FSH site on 4q35 (Tawil and Van Der Maarel, 2006). EDMD produces a scapuloperoneal pattern of weakness, as well. Mutations in the desmin gene on chromosome 2q35 and FHL1 on Xq26.3 have been demonstrated to cause some cases of scapuloperoneal dystrophy; these are also categorized as myofibrillar myopathies (Narayanaswami et al., 2014). In FSHD, a discrepancy exists between

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Fig. 109.20 Oculopharyngeal Dystrophy. Facial appearance of patient who has ptosis and no eye movements.

the strength of the ankle dorsiflexors, which are weak, and the plantar flexors, which are strong. The same is true of the scapuloperoneal syndrome, but facial muscles are spared. Often the patient presents with a foot drop, and examination reveals the shoulder weakness. Biopsy, EMG, and other laboratory tests reveal nonspecific myopathic features. Because other hereditary scapuloperoneal syndromes due to neuropathy and anterior horn cell disease exist, it is important to confirm the diagnosis with appropriate tests in any patient with a scapuloperoneal syndrome. Preservation or even hypertrophy of the extensor digitorum brevis (used to compensate for tibialis anterior weakness) is a clinical clue toward a myopathic etiology, as this would be unlikely in a neurogenic foot drop. Ankle-foot orthoses are the only useful treatment and may improve function by correcting foot drop. Oculopharyngeal muscular dystrophy. Oculopharyngeal muscular dystrophy (OPMD) is an inherited autosomal dominant disorder with almost complete penetrance. It has an uneven geographical distribution, with foci of cases in Quebec, Germany, Uruguay (Montevideo), and the Spanish-American populations of Colorado, New Mexico, and Arizona. Isolated families also appear throughout the rest of the world. The disease is caused by an expansion of GCG repeats in the gene that encodes for polyadenylate-binding protein nuclear 1 (PABPN1, formerly PABP2) located on chromosome 14q11.2-13 (Brais et al., 1995; Stajich et al., 1996). This nuclear protein is involved in mRNA polyadenylation, but the mechanisms by which mutations cause OPMD are not yet clear. OPMD usually begins in the fifth or sixth decade of life, but onset can be in the fourth decade. Longer PABPN1 expansions are correlated with an earlier age of onset (Richard, 2017). Patients present with extraocular muscle weakness and mild ptosis. Initially the ptosis may be quite asymmetrical, but as the muscles weaken, both lids eventually become severely ptotic, and eye movements diminish in all directions (Fig. 109.20). Considerable variation in the severity of the extraocular palsies exists, but ptosis is constant. Concomitant with or shortly after the development of ocular symptoms, patients notice difficulty swallowing. Saliva pools in the pharynx, and at the extreme stages of the illness, dysphagia may be complete. Facial weakness occurs in a number of patients, and hip and shoulder weakness are common in the late stages. Death may occur from emaciation and starvation. The

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Fig. 109.21 Oculopharyngeal Dystrophy. Rimmed vacuoles are common in this illness (hematoxylin and eosin stain).

terminal event is often pneumonia initiated by aspiration of secretions. Although the symptoms associated with this disease may be severe, patients’ life spans may be unaffected, making management of their nutritional status all the more important. Muscle biopsy can usually be avoided, since genetic testing reveals the diagnosis. However, biopsy of weak muscles may show dystrophic findings, random variation in fiber size, necrotic fibers, some fibrosis, and occasional internal nuclei. In addition, fibers may contain autophagic vacuoles (rimmed vacuoles) (Fig. 109.21), a feature common to this illness as well as to IBM and various hereditary distal myopathies/ dystrophies. A hallmark of the illness is the presence of small 8- to 10-nm intranuclear tubulofilaments (Blumen, 1999). These occur as palisading filamentous inclusions. The filaments are unbranched and may be stacked side by side or may occur in tangles. In addition, there is often evidence of abnormal mitochondria as well as nemaline rods, particularly in pharyngeal muscles. PABPN1 is an integral part of the muscle OPMD inclusions. The inclusions also contain components of the ubiquitin-proteasome pathway, transcription factors, and mRNA-binding proteins. Treatment of OPMD is supportive. The swallowing difficulties should be treated first by a soft diet; pureed foods represent the next step in treatment. Feeding with a nasogastric tube may be a temporary solution, but eventually gastrostomy is essential. Surgery to correct ptosis may be very successful, as opposed to results seen in other causes of ptosis such as myasthenia gravis or Kearns-Sayre syndrome (KSS).

Distal Muscular Dystrophies/Distal Myopathies Several muscle diseases show a predominantly distal pattern of weakness (Narayanaswami et al., 2014; Udd, 2009). Initial diagnosis of the distal myopathies is often a hereditary or acquired neuropathy or motor neuron disease, because distal dysfunction is more characteristic of neuropathic disorders. Mild elevations in serum CK occur in neuropathic disorders, but CK concentrations over 500 IU/L should raise suspicion of a myopathic process. Serum CK concentrations can be normal in some distal myopathies; therefore CK alone does not

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exclude a myopathy. EMG distinguishes a distal myopathy from a neuropathic disorder. Furthermore, myasthenia gravis can rarely present with predominantly distal weakness, so repetitive nerve stimulation can also be helpful. Treatment of distal myopathy is largely symptomatic. In a patient with a severe wrist drop, a cock-up splint may be helpful to preserve hand function. Similarly, an ankle-foot orthosis may treat the foot drop. Several classically described distal myopathy syndromes are described below. Although not described in detail below, mutations in Kelch-like homologue-9 (KLHL9) and adenylosuccinate synthetase-like 1 (ADSSL1) have also been shown to lead to distal myopathy beginning in childhood. With the discovery of the genetic underpinning of these disorders, many have been found to be allelic with forms of LGMD and other disorders. Likewise, mutations in genes most commonly associated with limb–girdle phenotypes—DNAJB6, MYOT, DES, and CAV3, for example, discussed previously—have also been shown to occasionally cause a distally predominant pattern of weakness. Other myopathies associated with distal weakness include myotonic dystrophy type 1, IBM, sarcoid myopathy, focal myositis, and certain late-onset forms of congenital myopathy (e.g., centronuclear and nemaline myopathies, especially in association with NEB, ACTA1, and RYR1 mutations). Age of onset, inheritance pattern, histopathology, and pattern of weakness are most useful in distinguishing the distal myopathies from one another. As genetic testing technology has improved and become more affordable, next-generation sequencing panels encompassing many genes have improved diagnostic yield over targeted single-gene testing (Amandine et al., 2016). Clinical and histopathological findings may still be useful when interpreting VUS or if no pathogenic mutation is found. Miyoshi myopathy. Inherited as an autosomal recessive disease, Miyoshi myopathy begins early, often in adolescence (Bejaoui et al., 1995). Mutations in the dysferlin gene that also cause LGMD2B were initially found to be responsible for Miyoshi myopathy, but subsequently mutations in the ANO5 gene that also cause LGMD2L have been found to cause a Miyoshi phenotype (Narayanaswami et al., 2014). The weakness is characteristically in the foot plantar flexors, with severe gastrocnemius atrophy. This causes a thin, tapering leg. Patients are unable to stand on their toes, and they walk up stairs in a clumsy, jerky fashion. The illness is progressive, although it remains confined to the legs. Ultimately, hip weakness develops, and ambulation may become difficult in midlife. The serum CK concentration is extremely elevated and reaches levels of several thousand international units even before the patient becomes symptomatic. Families exist in which some members exhibit a distal myopathy and others the more traditional proximal variety. The muscle biopsy shows dystrophic changes but no autophagic vacuoles. Welander myopathy. This autosomal dominant myopathy has only been reported in Scandinavians, where it remains relatively common. Welander myopathy begins in the hands (finger and wrist drop) around age 40–60 and later involves the legs and feet (foot drop) (Narayanaswami et al., 2014). The disease is not entirely restricted to muscle. Careful evaluation may show mild distal hypesthesia and temperature loss associated with some loss of small myelinated fibers. Electrodiagnostic testing, however, shows little evidence of denervation and ample evidence of myopathy. Muscle biopsy shows myopathic findings, superimposed on which are the rimmed vacuoles characteristic of several other distal myopathies. Serum CK concentration is normal or slightly elevated. Welander myopathy is caused by mutations in T-cell-restricted intracellular antigen (TIA1) which is in the RNAbinding protein (Hackman et al., 2012). A particular variant in TIA1 has been shown to cause a similar phenotype only in the presence of a

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second mutation in the SQSTM1 gene. SQSTM1 links to Paget disease of bone, as well (Niu, 2018). Udd myopathy. Udd myopathy is due to mutations in titin as discussed previously, and thus allelic with LGMD2J and HMERF. It is an autosomal dominant, adult-onset (fifth or seventh decade) dystrophy with predilection for anterior tibial muscles. Patients present with progressive foot drop typically beginning after age 35 (Hackman et al., 2002; Narayanaswami et al., 2014). Unlike other titinopathies, cardiomyopathy is rare. Serum CK concentration is normal or only slightly elevated. Muscle biopsies in Udd myopathy often demonstrate rimmed vacuoles. Markesbery-Griggs myopathy. Markesbery-Griggs myopathy is caused by mutations in ZASP as mentioned in the MFM section and presents with progressive foot drop, usually after age 35, and its inheritance is autosomal dominant. Over time, proximal leg and distal arm weakness (wrist and finger extensors) develops (Griggs et al., 2007; Narayanaswami et al., 2014). Cardiomyopathy is common. Serum CK concentration is normal or usually only slightly increased. The ECG may demonstrate conduction defects or arrhythmia. An echocardiogram may reveal a dilated or hypertrophic cardiomyopathy. EMG demonstrates markedly increased insertional and spontaneous activity with fibrillation potentials, positive sharp waves, and myotonic discharges. Motor units are myopathic in morphology and recruit early. Muscle biopsies demonstrate fibers with rimmed vacuoles and other features seen in the myofibrillar myopathies (Selcen and Carpén, 2008). Therefore Markesbery-Griggs myopathy can be classified as one of the myofibrillar myopathies (Narayanaswami et al., 2014), discussed in greater detail previously.

GNE myopathy (Nonaka myopathy/autosomal recessive hereditary inclusion body myopathy). Nonaka and colleagues initially

described this early adult-onset distal myopathy in Japan. Other groups reported similar patients with so-called autosomal recessive hIBM (Udd, 2009). The clinical phenotype is similar to that of Markesbery-Griggs and Udd myopathies, with weakness initially involving the anterior tibial muscles in the legs and extensor forearm muscles (Narayanaswami et al., 2014). However, inheritance is in an autosomal recessive fashion and onset occurs at less than 30 years of age. The muscle biopsy results are also quite similar to those of Markesbery-Griggs, Udd, and Welander myopathies in that rimmed vacuoles are observed. Further EM reveals 15- to 18-nm tubular filaments typical of IBM. However, unlike IBM, no significant inflammatory process occurs in this hIBM. Nonaka myopathy/autosomal recessive inclusion body myopathy is caused by mutations in the gene encoding for UDP-Nacetylglucosamine-2-epimerase/N-acetylmannosamine kinase, or GNE, on chromosome 9p1-q1 (Eisenberg et al., 2001). The recommended term for this disorder is now GNE myopathy. The mechanisms by which mutations in this gene lead to the myopathy are unknown but may relate to a secondary reduction in sialic acid production. Laing myopathy. This autosomal dominant distal myopathy is characterized by weakness of the anterior tibial muscle groups and the neck flexors (Laing et al., 1995; Narayanaswami et al., 2014). Onset is in childhood or early adult life. Serum CK concentrations are normal or only slightly elevated, and EMG is myopathic. Cardiomyopathy is sometimes the initial symptom. Unlike Markesbery-Griggs myopathy, Udd myopathy, and Nonaka myopathy/hIBM, rimmed vacuoles are not a feature of the muscle specimen in Laing distal myopathy. Mutations in the slow/beta cardiac myosin heavy chain 1 (MyHC1) gene or MYH7 located on chromosome 14q11 are causative (Lamont et al., 2006). MyHC is the major myosin isoform expressed in type 1 muscle fibers. Of note, MYH7 mutations have also been identified in hyaline body myopathy (discussed later in Congenital Myopathies) (Tajsharghi et al., 2003).

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Williams myopathy. This myopathy is associated with onset in the teens to fifth decade of life of predominantly lower extremity weakness that can affect proximal or distal muscles either in the arms or legs initially (Duff et al., 2011; Guergueltcheva et al., 2011; Luan et al., 2010; Narayanaswami et al., 2014; Williams et al., 2005). Some patients develop a cardiomyopathy. Serum CK is usually mildly elevated and EMG is myopathic. Muscle biopsies may reveal features of MFM. Vocal cord pharyngeal distal myopathy. This autosomal dominant myopathy typically presents in the third to fourth decade of life with preferential weakness of ankle dorsiflexion and wrist/ finger extension (Feit et al., 1998; Muller et al., 2014). Weakness of the pharyngeal and vocal cord muscles is also characteristic, but not universal. As the disease progresses, respiratory muscle weakness is common. Serum CK can be normal or moderately elevated and myopathic features are commonly noted on EMG. Muscle biopsy typically reveals rimmed vacuoles; electron microscopy can show nuclei with abnormal invaginations. Mutations in the MATR3 gene encoding matrin-3 protein have been found to be responsible (Senderek et al., 2009). Matrin-3 is a nuclear matrix protein; MATR3 mutations have also been reported to cause amyotrophic lateral sclerosis.

Multisystem Proteinopathy Multisystem proteinopathy is an autosomal dominant inherited degenerative disorder that can affect multiple body systems including muscle, bone, and the CNS (Taylor, 2015). This spectrum of disease was first described with the name hIBM with Paget disease of bone and frontotemporal dementia (IBMPFD), in association with mutations in valosin-containing protein (VCP). This is a ubiquitously expressed ATPase; pathogenic mutations lead to accumulation of proteinaceous material in various body tissues, explaining the wide range of clinical phenotypes. The name multisystem proteinopathy was suggested to replace IBMPFD, as the spectrum of consequences has been shown to include type 2 CMT, parkinsonism, and motor neuron disease. An identical spectrum of disease has since been shown in association with mutations in HNRNPA1, HNRNPA2B1, and SQSTM1 (Bucelli et al., 2015; Kim et al., 2013). The myopathy that can occur in association with multisystem proteinopathy is heterogeneous, including limb–girdle and scapuloperoneal patterns of weakness. The distal form tends to preferentially ankle dorsiflexion and may be asymmetric. The onset of weakness is adultonset, typically in the 40s. Serum CK levels are normal to slightly elevated. Those with Paget disease of bone may have an elevated alkaline phosphatase. Muscle biopsy reveals rimmed vacuoles as well as inclusions that stain for ubiquitin and TDP-43. Neurogenic features such as type grouping can also be seen, perhaps due to the ability of these mutations to cause motor neuron disease.

Myotonic Dystrophies Myotonic dystrophy type 1. Myotonic dystrophy type 1 (dystrophic myotonia type 1 or DM1) is a trinucleotide repeat disorder that affects both muscle and numerous other body systems. In addition to muscle wasting and weakness, myotonia—impaired relaxation of muscle— is characteristic of the disease. Myotonia can also be seen in some nondystrophic ion channelopathies (see below). DM1 is inherited in an autosomal dominant fashion and has an incidence of approximately 1/3000–8000 live births (Ashizawa et al., 2018). The myopathy is caused by mutations in the gene that encodes for myotonic dystrophy protein kinase (DMPK), located on chromosome 19q13.3. The mutation occurs in an untranslated region of the gene. This region normally contains 5–30 repeating sequences of three nucleotides (CTG

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Fig. 109.22 Infantile Myotonic Dystrophy. This child is severely intellectually disabled and has a marked inverted-V mouth.

Fig. 109.23 Myotonic Dystrophy Type 1. Facial appearance includes ptosis, hollowing of the masseter and temples, and facial weakness.

trinucleotide repeats). In DM1, these CTG repeats expand into the hundreds or thousands. In general, the size of the expansion reflects the severity of the illness. Children with severe congenital myotonic dystrophy may have very large expansions (>750 repeats). Mothers with more than 100 repeats are more at risk for having a child with this severe infantile form. Cardinal features are hypotonia, facial paralysis, failure to thrive, and feeding difficulties. Affected infants are prone to frequent respiratory infections, which may develop into pneumonia. The upper lip forms an inverted V or “shark mouth” (Fig. 109.22). Clubfeet are common, and the children are severely intellectually disabled. The tendency of the expansion to grow with each meiosis explains the phenomenon of anticipation, in which succeeding generations experience the illness earlier and more severely. The reverse is true of some rare patients with paternally inherited myotonic dystrophy, in which the expansion reduces in size and the clinical state may return to normal or near normal. Further complicating the issue of relating the severity of the phenotype to the genetic defect is the fact that the degree of the gene’s expansion may vary among the different tissues in the body. The mutation is not in the coding region of the gene, and other experiments with knockout mice or mice that overexpress the protein show no marked abnormality in the muscle or other systems. Studies have demonstrated that the transcribed mRNA is directly toxic, in part by sequestering RNA-binding proteins such as muscle-blind protein, thereby leading to abnormal splicing of various mRNA transcripts, including those of the muscle chloride ion channel (Mankodi et al., 2002; Mulders et al., 2009; Osborne et al., 2009; Wheeler and Thornton, 2007). Few diseases are as easy to recognize as DM1 once the diagnosis is considered. Conversely, misdiagnosis occurs when the presenting complaint may be unrelated to the basic problem. Patients may present to many different specialists—cardiologists for heart block, gastroenterologists for gastric dysmotility, and developmental pediatricians for intellectual disability. The severity of DM1 ranges from mild weakness in some adults to profound intellectual disability and severe weakness in children.

The typical picture is of an illness beginning in early teenage life, starting with noticeable weakness of the hands and often foot drop. DM1 is one of the rare forms of dystrophy that seems to affect the distal muscles more severely. A predilection for neck muscle involvement exists, and the sternocleidomastoid muscles are often atrophic and poorly defined. A rather long face with a mournful expression is accentuated by hollowing of the temples associated with masseter and temporalis atrophy. In the fully developed disease, the eyes are hooded and the mouth slack and often tented (Fig. 109.23). The muscular weakness is not limited to the distal muscles; shoulder, hip, and leg weakness may be quite prominent. In middle age, repeated falls are common. With time, the weakness of individual muscles becomes severe, and the myotonia may be lost. Patients with advanced disease may have no myotonia of the small muscles of the hand, although pronounced myotonia of the deltoids or forearm muscles exists. The voice alters; it may be hollow and echoing, suggesting palatal weakness. Facial weakness makes it difficult to pronounce consonants. Difficulty in swallowing is common but usually a minor complaint. Recurrent dislocation of the jaw occurs, particularly when the patient attempts to open the mouth wide, as in biting an apple. The demonstration of myotonia is either by sharp percussion of the muscle with a reflex hammer or after firm voluntary contraction. Either maneuver elicits a sustained involuntary contraction of the muscle, which fades slowly over a matter of seconds. Percussion of the thenar eminence, a popular way of eliciting myotonia, produces a sharp abduction of the thumb and a firm contraction of the thenar eminence, which gradually relaxes and allows the thumb to return to the resting position. It is often easier to demonstrate percussion myotonia by percussion of the posterior muscles of the forearm. The normal response to percussion of the forearm is also a brisk contraction of the finger extensors or the wrist extensors, but the wrist or fingers then fall into the resting position without delay. In the myotonic patient, the fingers extend sharply, with a subsequent drift downward toward the normal position or even wrist extension that maintains for some seconds. Patients seldom complain spontaneously about myotonia, but when questioned, they may confess to finding it difficult to release a key after firmly grasping it or to let go of a hammer or vacuum cleaner, particularly in cold weather.

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Cardiac disease is a common complication of DM1. Conduction disturbances and tachyarrhythmias occur commonly in addition to cardiomyopathy. The cardiomyopathy correlates in severity with the neuromuscular disease and the extent of the molecular defect in some but not all studies; the rate of progression differs widely among individuals. Sudden death is not infrequent in these patients, and may be caused by ventricular arrhythmias or complete heart block. This can even occur at an early stage of disease. Some studies show a familial tendency toward cardiac complications. The histopathology is of fibrosis (primarily in the conducting system and sinoatrial node), myocyte hypertrophy, and fatty infiltration (Phillips and Harper, 1997). EM shows prominent I-bands and myofibrillar degeneration. Excessive daytime somnolence is a common problem in DM1 (Damian et al., 2001; Giubilei et al., 1999). The uncontrollable urge to sleep may be mistaken for narcolepsy. It is accompanied by a disturbance of the nighttime sleep pattern. Patients have an abnormal central ventilatory response, without the usual hyperpnea produced by an increasing carbon dioxide concentration. This is associated with an abnormal sensitivity to barbiturates, morphine, and other drugs that depress the ventilatory drive. General anesthetic carries some risks, and the occurrence of complications, usually respiratory, was almost 10% in one series (Mathieu et al., 1997). Anesthesiologists must be aware of the possibility of complications with these drugs. Likewise, women with DM1 are at increased risk of complications during pregnancy and delivery (Ashizawa et al., 2018). In addition to complications from analgesics and sedating medications, respiratory insufficiency and failed labor can occur. A high-risk obstetrician-gynecologist (OB-GYN) obstetrics/gynecology provider should be involved in these women’s care. Several other organs are commonly involved in the disease. Cognitive impairment is common, including executive dysfunction and visuospatial processing, and is progressive through adulthood (Gallais et al., 2017). Neurobehavioral abnormalities are also common. Cataracts are almost universal. Detection may only be by slit-lamp examination. Commonly, multihued specks appear in the anterior and posterior subcapsular zones. Endocrine abnormalities include disturbances of the thyroid, pancreas, hypothalamus, and gonads. Testicular atrophy, with disappearance of the seminiferous tubules, leads to male infertility. In the female, habitual abortion and menstrual irregularities are common. Although diabetes mellitus is no more common in the myotonic population than in the general population, a glucose tolerance test is often associated with abnormally high glucose levels, particularly late in the test. An associated overproduction of insulin seems to be due to abnormal resistance of the insulin receptor. Smooth muscle involvement accounts for several problems. Cholecystitis and symptoms referable to gallbladder function are frequent. Mild dysphagia and decreased peristalsis in the hypopharynx and proximal esophagus are present. Patients often complain of constipation and urinary tract symptoms. DNA analysis is the definitive diagnostic test for myotonic dystrophy. Patients with clinical evidence of disease and individuals at risk require testing. Prenatal diagnosis is reliable and uses chorionic villus biopsies or cultured amniotic cells. Once a diagnosis of myotonic dystrophy has been established in one family member, other family members require genetic screening. When clinical suspicion is not high enough to proceed straight to genetic testing, EMG is the most helpful laboratory study. In addition to the presence of myopathic features, the characteristic myotonic discharges are seen (see Chapter 36). On insertion of the needle, bursts of repetitive potentials are noted. These potentials wax and wane in both amplitude and frequency; when played over a loudspeaker, they resemble the sound of a diving propeller airplane and are called dive bomber or motorcycle potentials. Muscle biopsy in the fully developed

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Fig. 109.24 Myotonic Dystrophy Type 1. There are numerous internal nuclei, some scattered pyknotic nuclear clumps, and marked variability in fiber size. One ring fiber can be identified by its circular dark-staining appearance (hematoxylin and eosin stain).

Fig. 109.25 Myotonic Dystrophy Type 1. Myosin adenosine triphosphatase stain at pH 9.4 demonstrates that the majority of type 1 fibers are small. Type 1 fiber atrophy is noted in early cases and is obscured as the disease becomes more severe.

illness is markedly abnormal (Figs. 109.24 and 109.25), demonstrating random variability in the size of fibers and fibrosis. In addition, multiple nuclei pepper the interior of the fibers. Ring fibers are numerous, in which small bundles of myofibrils are oriented at 90 degrees to the majority, rather like a thread wrapped around a stick. Other laboratory studies are less helpful. Serum CK is often abnormal. Some patients demonstrate low levels of immunoglobulin G. Abnormalities seen on

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CHAPTER 109 Disorders of Skeletal Muscle head MRI include cerebral atrophy, increased white-matter signals on T2-weighted images, and thickening of the cranial vault (Miaux et al., 1997). These abnormalities have little significance. The Myotonic Dystrophy Foundation recently supported the release of expert consensus based guidelines for the supportive management of DM1 (Ashizawa et al., 2018). Because of the potential for sudden death or other serious cardiac complications even in asymptomatic patients, cardiac surveillance and management is of utmost importance. Suggestions for clinical management include a careful cardiac history and a 12-lead ECG at least every year, with a low threshold for use of 24-hour Holter monitoring. Referral to cardiology for co-management is recommended once patients develop symptoms, ECG abnormalities, or reach the age of 40. Patients may require antiarrhythmics, a pacemaker, or ICD placement. Perhaps because of vigilance regarding the cardiac manifestations of the disease, pulmonary complications are now the leading cause of death in DM1 patients. Regular monitoring of pulmonary function testing is recommended. A sleep study should be obtained in those with symptoms suggestive of sleep apnea; nocturnal ventilatory support may be required. Annual eye examinations are advised to monitor for cataracts. Ankle-foot orthoses can be used to treat foot drop. Wrist splints are less useful. Moderate intensity exercise may be helpful. The sodiumchannel blocker mexiletine was shown in a double-blind randomized placebo-controlled trial to be effective at reducing grip myotonia as measured by relaxation time (Logigian et al., 2010). Other drugs that can be used include quinine, phenytoin, procainamide, and acetazolamide. These are typically avoided in those with cardiac involvement. Patients are typically bothered more by weakness than myotonia, so their clinical utility may be modest. Modafinil, 200–400 mg/day, CTD improves hypersomnolence in DM1 patients (Damian et al., 2001).

Myotonic dystrophy type 2 or proximal myotonic myopathy.

Whereas DM1 has a predilection for distal muscles, patients with proximal myotonic myopathy (PROMM) experience proximal stiffness, pain, and weakness (Moxley, 1996; Udd et al., 1997). Like DM1, PROMM is an autosomal dominant trait, and cataracts are characteristic. Gonadal atrophy and cardiac abnormalities occur, but less frequently than in DM1. Initial complaints usually arise in adult life and are a combination of muscle stiffness and unusual muscle pain, which commonly affects the thighs and may be asymmetrical. Grip myotonia is noted, and the relaxation phase is jerky. The severity of the myotonia may vary from day to day, and a “warm-up” phenomenon occurs in which the stiffness disappears after repeated contraction and relaxation. The pain is a sense of discomfort and varies from sharp to a deep visceral ache. Prognosis is relatively good. Individuals with PROMM do not show the slow decline in ability and early cardiorespiratory death so often noted in myotonic dystrophy, but cardiac involvement can occur in a minority. Cataracts, frontal balding, and diabetes are all common associated features. EMG shows myotonic discharges only after a careful search in several muscles. Muscle biopsy shows features similar to DM1. Serum CK concentration may be elevated. The genetic defect has been localized to mutations in the gene that encodes for zinc finger 9 (ZNF9) on chromosome 3q21 (Liquori et al., 2001). The mutations are expanded CCTG repeats in intron 1. As with DM1, this expanded repeat leads to expression of a toxic pre-mRNA, which as in DM1, sequesters RNA-binding proteins, leading to aberrant splicing of other mRNA species including those of ion channels (Mulders et al., 2009; Osborne et al., 2009; Wheeler and Thornton, 2007).

Ion Channelopathies A group of illnesses that range from myotonic syndromes to the periodic paralyses results from abnormalities in ion channels (Cannon, F ECF

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2010; Matthews et al., 2010). The molecular basis for these illnesses reorients classification. The ion channels are fundamentally important in controlling the passage of ions across the cell membrane and in the shift of ions from one cell compartment to another. These proteins are associated with the cell membrane and are responsible for such phenomena as the muscle action potential. Electrical potential across the cell membrane (voltage-gated) or by ligands such as glutamate influence the proteins. Segments of these proteins have amino acid sequences that are remarkably similar across a wide range of species (conserved segments). It is logical that any change in the conserved segment of a protein might produce trouble for the organism. Some of these mutations are presumably lethal, affecting as they do such an important functional component of the cell. Other mutations may produce intermittent symptoms (e.g., the periodic paralyses). In skeletal muscle, sarcolemmal voltage-gated calcium channels are responsible for excitation-contraction coupling. These are called L-type because of their long-lasting effect and are sensitive to dihydropyridines such as nifedipine. The calcium channel in muscle is made of five subunits: α1, which is the most important and forms the ion pore across the membrane; α2, β, γ, and δ. The type of α1 subunit determines the sensitivity of the calcium channel. The subunit is formed from four similar transmembrane regions (domains D1–D4), each made of six membrane-spanning proteins, S1–S6, all linked in series by “loops” that extend into the cytoplasm or extracellularly; S4 is highly charged by virtue of the richness of positively charged amino acids. It may confer voltage sensitivity to the channel. Neurological conditions linked to abnormalities in the L-type calcium channel include hypokalemic periodic paralysis (Cannon, 2010; Matthews et al., 2010). The ryanodine receptor controls the flux of calcium from the sarcoplasmic reticulum into the cytoplasm, thus playing an important part in activating the contractile mechanism of muscle. The subtype in skeletal muscle is RYR1. The ryanodine receptor is associated with the L-type calcium channel, such that when the calcium channel opens, the ryanodine receptor opens, as well. Ryanodine receptors are made of four identical subunits, each of which is approximately 550 kD. Mutations in the ryanodine receptor are associated with central core myopathy, malignant hyperthermia, and late-onset axial myopathy (e.g., bent spine syndrome). The sodium channel is structurally very similar to the calcium channel. The α subunit, a 260-kD protein, confers the sodium channel activity with four domains made of six membrane-spanning proteins connected in similar fashion. Again, the S4 segment is highly charged, which might make it suitable for responding to voltage changes. Mutations in a gene for the sodium channel are the most common cause of hyperkalemic periodic paralysis and paramyotonia congenita. Some families with hypokalemic periodic paralysis (hypoKPP type 2) have mutations in the sodium channel (Bulman et al., 1999). Defects in the chloride channel occur in some patients with either autosomal dominant or recessive myotonia congenita. The chloride channel has a different structure, being a homotetramer in which each unit contains approximately 1000 amino acids. Finally, the potassium channels are the most ubiquitous and diverse group of ion channels. They are composed of monotetramers or heterotetramers of four α subunits. Mutations in various K+ channel genes have been associated with hypokalemic periodic paralysis and Andersen-Tawil syndrome.

Calcium Channel Abnormalities (Familial Hypokalemic Periodic Paralysis Type 1) The inheritance of familial hypokalemic periodic paralysis is autosomal dominant. Most affected patients (hypoKPP1) have mutations in the CACL1A3 gene, which encodes for the α1 subunit of the dihydropyridine-sensitive calcium channel located on chromosome 1q31-32.

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In hypoKPP2, mutations are found in the SCNA4A sodium channel gene, which is more commonly associated with hyperKPP, paramyotonia congenita, and the potassium-aggravated myotonias. Most mutations in hypoKPP1 and hypoKPP2 involve the voltage-sensitive S4 segment of domains 2 and 4, resulting in a substitution of histidine for arginine. The mechanisms for the episodic weakness in hypoKPP are not completely understood, but these substitutions may result in aberrant depolarization via the proton gating pore during attacks (Cannon, 2010). The onset of familial hypoKPP is most common in the second decade. The attacks of weakness begin with a sensation of heaviness or aching in the legs or back. This sensation gradually increases and is associated with weakness of the proximal muscles. Distal weakness may occur as the attack develops. The paralysis may be severe enough that the patient cannot get up from bed or raise the head from the pillow. Severe compromise of respiratory muscles is unusual, although a mild decrease in respiratory function may occur. At the height of the weakness, the muscle is electrically and mechanically inexcitable, and reflexes are lost. The muscles feel swollen and may be firm to palpation. Usually an attack lasts for several hours, even up to a day, and the patient’s strength returns as suddenly as it left. Often a mild residual weakness clears more slowly, and permanent weakness may ensue. The attacks vary in both severity and frequency and may occur as often as several times a week but usually are isolated and separated by weeks to months. Because the disorder probably is associated with a shift in potassium, provocative factors include heavy exercise followed by a period of sleep or rest, a heavy carbohydrate load, or any other cause of increased insulin secretion. The attack often has a morning onset after waking, probably because a movement of ions such as potassium across the muscle membrane occurs during sleep. Epinephrine, norepinephrine, and corticosteroids may have a provocative effect. Attacks are most common in the third and fourth decades of life. Spontaneous improvement may occur with age. During an attack, the serum potassium concentration falls. The weakness may commence at serum potassium concentrations at the low end of normal and become quite profound by the time the serum potassium concentration reaches 2–2.5 mEq/L. Bradycardia and ECG changes may occur. Prolongation of the PR and QT intervals and T-wave flattening are associated with prominent U waves. In patients with complete paralysis, motor nerve conduction studies may show reduced amplitudes or absent compound muscle action potentials (CMAPs). The paralyzed muscle shows no electrical activity on EMG. Between attacks, exercise testing can be helpful. Baseline ulnar CMAPs are recorded, then the patient is first instructed to exercise the muscle for 5 minutes. In half of patients, CMAPs recorded at 1-minute intervals during the exercise period demonstrate an increment of the CMAP amplitudes. Thereafter, continued periodic recording of CMAPs reveals significant decrement 10–20 minutes following exercise (Fournier et al., 2004, 2006). The test is not specific for subtype of channelopathy; however, genetic testing is available to confirm the specific diagnosis. Muscle histology may be normal but usually shows myopathic changes. A common feature of familial hypokalemic periodic paralysis is the presence of vacuoles within the fibers, particularly in association with permanent weakness. Tubular aggregates are a feature of hypokalemic periodic paralysis caused by sodium channel mutations. Attacks of paralysis should be treated with oral potassium. Renal function must be normal before administering potassium to a patient with paralysis. Preventive treatment has traditionally relied on acetazolamide. This drug, a carbonic anhydrase inhibitor, may produce a mild metabolic acidosis, which perhaps influences the potassium shifts that occur in the disease. Side effects of acetazolamide include tingling in the digits and a tendency for the formation of kidney stones. Hypersensitivity reactions also occur. The FDA recently approved F ECF

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dichlorphenamide, also a carbonic anhydrase inhibitor, specifically for treatment of both hypoKPP and hyperKPP based on a randomized, double-blind, placebo-controlled trial demonstrating significant reduction in attack frequency in patients with hypoKPP (Sansone et al., 2016). Triamterene or spironolactone is useful as an adjunctive treatment along with a low-sodium or low-carbohydrate diet for maximum effect.

Secondary Hypokalemic Paralysis Thyrotoxic periodic paralysis is more common in Asians and affects men more frequently than women. Inheritance is autosomal dominant and has been associated with mutations in two genes that encode for two different potassium channel proteins (Ryan et al., 2010; Wang et al., 2014). Kidney failure or adrenal failure may be associated with changes in potassium. Renal tubular acidosis secondary to genetic defects in the kidney or the abuse of inhalants (e.g., toluene) can cause hypokalemia and paralysis as well. A more common form of potassium-induced weakness is in patients receiving potassium-depleting diuretics. Other compounds, such as licorice, are associated with potassium loss.

Sodium Channel Abnormalities Potassium-sensitive periodic paralysis. The potassium-sensitive periodic paralyses and myotonias are associated with mutations in the SCNA4A gene that encodes the α subunit of the sodium channel; the gene is located on chromosome 17q (Matthews et al., 2010; Statland et al., 2012; Tan et al., 2011; Trivedi et al., 2013). Even in early descriptions of these disorders, the association of decreased electrical activity, paralysis, and signs of hyperactivity (paramyotonia) were recognized. The proper activity of the sodium channel depends on a complicated series of activation and deactivation processes that open the pore to allow the passage of sodium but also protect the cell against inadvertent excess sodium flux. The channel may exist in a number of different states: closed, open, and inactivated. Physiological studies have suggested that the domain IV S3 segment has a dominant role in the recovery of inactivated channels, whereas the S4 segment is concerned with deactivation and inactivation of the open channel (Ji et al., 1996). Among the several known mutations of the sodium channel, some impair fast inactivation of the sodium channel or shift the impulse to hyperpolarization. Evidence exists that two common mutations in hyperkalemic periodic paralysis in domain II (S5) and domain IV (S6) cause defective slow inactivation, accentuating the weakness (Hayward et al., 1997). Mutations within the domain III–IV linker, which cause myotonia with or without weakness, do not impair slow inactivation. Studies of muscle during a paralytic attack show that it is slightly depolarized. Intracellular potassium levels decrease and sodium, water, and chloride content are increased. Studies of intercostal muscle biopsies in vitro show a high level of spontaneous muscle activity, even in normal physiological saline. Increasing the external concentration of potassium gradually depolarizes the cells and is associated with an increase in sodium conductance. Tetrodotoxin increases sodium conductance, implying that this part of the sodium channel function is unaffected. Examination of sodium currents of cultured myotubes from the muscles of patients using increased potassium concentrations in the medium resulted in an increased open time or slowed inactivation of the sodium channel associated with sustained depolarization. In patients with paramyotonia congenita, cooling of intact muscle fibers obtained from intercostal biopsy samples reduced the resting membrane potential from approximately −80 to −40 mV, at which point the fibers were inexcitable. As the muscle cools, it passes through a phase of hyperexcitability. Tetrodotoxin prevents inexcitability by blocking sodium channels. The clinical features reflect the physiological findings. 02 .4.(1( 4 (

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CHAPTER 109 Disorders of Skeletal Muscle The predominant symptom in patients with hyperkalemic periodic paralysis is weakness provoked by potassium exposure. Myotonia may be present, and some patients complain of the symptom, but the predominant difficulty is recurrent bouts of paralysis. The allelic disease paramyotonia congenita causes muscle stiffness, and bouts of weakness are mild, often provoked by exposure to cold. In some families, the distinction seems clear, but there are others with a somewhat mixed picture. The clinical features of the two conditions follow. Hyperkalemic periodic paralysis. Inheritance of potassiumsensitive periodic paralysis (hyperKPP) is autosomal dominant, with strong penetrance and involvement of both sexes (Matthews et al., 2010). Onset of symptoms is during infancy or early childhood. The infant’s cry may become suddenly altered or unusual, or the child may be found lying quietly in the crib. Some parents notice an unusual stare as these babies develop, particularly on exposure to cold. The first attack commonly occurs in the first few weeks of school because of the enforced sitting. By adolescence, the attacks are characteristic. Often, rest after exercise provokes an attack, and the weakness develops quite rapidly, often within a matter of minutes. The weakness is milder than in the hypokalemic variety, and the attacks last for a shorter period. Patients may be able to walk off the symptoms if they undertake exercise early in the attack. Many prefer not to do so because an attack itself is mild and followed by a period of relative freedom from symptoms. In addition to rest after exercise, other provocative factors include exposure to cold, anesthesia, and sleep. Patients often avoid fruit juices with high potassium content, having noticed their deleterious effect. Many patients have two kinds of attacks, light and heavy. During a light attack, there is a feeling of fatigue and mild weakness that usually disappears in less than an hour. A heavy attack, however, may be associated with more severe paralysis, even to the point where the patient is unable to arise from the chair or bed. The frequency varies from two or three mild attacks a day to episodes months apart. Residual weakness may occur in middle age and beyond. Paramyotonia congenita. Mutations in the SCNA4A gene also lead to paramyotonia congenita. This condition may or may not be associated with episodic weakness (Matthews et al., 2010; Statland et al., 2012; Tan et al., 2011; Trivedi et al., 2013). Unlike the myotonia in myotonic dystrophy, in paramyotonia, repeated exercise accentuates myotonia, a feature most easily appreciated in the eyelids. Patients may complain of this as aching or stiffness. A clinical test is to have the patient forcibly close his or her eyes in a repetitive manner. After each repetition, the difficulty with relaxation may be accentuated until eventually the patient cannot open the eyes at all. Exposure to cold not only worsens the myotonia but may also provoke muscle weakness, symptoms patients may notice when swallowing ice cream or going out into winter weather to shovel snow. A useful test for paramyotonia is to soak a small towel in ice water and lay it over the patient’s eyes for 2 minutes. Eyelid myotonia is demonstrable by having the patient sustain an upward gaze for a few seconds and then look down. The eyelids remain up, baring the sclera above the iris. When muscle is sufficiently chilled, the paramyotonia disappears, and the muscle is flaccid and paralyzed. The weakness may far outlast the exposure to cold, and it is common for the muscle not to regain its full use for hours after returning to room temperature. Strong voluntary contraction also may be associated with a long-lasting decrease in strength, which is not clearly due to an increase in myotonia. Immersing the forearm in ice water may also produce obvious weakness, which may have been lacking on the initial examination. The diagnosis of potassium-sensitive conditions relies on demonstration of the genetic defects. However, the diagnosis should be suspected when high serum potassium levels coincide with bouts of weakness. In patients with paramyotonia, EMG of the resting muscles

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at room temperature shows myotonic discharges that are present on percussion or with movement of the needle. The most remarkable findings are demonstration of decrementing CMAP amplitudes on the repeated short exercise test, which is worse when performed with the extremity cooled (Fournier et al., 2004, 2006; Tan et al., 2011; Trivedi et al., 2013). Additionally, there are often after-discharges evident following brief activity on CMAP studies. The ECG may show the changes of hyperkalemia, and the serum CK concentration may be elevated during or after an attack. Provocative testing, if considered, requires care because the administration of potassium may be dangerous. The presence of any cardiac abnormality contraindicates provocative testing. Oral potassium may be administered using approximately 1 mEq/kg. The maximum rise in potassium occurs 90–180 minutes after administration. If this dose of potassium does not provoke an attack and the index of suspicion is high, administer 2 mEq/kg orally on a subsequent occasion. Muscle biopsies show tubular aggregates in patients with paralysis, particularly in patients with fixed weakness. Myopathic changes include internal nuclei, vacuoles, and fibrosis. The muscle biopsy may be abnormal in paramyotonia congenita, showing variability in the size of fibers, with internal nuclei and occasional vacuoles. Acute attacks usually do not require treatment because they are mild and brief. Often patients learn to eat a candy bar or drink a sweet drink as a way of warding off an attack. Intravenous calcium gluconate treats greater weakness. Intravenous sodium chloride sometimes may abort an attack. Maintenance therapy with dichlorphenamide or acetazolamide can be helpful. The combination of hydrochlorothiazide with potassium may be effective, although the reason is unclear. Mexiletine 200 mg orally three times a day CTD may provide relief to patients with myotonia (Statland et al., 2012). Potassium-aggravated myotonias. This group of disorders includes myotonia fluctuans, myotonia permanens, and acetazolamide-responsive myotonia. Mutations in the SCNA4A gene are causative. Myotonia made worse by exercise or potassium ingestion, usually beginning in adolescence, is characteristic. Affected individuals do not suffer attacks of weakness. Myotonia is only sometimes evident in myotonia fluctuans but more consistently evident in myotonia permanens. The myotonia may improve with mexiletine (Statland et al., 2012). Acetazolamide-responsive myotonia resembles myotonia congenita clinically, but affected patients also often have significant muscle pain; the myotonia and pain are relieved by acetazolamide. Secondary hyperkalemic periodic paralysis. Weakness due to high levels of potassium occurs in situations other than familial hyperkalemic periodic paralysis. The difference between secondary hyperkalemic periodic paralysis and the familial condition is that extremely high levels of potassium are required in secondary hyperkalemic periodic paralysis before weakness occurs. Causes for secondary hyperkalemic periodic paralysis include renal failure or potassium administration associated with potassium-retaining diuretics. Hypokalemic periodic paralysis type 2. Although the majority of patients with hypokalemic periodic paralysis (type 1) have mutations in the calcium channel, approximately 9% of cases are due to mutation in the SCNA4A muscle sodium channel gene (hypoKPP2) (Bulman et al., 1999; Cannon, 2010; Sternberg et al., 2001). The clinical and laboratory features are similar to the more common type of hypokalemic periodic paralysis, but there are some differences that may help distinguish the subtypes. Patients with hypoKPP2 may be more likely to have severe myalgias following the paralytic attacks, tubular aggregates on muscle biopsy rather than vacuoles, and worsening of symptoms on acetazolamide.

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Potassium Channelopathy Andersen-Tawil syndrome. Andersen-Tawil syndrome (ATS) is characterized by the constellation of periodic paralysis, cardiac dysrhythmias, and dysmorphic features (Sansone et al., 1997). The disorder is a genetically heterogeneous syndrome inherited in an autosomal dominant fashion. Some cases are caused by mutations in the potassium channel gene (KCNJ2) located on chromosome 17q23. The attacks of paralysis may occur in early childhood or be delayed until later. Attack frequency is low and occurs with both high and low potassium. It therefore differs from the more usual hypokalemic variety, in which low potassium levels are expected. Affected members of the family often show dysmorphic features including wide-spaced eyes, low-set ears, a small chin, clinodactyly of the fifth finger, and syndactyly of the toes. Permanent muscle weakness occurs in some patients. The importance of recognizing the syndrome lies in the frequent occurrence of cardiac involvement. This varies from a prolongation of the QT interval through ventricular tachycardia to fatal cardiac arrest. The risk of cardiac complications is sufficiently high that provocative hypokalemic or hyperkalemic testing is contraindicated. Several members of affected families have been described in whom only fragments of the syndrome exist (e.g., clinodactyly, an abnormal QT interval), so a full evaluation of the pedigree is necessary.

Chloride Channelopathy Myotonia congenita. Two major forms of myotonia congenita exist: autosomal dominant and autosomal recessive (Matthews et al., 2010; Statland et al., 2012; Tan et al., 2011; Trivedi et al., 2013). Both are associated with abnormalities in the chloride channel, the gene for which (CLCN1) resides on chromosome 7q35. Introducing the mutant chloride channel into a cell system abolishes the chloride current and deranges the normal function of the chloride channel (Fahlke et al., 1997). The patient’s muscles show reduced chloride conductance and greater than normal membrane resistance. The action potential in a normal muscle cell is associated with an outflow of potassium, which may accumulate in the transverse tubules simply because the physical structure of the tubule does not favor easy diffusion. Ordinarily, this does not present a problem because the chloride conductance is so large that the relatively free passage of chloride ions negates the effect of any small change in potassium. With impeded chloride conductance, the increase in potassium concentration in the transverse tubules may lead to enough depolarization to activate the sodium channels again and hence lead to repetitive electrical discharge of the membrane, producing electrical and clinical myotonia. The original description of the dominant disease was by Thomsen among members of his family. It is usually milder than the recessive form described by Becker, in which myotonia may be associated with some weakness. It is sometimes difficult when faced with a sporadic case to decide on the pattern of inheritance. This is true because members of affected families who carry the abnormal mutation may be asymptomatic or only mildly involved. This necessitates a thorough evaluation of the family, with appropriate genetic testing. On initial examination, especially if the patient has been sitting in the waiting room for some time, apparent weakness may be present because a severely myotonic muscle lacks full voluntary power. With repetitive activity, the muscle loosens up, and strength usually returns to normal. This is particularly true of proximal limb muscles. Symptom descriptions are stereotyped. After resting, the muscles are stiff and difficult to move. This is obvious when the patient arises from a chair. They move en bloc, with a stiff wooden appearance. As they continue, they then can walk freely and finally can run with ease. All the muscles of the body share this abnormality, and while it is most F ECF

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noticeable in the limbs, the face and tongue are also involved. In addition, particularly in the recessive form of the illness, muscular hypertrophy may be pronounced. In myotonia congenita, EMG shows well-marked myotonia with none of the associated dystrophic features. In contrast with paramyotonia congenita, the short-exercise nerve conduction test demonstrates less profound decrement of CMAP amplitude that lessens with successive trials (Fournier et al., 2004, 2006; Tan et al., 2011; Trivedi et al., 2013). Muscle biopsy may demonstrate an absence of type 2B fibers, an unexplained finding, and also may reveal some increase in the size of fibers and internal nuclei as well as other mild nonspecific changes. Unlike most patients with myotonic dystrophy, in myotonia congenita, the myotonia may be disabling. Treatment with mexiletine is often beneficial (Statland et al., 2012). Older options include quinine, procainamide, and phenytoin.

Metabolic Myopathies Any disturbance in the biochemical pathways that support ATP levels in the muscle inevitably results in exercise intolerance. One common symptom is muscle fatigue, a sense that the muscle will no longer perform in a normal fashion. This is true fatigue and not simply a feeling of tiredness or weariness. It may be difficult for the patient to describe the fatigue in terms the physician can understand, because it has nothing to do with the sensations experienced by a healthy person after strenuous exercise. It has an unpleasant quality, and patients describe it in terms of a barrier through which they cannot break. Other symptoms include muscle pain and sometimes muscle cramps. The normal fatigue of strenuous exercise is painless. Muscle pain after strenuous exercise (e.g., the next day) is almost universal in the untrained individual, but pain during exercise is more the hallmark of disturbed muscle function. Normally functioning muscle appears to have a series of safety mechanisms that prevent humans from exercising it to the point of destruction. In the metabolic muscle diseases, maintenance of ATP levels is impaired, and the protective mechanism that functions in the normal person is absent. Forced exercise in patients with a metabolic myopathy causes muscle pain followed by muscle contracture, in which state the muscle is hard, swollen, and tender. This reflects actual muscle destruction. It may be associated with the release of myoglobin into the blood and urine, sometimes noticed as a change in the color of the urine, which may resemble weak tea or cola. Fatigue, muscle pain, contractures, and myoglobinuria are increasingly severe effects of the biochemical defect. In treating these illnesses, preventing the development of myoglobinuria is essential because it carries the potential for renal tubular necrosis. This group of diseases is divisible into three major categories: disorders of carbohydrate metabolism, disorders of lipid metabolism, and disorders of mitochondrial function. Finally, there are some conditions that in theory should disturb pathways for ATP maintenance but do not seem to cause any exercise intolerance. A tissue with depleted ATP stores is probably dead tissue. Even in the metabolic myopathies, the muscle seldom reaches this critical state. What does happen, however, is that overworked support pathways produce unwelcome by-products, which probably cause the symptoms of disease.

Disorders of Carbohydrate Metabolism Myophosphorylase deficiency. Intramuscular carbohydrate stores play an important part in the early stage of exercise, before the compensatory mechanisms of an increased supply of bloodborne metabolites and increased lipid metabolism supply the added demand. The first of the biochemical disorders to be recognized

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CHAPTER 109 Disorders of Skeletal Muscle was a disorder of carbohydrate metabolism called myophosphorylase deficiency (McArdle disease). In 1952, McArdle noted that a young man who presented with exercise intolerance experienced pain and tightness of his muscle on forced exercise. Ischemic forearm exercise caused a painful contracture of the muscle within a minute or so. Insertion of an EMG needle showed that there was no electrical activity, thereby differentiating this contracture from a muscle cramp. McArdle commented that the phenomenon resembled the reaction of a fish muscle poisoned by iodoacetate, a compound that blocks glycolysis. Subsequent studies showed the defect to be an absence of myophosphorylase activity, encoded by a gene on chromosome 11q13. There are two forms of phosphorylase: phosphorylase a, which is the active tetramer, and phosphorylase b, an inactive dimer. Conversion of the inactive form to the active form is catalyzed by phosphorylase b kinase, which itself is activated by a protein kinase under the control of cyclic adenosine monophosphate (cAMP). Any abnormality of this cascade of reactions will result in the absence of phosphorylase activity. Both phosphorylase a and phosphorylase b kinase deficiencies are known to cause exercise intolerance. Inheritance of either illness appears inherited as an autosomal recessive trait. Onset of symptoms is during the first 10 years of life, but only in retrospect. As children, patients may complain of being tired and unable to keep up with their playmates. The classic symptoms appear in teenage years. Fatigue and pain begin within the first few minutes of exercise, particularly if it is strenuous. There is a sensation of hitting a barrier, which causes the patient to slow down. If exercise is continued, pain develops within the muscle, which at first is deep and aching but gives way to the rapid development of a painful tightening of the muscle. The muscle is hard and contracted, and any attempt to straighten it results in great pain. The muscle contracture may last for several hours and can be differentiated from a muscle cramp on two counts: the EMG is electrically silent, and the duration of the contracture is far longer than that of a physiological cramp, which disappears after a few minutes at most. Another aspect of McArdle disease is the development of the second-wind phenomenon. If, with the onset of fatigue, the patient slows down but does not stop, the abnormal sensation may disappear, and thereafter the muscle may function more normally. By gradually increasing the level of exercise, the patient may be able to break through the barrier and then may be able to exercise at an adequate level for longer periods. This second-wind phenomenon, which is related to the phenomenon normally experienced by distance runners, may be marked in patients with phosphorylase deficiency. It probably is associated with a change in the blood supply in the muscle and with an intrinsic change in the muscle’s metabolism. The second-wind phenomenon usually is associated with a rise in fatty acid use and blocked by nicotinic acid. Other unusual forms of phosphorylase deficiency exist. One such patient was an infant girl who died of respiratory failure. Phosphorylase deficiency also occurs in an occasional patient with proximal weakness and neither cramps nor fatigue. On examination, these patients are superficially normal with neither wasting nor weakness, although they may be reluctant to exert full force during muscle strength testing because of the possibility of exacerbating muscle pain. A simple diagnostic clinical test is the exercise forearm test. A butterfly needle is inserted in the antecubital fossa, and baseline lactic acid and ammonia levels are obtained. The patient then opens and closes the hand repeatedly as fast as possible for 1 minute. Importantly, ischemia of the arm is unnecessary (i.e., ischemic forearm test). In fact, ischemic exercise may lead to myoglobinuria. Serum lactic acid and ammonia concentrations should be measured at 1, 2, 3, and 5 minutes after the exercise. The normal response is a three- to fourfold rise in

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lactic acid and ammonia. In patients with phosphorylase, phosphorylase b kinase, phosphoglycerate mutase, phosphoglycerate kinase, lactate dehydrogenase (LDH), and enolase deficiencies, the lactic acid concentration does not increase, but the ammonia concentration does. Measuring the ammonia concentrations serves as a control to ensure the patient was sufficiently exercising. A rise in lactic acid without a rise in ammonia occurs in myoadenylate deaminase deficiency. Light microscopic examination of muscle histology may show an increase in glycogen and the presence of subsarcolemmal blebs. Muscle necrosis also may be noted. Routine stains are usually normal. However, the histochemical reaction for myophosphorylase shows reduced or no activity, and biochemical assay of muscle enzyme activity shows reduced concentrations. Phosphofructokinase deficiency. PFK is the enzyme that converts fructose 6-phosphate to fructose 1,6-diphosphate and is a step in the glycolytic chain downstream from that activated by phosphorylase. The reaction is rate limiting for glycolysis. Inheritance of PFK deficiency is as an autosomal recessive trait, the gene is on chromosome 1, and heterozygotes have decreased but not absent levels of enzyme activity. PFK deficiency is an autosomal recessive disorder that is almost identical clinically to phosphorylase deficiency, although the second-wind phenomenon is uncommon. Most attacks are associated with nausea, vomiting, and muscle pain. There may also be mild hemolytic anemia with increased levels of bilirubin, and increased reticulocyte counts due to deficiency of red blood cell PFK. Like phosphorylase, PFK is a tetramer of different subunits, M and R. Muscle PFK is composed of identical M subunits, whereas the enzyme in the red blood cell comprises both M and R types. In PFK deficiency, the M subunit is missing but the R subunit is preserved, resulting in absence of muscle PFK and impairment of PFK in the red blood cell. Phosphoglycerate kinase deficiency. Phosphoglycerate kinase is involved in another step in the glycolytic pathway. Its absence from muscle produces a predictable picture very similar to that of phosphorylase deficiency. Venous lactate concentrations do not rise after exercise, as would be expected. The muscle biopsy histology is normal, with a normal glycogen concentration. Phosphoglycerate kinase is a single polypeptide. The gene for this disorder is on chromosome Xq13. Several different point mutations occur that produce abnormalities in the red blood cell, with hemolytic anemia, intellectual disability, and seizures. Phosphoglycerate mutase deficiency. Phosphoglycerate mutase exists as a dimer with M and B subunits. The predominant form in normal muscle is MM. A small amount of residual activity may be present in muscle because of the existence of the BB form. Patients with an absence of the enzyme have attacks of muscle pain and myoglobinuria and, in one case, typical attacks of gouty arthritis. The high uric acid level may be associated with an overactivity of the adenylate kinase/ adenylate deaminase reaction. This occurs in many metabolic disorders and produces uric acid as its end product. Exercise testing shows some elevation of lactate, but not to the levels usually seen. The responsible gene is located at chromosome 7p12-13. Lactate dehydrogenase deficiency. Exercise intolerance, fatigue, and myoglobinuria are symptoms of LDH deficiency. Some differences exist in the laboratory studies between this entity and the others discussed here. In most muscle diseases, muscle LDH and serum CK concentrations fluctuate together. In this illness, not surprisingly, a marked discrepancy existed between the high levels of CK and the low levels of LDH. Furthermore, because the action of LDH in exercise is to convert pyruvate to lactate, pyruvate rises after ischemic forearm exercise, but lactate does not. The responsible gene is at chromosome 11p15.4.

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β-Enolase deficiency. Three patients have been reported with exercise intolerance, myalgias, and episodic hyperCKemia caused by mutations in the gene encoding β-enolase. α-Glucosidase deficiency (acid maltase deficiency). Acid maltase deficiency, or Pompe disease, is an autosomal recessive disorder caused by a deficiency of lysosomal α-glucosidase. Pompe disease may present in three major forms: a severe infantile form, a juvenile-onset type, or as a milder adult-onset variant (American Association of Neuromuscular and Electrodiagnostic Medicine, 2009; Katzin and Amato, 2008). Infantile Pompe disease, the classic form, is characterized by generalized weakness and hypotonia, cardiomegaly, and mild to moderate hepatomegaly with onset in the first several months of life. Infants often have an enlarged tongue (i.e., macroglossia). The weakness and cardiomyopathy are progressive, and the disease is invariably fatal by 2 years of age, secondary to cardiorespiratory failure. Juvenile-onset Pompe disease usually manifests in the first decade of life with slowly progressive proximal weakness such that it resembles Duchenne or some other form of LGMD. Ventilatory muscles may be preferentially affected, and many die in the second or third decade of life. Adult-onset Pompe disease usually manifests in the third or fourth decade (range 18–65 years, mean 36.5 years). Patients develop generalized proximal greater than distal muscle weakness resembling PM or an adult-onset type of LGMD. As in the infantile and juvenile forms of the disease, a predilection exists for involvement of respiratory muscles. Serum CK levels are moderately elevated in Pompe disease, but adults may have normal CK levels. EMG reveals increased insertional and spontaneous activity in the form of fibrillation potentials, positive sharp waves, complex repetitive discharges, and even myotonic discharges. In mild forms of the disease, these irritative discharges may be evident only in the paraspinal muscles. ECG may demonstrate nonspecific abnormalities including Wolff-Parkinson-White syndrome. Echocardiograms can show hypertrophic cardiomyopathy. Pulmonary function tests reveal decreased FVC along with reduced maximal inspiratory and expiratory pressures that worsen in the supine position, suggestive of diaphragm involvement. Glycogen-filled vacuoles that intensely stain for acid phosphatase within muscle fibers are characteristic histopathological findings. However, in late-onset Pompe disease, muscle biopsies may reveal only nonspecific abnormalities. Assay of α-glucosidase activity in muscle fibers, fibroblasts, leukocytes, lymphocytes, and in the urine establishes the diagnosis (American Association of Neuromuscular and Electrodiagnostic Medicine, 2009; Katzin and Amato, 2008). A good screening test is the dried blood spot, which measures enzyme activity. Diagnosis can be confirmed by genetic testing. Diagnosis is important, particularly in the classic infantile-onset cases, as treatment is now available for this disorder. Intravenous recombinant α-glucosidase enzyme appears to be safe and beneficial for infants with Pompe disease (Kishnani et al., 2007) but has a more modest effect in late-onset Pompe disease (Kuperus et al., 2017; van der Ploeg et al., 2010). Treatment of the glycolytic disorders. Except for Pompe disease, effective medications for the glycolytic disorders are unavailable. Patients should be counseled to avoid situations that might precipitate myoglobinuria. Attempts to bypass the metabolic block by using glucose or fructose prior to any significant physical activity may help to some extent, but, while feasible, routine use would lead to weight gain. Administration of branched-chain amino acids and a proteinenriched diet also has been suggested, but there is no evidence that these regimens are any more effective than a well-balanced diet. One maneuver for patients with McArdle disease is to develop the patient’s awareness of the second-wind phenomenon. Graded exercise on a treadmill can train the patient to recognize how to slow down with the

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first onset of symptoms and then resume exercise in small increments. This type of training requires an exercise physiology laboratory.

Disorders of Lipid Metabolism Carnitine palmitoyl transferase deficiency. The synthesis of ATP that results from the oxidation of fatty acids requires a system as complex as that seen in glycolysis. Fatty acids, not used at the beginning of exercise, become increasingly important after 20–30 minutes of endurance exercise. After an hour, they represent the major energy supply. Consequently, defects in lipid metabolism give rise to symptoms after sustained activity. Carnitine palmitoyl transferase (CPT) is the enzyme that links carnitine to long-chain fatty acids, a linkage necessary to transport the fatty acid across the mitochondrial membrane from outside to inside (CPT-I). It is also responsible for unhooking carnitine when the complex reaches the inside (CPT-II). CPT-II deficiency is one of the more common biochemical abnormalities in muscle. Inheritance of the disorder is as an autosomal recessive trait. Typically, CPT deficiency manifests with myoglobinuria after strenuous exercise (e.g., mountain climbing, playing four sets of tennis) sometime during the first three decades of life. Affected individuals are particularly predisposed to these attacks if exercise occurs in the fasting state or when they have an infection. This is not surprising because with fasting and infection the body is more dependent on fatty acid metabolism. Attacks of myoglobinuria in CPT deficiency are often more severe and have a greater tendency to cause renal damage than those occurring in glycolytic disorders. The cause may be that the symptoms come on so rapidly in the glycolytic disorders that cessation of exercise immediately returns the muscle to its resting condition. In disorders of lipid metabolism, the patient is often far away from home and out of necessity must use muscles that have already been damaged. Even when the muscle stops working, it still depends on fatty acid metabolism. Patients with CPT deficiency often notice that their stamina depends on their diet. Some carry a candy bar to eat during exercise. Others know that exercise in a fasting state is far more difficult for them. Despite these limitations, some patients with CPT deficiency are quite athletic and may be weightlifters or sprinters rather than marathon runners. Both activities draw on carbohydrate energy supplies and use glycolytic fibers, not the oxidative fibers. There is no abnormality on examination. Indeed, these patients are uniformly muscular, perhaps because their favorite exercise is weightlifting. Genetic testing is available to test for mutations in the CPT-II gene. The CK concentration may be normal unless the patient has had a recent attack of muscle damage. The muscle biopsy in CPT deficiency is normal unless necrosis is associated with a recent bout of muscle damage. Biochemical analysis of the muscle biopsy reveals the deficiency of CPT, but the fact that one must suspect the diagnosis to ask for the assay makes it helpful only as a confirmatory test. One useful screening test is a respiratory exchange ratio (RER). The ratio of carbon dioxide produced to oxygen consumed gives an indication of the type of fuel used by the patient. In a normal individual at rest, the RER is approximately 0.8 because fatty acids are the predominant source of fuel at rest. In CPT deficiency, the RER is seldom much below 1.0, even with the patient at complete rest. It may be worthwhile to obtain incremental bicycle ergometry results because, in addition to the RER, the Vo2max (maximal oxygen consumption) and work max also can be determined. Usually both are decreased. The maximum heart rate is normal, indicating full effort. Forearm exercise testing is of little value in CPT deficiency because the test stresses glycolytic pathways, and hence the results of the test are normal. Patients with CPT deficiency should be cautioned to avoid any situation that provokes muscle pain and puts them at risk for

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CHAPTER 109 Disorders of Skeletal Muscle myoglobinuria. The physiological effect of fasting should be explained and the patient warned to not attempt exercise under such conditions and not to fast when they have an infection. The use of glucose tablets or candy bars during exercise may raise exercise tolerance slightly. If myoglobinuria is noted, the patient should be admitted to the hospital and renal function monitored. Forced alkaline diuresis may be helpful in some cases. All exercise should be discontinued and the patient confined to bed rest until CK levels return to normal and renal function is uncompromised. Carnitine deficiency myopathy. Carnitine is an important compound in intermediary metabolism. It influences the balance between free coenzyme A (CoA) and acylated CoA in the mitochondria and transfers long-chain fatty acids across the mitochondrial membrane under the action of the enzyme CPT. Sources of carnitine are dietary, as well as liver and kidney synthesis. Carnitine is transported to muscle, which actively takes it up. Many metabolic processes produce acylCoA for use in metabolic pathways; it is then degraded by the liver or excreted by the kidneys. The formation of acylcarnitine is often a step in these processes, enabling the transport of fatty and organic acids across membranes such as the mitochondrial membrane. A surplus of acyl-CoA may cause a variety of damage. It inhibits reactions as diverse as the oxidation of pyruvate, steps in the tricarboxylic acid cycle, and gluconeogenesis. Thus an adequate amount of carnitine is necessary for normal function. One judges the adequacy of the carnitine supply from its absolute value and the percentage of free (nonacylated) carnitine. If free carnitine is absent, carnitine deficiency exists, no matter how much total carnitine is present. Because 98% of the body carnitine is in muscle, it is not surprising that carnitine deficiency is associated with neuromuscular disease. In most patients with carnitine deficiency, the loss of free carnitine is due to a defect in some other enzyme system that results in an overproduction of organic acids or a defect in acyl-CoA disposal. Primary carnitine deficiency is caused by mutations in the sodium-dependent carnitine transporter gene, OCTN2 (also called the SLC22A5 gene), located on chromosome 5q33.1 (Nezu et al., 1999). Causes of secondary carnitine deficiency include multiple acyl-CoA dehydrogenase deficiencies, resulting in an overabundance of organic acids, which then bind the available carnitine; propionyl-CoA carboxylase deficiency; methylmalonyl-CoA mutase deficiency; and a number of mitochondrial disorders. Hemodialysis, cirrhosis, pregnancy, Reye syndrome, valproate therapy, and renal Fanconi syndrome also deplete carnitine stores. In muscle carnitine deficiency, serum levels of carnitine are often normal, but muscle contains reduced total and free carnitine concentrations. Systemic carnitine deficiency includes carnitine deficiency in muscle, liver, and serum. The most common clinical picture in muscle carnitine deficiency is a slowly progressive weakness with sudden exacerbations or a fluctuating course. Fatigue and exercise-related pains occur but usually do not constitute major complaints; myoglobinuria is usually absent. The weakness is usually proximal, and the symptoms begin during childhood or early teenage life. In addition to the limb and some trunk weakness, facial and bulbar weakness occurs. Systemic carnitine deficiency also begins in infancy and childhood, but the muscular weakness occurs in association with an encephalopathy resembling Reye syndrome. Protracted vomiting is the initial symptom of the encephalopathy. Changing levels of consciousness, culminating in coma, follow. Hypoglycemia occurs in most patients, and there may be evidence of liver damage, with an enlarged tender liver or increased serum levels of hepatic enzymes. Hypothrombinemia, hyperammonemia, and excess lipid in the liver are also common. Fasting, because it throws the body into a dependence on fatty acids, may exacerbate the symptoms of carnitine deficiency.

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Fig. 109.26 Carnitine Deficiency. This lipid stain demonstrates deposition of fat in muscle fibers.

The EMG frequently appears myopathic, but no specific findings lead to the diagnosis of carnitine deficiency. The disorder may be suspected on muscle biopsy because of the accumulation of lipid droplets in muscle fibers (Fig. 109.26), but the biochemical measurement of carnitine, both free and total, is necessary to establish the diagnosis. If abnormal, it will initiate the search for the underlying defect. The treatment of carnitine deficiency by replacing carnitine is not uniformly successful. Adults receive approximately 2–4 g/day of l-carnitine in divided doses, with the equivalent of 100 mg/kg in infants and children. No serious side effects occur, although patients may find l-carnitine unpleasant because of accompanying nausea and the fishy odor of the sweat. The results of such treatment vary. Some patients show dramatic improvement, whereas others feel no change at all. The effectiveness of other forms of treatment is equally variable. One patient responded to riboflavin in high doses and others to prednisone. Dietary manipulations such as reducing the amount of longchain fatty acids in the diet and supplying a medium-chain triglyceride diet also are successful in some patients. Other disorders of lipid metabolism. Other less common disorders of lipid metabolism include multiple acyl-coenzyme A dehydrogenation deficiency (MADD), neutral lipid storage disease with myopathy (NLDSM), and neutral lipid storage disease with ichthyosis (NLDSI) (Ohkuma et al., 2009). These disorders can present in early childhood or adult life with weakness. MADD is an autosomal recessive disorder caused by mutations affecting electron transfer flavoprotein (ETF) or ETF dehydrogenase (ETFDH). MADD should be suspected in patients whose muscle specimens show increased lipid deposition and whose serum and urine have increased concentrations of organic acids of multiple carbon lengths. Neutral lipid storage disease is characterized by systemic accumulation of triglycerides in the cytoplasm and includes two distinct diseases: NLSDM and NLSDI (also called Chanarin-Dorfman syndrome). NLSDM may present as a distal myopathy with progressive foot drop and is caused by mutations in a gene that encodes adipose triglyceride lipase (ATGL). This enzyme catalyzes the initial step in triglyceride hydrolysis. A helpful laboratory feature is the presence of Jordan bodies, which are lipid inclusions in white blood cells seen on a blood smear. As the name

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implies, individuals affected with NLSDI have associated skin lesions. This disorder is caused by the mutations in the gene that encodes the coactivator of ATGL.

Disorder of Abnormal Nucleotide Metabolism Myoadenylate deaminase deficiency. Approximately 1% to 2% of the population has a deficiency of the enzyme, myoadenylate deaminase (AMP deaminase, or AMPDA). Inheritance of the disorder is autosomal recessive. The enzyme plays a role in supporting ATP levels by acting in conjunction with adenylate kinase. Adenylate kinase converts two molecules of adenosine diphosphate to one each of ATP and AMP. Adenylate deaminase then converts AMP to inosine monophosphate, with production of ammonia. Muscle stress activates the reaction. Early studies suggested that patients with AMPDA deficiency had myalgia or exercise intolerance. However, many people with AMPDA deficiency are asymptomatic and perfectly normal. Reports of enzyme deficiency vary from congenital hypotonia to amyotrophic lateral sclerosis. This poor correlation between the enzyme defect and the clinical symptoms makes it difficult to know how to interpret the entity. No abnormalities on muscle biopsy under light microscopy exist, although the histochemical reaction for AMPDA is absent. The forearm exercise test is a useful screening test. Patients with AMPDA deficiency produce normal amounts of lactate but little or no ammonia and hypoxanthine, both of which are by-products of the AMPDA reaction.

Mitochondrial Myopathies Mitochondria are responsible for producing energy for cells by generating ATP from the by-products of carbohydrates, fatty acids, and amino acids. The clinical spectrum of mitochondrial disorders is broad and often multisystemic. Due to the high resting energy requirement of the brain, the CNS is often affected by mitochondrial disorders. The energy requirement of skeletal muscle is by contrast quite low at rest, but in exercise becomes much higher. In a group of diseases known as the mitochondrial myopathies, exercise intolerance results. Mitochondrial myopathies can lead to fixed weakness, as well. Acetyl-CoA is the final product of both fatty acid metabolism and glycolysis and feeds into the tricarboxylic acid (Krebs) cycle. The final oxidative pathway, in which electrons are transferred to ATP, involves the respiratory chain in mitochondria. Under normal conditions, the rate of mitochondrial oxidation couples to the need for ATP. If ATP turnover is rapid, mitochondrial oxidation turns on, with the resulting consumption of oxygen and other metabolites. When ATP turnover is minimal, mitochondrial oxidation is relatively quiescent. The body’s response to the increased demands of exercise (and increased mitochondrial oxidation) is predictable. The higher oxygen consumption necessitates augmented delivery of oxygen to the muscle, evidenced by vasodilation, tachycardia, increased cardiac output, and respiration. The heat generation that accompanies this process results in sweating. These are the normal accompaniments of vigorous exercise. When mitochondrial function is impaired, maintaining the required ATP levels even at rest may require fully activated mitochondrial oxidation. In this situation, the patient at rest may experience all the symptoms that normally accompany vigorous exercise. In addition, because the oxidative mechanisms are insufficient to cope with ATP demands, anaerobic mechanisms come into play and produce high blood lactate concentrations. The original description of a mitochondrial disorder was by Luft and colleagues in 1962 (Luft, 1962), although the muscle symptoms were minor. Both patients were women who experienced sustained fever, profuse sweating, and heat intolerance. One preferred to spend her time in a room cooled to 4°C. Other symptoms were excessive thirst

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and appetite, and polyuria. General physical examination demonstrated a rapid heartbeat and respiration, profuse sweating, and warm flushed skin. Blotchy erythematous changes of the skin over the legs occurred. Although some degree of muscle weakness occurred, it was mild and not localized. Many well-described syndromes associated with mitochondrial disorders include prominent muscle complaints. Onset of symptoms is often in childhood, with exercise bringing a heavy feeling in the limbs and muscle aches. After exercise, patients may become tired, nauseated, and breathless. Symptoms may progress over the years until patients are capable of only a limited amount of exercise. Triggers for acute attacks include unaccustomed activity, fasting, or small quantities of alcohol. Acute attacks are also often accompanied by elevated blood lactate levels. In their most severe forms, mitochondrial diseases are detectable at rest. After excluding hyperthyroidism or intoxication with unusual compounds (e.g., dinitrophenol) that uncouple mitochondrial oxidation, few explanations exist for patients who have high pulse and respiratory rates at rest, with a serum lactate level of more than 8 mEq/L. In patients who are less severely affected, incremental bicycle ergometry is the most useful test. Increasing the workload even to low levels results in an excessive rise in pulse rate and oxygen consumption, with a low work max. This discrepancy between normal Vo2max, normal heart rate, and a very low work max is characteristic of the illness. If bicycle ergometry is not available, incremental forearm exercise may demonstrate excessive lactate production for the levels of work used and unusually high venous oxygen saturation. Muscle biopsy can demonstrate findings consistent with a mitochondrial myopathy, but rarely allows for a specific underlying genetic diagnosis. Routine light microscopy of muscle may show ragged-red fibers or may be relatively normal; EM sometimes shows abnormal mitochondria. Ragged-red fibers are not specific and are part of normal aging, although not in such quantities. The biopsy may reveal scattered fibers that lack COX—complex IV in the respiratory chain. These same fibers are frequently strongly succinate dehydrogenase (SDH) CoQ reductase positive—complex II in the respiratory chain. SDH is encoded entirely by nuclear genes. whereas COX is encoded by a mix of nuclear and mitochondrial DNA, which may explain this discrepancy. EM examination shows bizarre distortions of the mitochondria. Even though the typical clinical picture associated with ragged-red fibers in the biopsy makes the diagnosis apparent in many patients, there are some with few pathological changes and even normal biochemistry. Assay of mitochondrial enzyme activity and mutational analysis of the mitochondrial DNA (mtDNA) confirms the diagnosis. Biochemical evaluation of the respiratory chain can help localize the defect, but, similar to history, the findings may still be nonspecific. As an example, biochemical analysis frequently shows COX deficiency; this does not guarantee a mutation in COX itself, as many upstream problems manifest as a secondary deficiency in this testing. Analysis of mitochondrial oxidation requires relatively large amounts of muscle. The introduction of noninvasive techniques to monitor muscle metabolism has had a major impact on the analysis of mitochondrial disorders, although it is perhaps less useful in the diagnosis of these conditions. Magnetic resonance spectroscopy of 31P compounds permits the analysis of ATP, creatine phosphate, inorganic phosphate, and pH in muscle. In mitochondrial disorders, a rapid fall in levels of creatine phosphate and an abnormal accumulation of inorganic phosphates exists. Equally important is a delay in the recovery of phosphocreatine levels to normal after exercise. Genetic testing in mitochondrial disorders is complicated because mitochondrial proteins are encoded both by mitochondrial DNA and nuclear DNA—disorders can result from mutations in either. As a

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CHAPTER 109 Disorders of Skeletal Muscle result, many patterns of inheritance can be seen. All the mitochondria in an embryo are derived from the mother. With hundreds of mitochondria in a single cell, typically not every mitochondria passed on carries the relevant pathogenic mutation. Mutated and normal mitochondrial DNA is thus randomly distributed among body cells in varying quantities. The number of abnormal mitochondria in a given cell must reach a certain threshold to impact energy production before any disease effects are expressed. This leads to variable phenotypic expression across body tissues. Genotype-phenotype correlation is poor, even for nuclear-encoded genes; mutations in a single gene can result in multiple different mitochondrial syndromes and a single mitochondrial syndrome can result from mutations in several distinct genes. There is no proven therapy for mitochondrial disorders. Treatment with a “cocktail” of compounds including riboflavin, ubiquinone, vitamin C, menadione, and niacin has been popular but of unproven efficacy. The following is a discussion of some of the more common mitochondrial disorders associated with myopathy.

Myoclonic Epilepsy with Ragged-Red Fibers The complete spectrum of Myoclonic epilepsy with ragged-red fibers MERRF includes myoclonus, generalized seizures (myoclonic and tonic-clonic), ataxia, dementia, sensorineural hearing loss, and optic atrophy, as well as muscular weakness and atrophy. Weakness and atrophy are usually more prominent in proximal muscles. In addition, some patients have a generalized sensorimotor polyneuropathy along with high-arched feet (pes cavus). The disorder can begin in childhood or adult life. While the course and severity are often progressive, they can be variable even within families. Cardiac muscle is also affected, and patients can develop arrhythmias or heart failure. Patients with MERRF can develop life-threatening hypoventilation in relation to surgery, sedation, or intercurrent infection. Serum CK can be normal or mildly elevated. Serum lactate also is often elevated. Electroencephalography (EEG) may demonstrate generalized slowing of the background activity as well as bursts of spikes and slow waves. MRI or CT scan of the brain reveals cerebral and cerebellar atrophy. Inheritance of MERRF is nonmendelian (inherited only through females). Approximately 80% of affected patients have a point mutation at nucleotide position 8344 of the mitochondrial genome resulting in an A-to-G transition in the transfer RNA for lysine (tRNALys) gene. Other mutations in this gene (positions 8356 and 8366), in the transfer RNA for leucine (tRNALeu) gene (the gene most commonly mutated in MELAS—see next section), and several other genes also have been reported in patients with MERRF. The mitochondrial tRNA gene mutations impair the translation of mtDNA-encoded respiratory chain proteins, with resultant decreased enzymatic activity. Mutation analysis of mtDNA in leukocytes or muscle shows mutations, but the frequency of abnormal mtDNA is greater in muscle.

Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-Like Episodes Biochemical and morphological evidence of mitochondrial abnormalities, high lactate levels in the serum or CSF, and stroke-like episodes characterize Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like Episodes MELAS. The onset is usually in childhood, but rare cases have onset as late as the eighth decade of life. Most patients present with recurrent migraine headaches, hemiparesis, hemianopsia, or cortical blindness. Exercise or intercurrent infection provokes attacks. Some patients develop progressive dementia after repeated attacks. Proximal muscle weakness is present in most patients, along with exercise intolerance. Many patients are short. Some patients also develop myoclonus, seizures, or ataxia.

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Serum CK may be normal or elevated. Lactate levels are elevated in the serum and CSF in the majority of patients. Cortical atrophy and focal low-signal abnormalities are evident on CT and MRI scans of the brain. Muscle biopsy results are indistinguishable from those of other mitochondrial myopathies, as described earlier. Defects in the activity of complex I, III, IV, and V activities appear in muscle specimens. Inheritance of MELAS is maternal in a nonmendelian pattern. Most cases are caused by an mtDNA mutation, an A-to-G substitution, in the gene encoding for tRNALeu at nucleotide position 3243. Mutations also occur at other positions in the tRNALeu gene, as well as in the genes for tRNAVal, tRNACys, and ND5 of complex 1, and in cytochrome b of complex III.

Mitochondrial Myopathies Associated with Recurrent Myoglobinuria Mitochondrial myopathy may present as exercise intolerance and recurrent myoglobinuria beginning in infancy or early adulthood. Laboratory and histopathological features are indistinguishable from other mitochondrial myopathies but serve to exclude the more common causes of myoglobinuria such as CPT2 deficiency, a glycogen storage disease, or a mild form of muscular dystrophy. This is a genetically heterogeneous group of disorders. Autosomal recessive inheritance associated with multiple mtDNA deletions, point mutations in tRNAPhe, microdeletions within the gene encoding for cytochrome c oxidase III mutations in NADH dehydrogenase (ND4), and in cytochrome b have all been reported.

Mitochondrial Myopathy, Lactic Acidosis, and Sideroblastic Anemia This rare disorder typically presents in early infancy or childhood with the eponymous triad. Both exercise intolerance and fixed weakness occur. Hypertrophic cardiomyopathy and respiratory muscle insufficiency occur in nearly half. Mutations in YARS2 and PUS1 have been implicated (Riley et al., 2010; Somerville et al., 2017).

Kearns-Sayre Syndrome KSS is characterized by the clinical triad of progressive external ophthalmoplegia (PEO), retinitis pigmentosa, and heart block, with onset usually before the age of 20 years. Mild weakness of the proximal arms and legs may be apparent. KSS is also associated with short stature, sensorineural hearing loss, dementia, ataxia, depressed ventilatory drive, and multiple endocrinopathies. Normal serum CK concentrations are typical, but lactate and pyruvate concentrations may be elevated. CSF protein is usually increased. ECG reveals conduction defects. Muscle biopsies demonstrate ragged-red fibers on Gomori trichrome stain (Fig. 109.27). The number of ragged-red fibers and COX-negative fibers correlate with the percentage of mitochondria with large deletions. Most patients with KSS have single large mtDNA deletions of varying sizes (ranging from 1.3 to 8.8 kb). Mitochondrial DNA deletions may be present in leukocytes and other tissues, but the sensitivity is much lower than that demonstrated in muscle. The large deletions usually involve several tRNA genes, thus impairing the adequate translation of mtDNA-encoded proteins.

Progressive External Ophthalmoplegia Ptosis and ophthalmoparesis, with or without limb weakness, are the presenting features of PEO. Unlike in KSS, pigmentary retinopathy, cardiac conduction defects, or other systemic manifestations (e.g., endocrinopathies) are not typical. Patients with PEO can develop

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Fig. 109.27 Kearns-Sayre Syndrome. Typical appearance of ragged-red fibers seen in biopsy (modified Gomori trichrome stain).

hypoventilation in response to sedatives and anesthetic agents. Patients with mtDNA deletions often have dysphagia in addition to the extraocular weakness, related to cricopharyngeal achalasia. Serum CK, serum lactate, and CSF lactate can be normal or elevated. CSF protein may be increased. In contrast to classic KSS, the ECG does not demonstrate cardiac conduction defects. Muscle pathology is indistinguishable from KSS. This is genetically a very heterogeneous disorder (Hirano and DiMauro, 2001). Autosomal dominant and maternally inherited forms of PEO are genetically distinguishable from the sporadic subtype. Some sporadic patients with PEO have single large mtDNA deletions indistinguishable from those seen in KSS. These patients could represent partial expressions of KSS. Importantly, these deletions are sporadic in occurrence. Point mutations have been demonstrated within various mitochondrial tRNA (Leu, Ile, Asn, Trp) genes in several kinships with maternal inheritance of PEO. In addition, reports are available of multiple mtDNA deletions in a few kinships with autosomal dominant inheritance. The molecular defects lie in nuclear genes involved in regulating the mitochondrial genome. Autosomal dominant PEO appears to be genetically heterogeneous because the disorder has been localized to mutations in the genes encoding for adenine nucleotide translocator 1 (ANT1) on chromosome 4q34-q35, Twinkle on chromosome 10q23.3-q24.3, and polymerase gamma (POLG) on 15q22-q26. ANT1 is responsible for transporting ATP across the inner mitochondrial membrane, while Twinkle and POLG1 are involved in mtDNA replication.

Mitochondrial DNA Depletion Syndrome The severity of muscle weakness in mitochondrial DNA depletion syndrome can vary. Fatal infantile myopathy is a severe early-onset form characterized by generalized hypotonia and weakness at birth. Weakness is progressive, leading to feeding difficulties, respiratory failure, and death usually within the first year of life. Some infants develop ptosis and ophthalmoplegia. A subclinical neuropathy is often evident on examination. Diminished or absent deep tendon reflexes are present. A benign infantile myopathy exists that resembles the fatal form of myopathy. Generalized hypotonia, weakness, and respiratory and feeding difficulties begin in infancy or early childhood. Although ventilatory assistance may be required, muscle strength often improves during the first year of life. Motor milestones may be delayed but are

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usually attained. Affected individuals can have a normal life expectancy, but some die in the first two decades of life. Serum CK can be normal or elevated, as can the serum lactate level. The associated renal tubular defect results in glycosuria, proteinuria, and aminoaciduria. MRI of the brain may reveal cerebral atrophy and patchy areas of hypomyelination of subcortical white matter. Muscle biopsies demonstrate ragged-red fibers, foci of intense NADH and SDH staining, and many COX-negative fibers. Inheritance of this disorder is autosomal recessive and is associated with a quantitative defect in mtDNA. Several different mutations of nuclear genes (e.g., thymidine kinase gene) important in regulating the mitochondrial genome are felt to be responsible for mtDNA depletion (Saad et al., 2001). The severity of the depletion correlates with the clinical severity of the disorder. As much as a 99% reduction in mtDNA is present in the fatal infantile myopathy form of the disease, while the more benign myopathy has a smaller depletion (36%–88%) of mtDNA.

Congenital Myopathies Occasionally, children exhibit a lack of tone at birth or shortly thereafter. In some, obvious weakness of the limbs accompanies hypotonia, and the baby lies immobile in the crib. These children may have spinal muscular atrophy, a congenital myopathy or muscular dystrophy, a metabolic disorder (e.g., a mitochondrial myopathy), or rarely, a toxic cause (e.g., botulism). Other babies move the limbs, if not normally, at least through their full range of movement, and do so spontaneously. Determining muscle strength in a baby is difficult; however, when no obvious weakness is discernible, the category of congenital hypotonia is used. One of the most common causes of congenital hypotonia is damage to the CNS. Cerebral hypotonia is not due to any primary abnormality in the muscle but presumably accompanies a disturbance of reflex tone. Selective atrophy of type 2 muscle fibers occurs, and lesions occur secondary to the neurological lesion. Babies with benign congenital hypotonia do not show any neurological abnormality other than hypotonia. Tendon reflexes are preserved or slightly diminished. Muscle biopsy and EMGs are normal, and serum CK levels are appropriate to the child’s age. As time progresses, the children can develop muscle tone, and normal motor development may ensue. In teenage life, these children may not gain the ranks of star high school athletes, but neuromuscular function is normal. The only treatment necessary in all these conditions is to encourage the child to participate in play therapy, with the aim of increasing motor activity. Referrals to physical and occupational therapists are important. The subsequent sections and recent reviews discuss the more common forms of congenital myopathy (May and Joseph, 2016; North et al., 2014).

Central Core Myopathy and Multiminicore Myopathy Central core myopathy is inherited in an autosomal dominant fashion and is caused by a mutation in the ryanodine receptor gene (RYR1) (May and Joseph, 2016; North et al., 2014). It is allelic to one form of hereditary malignant hyperthermia and, not surprisingly, malignant hyperthermia and central core can occur together. Patient with central core disease may be floppy shortly after birth, and as in so many of these myopathies, congenital hip dislocation is common. As the child grows older, delay in achieving motor milestones is the rule. At an age when the child should be running easily, he or she is often ungainly and clumsy. The family recognizes before long that the impairment is not getting any worse. Strength, although below normal, usually is not impaired enough to be severely disabling. As in some of the other illnesses, patients may be slender and short of stature. On examination, one observes

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diffuse weakness of the arms and legs. Mild facial and neck weakness also occur. Diminished deep tendon reflexes are the rule. Common skeletal abnormalities such as high-arched feet, a long face, and a high-arched palate are common. Some patients can have ventilatory muscle weakness. Recently, there have been reports of a late-onset axial myopathy in which patients present with truncal weakness (e.g., bent spine syndrome, neck extensor myopathy) who have RYR1 gene mutations (Jungbluth et al., 2009; Løseth et al., 2013). EMG shows nonspecific myopathic changes in central core disease. Serum CK concentrations are usually normal, although mild elevation may occur. The muscle biopsy is diagnostic; muscle shows a combination of type 1 fiber predominance and hypotrophy with central cores, an area in the muscle fiber where the central myofibrils are in disarray. On cross-section of the muscle, many of the oxidative histochemical reactions and the periodic acid–Schiff stain demonstrate an unstained central core running through the center of the fibers (Fig. 109.28). No specific treatment for central core disease is available. A brace may correct a deformity such as a foot drop. Advise patients about the possibility of malignant hyperthermia, a potentially fatal complication.

Nemaline Myopathy The presence of small rod-like particles in muscle fibers is the basis for diagnosis of nemaline myopathy. The modified trichrome stain best displays these rods (Fig. 109.29), but EM characterizes them best. They originate in the Z-disk and exhibit structural continuity with the thin filament. They have a regular structure, presenting as a tetragonal filamentous array when cut transversely and exhibiting periodic lines both perpendicular and parallel to the long axis. Major constituents of the rods include α-actinin, desmin, and nebulin, proteins normally present in the Z-line. The myopathy is genetically heterogenetic, with mutations having been identified in the genes that encode for α-tropomyosin (TPM3), β-tropomyosin (TPN2), nebulin (NEB), troponin T (TnT1), α-actinin (ACTA1), and cofilin-2 (CFL2) (Iannaccone and Castro, 2013; North et al., 2014; Wallgren-Pettersson and Laing, 2006). Autosomal dominant nemaline myopathy links to mutations in α-tropomyosin on chromosome 1q21-q23 (Laing et al., 1995). β-Tropomyosin is on chromosome 9p13, and cofilin-2 in chromosome 14q12 (Donner et al., 2002). Autosomal recessive nemaline myopathy has been associated with mutations in the genes that code for nebulin on chromosome 2q21.2-q22 (Pelin et al., 2002), and troponin T on chromosome 19q13 (Jin et al., 2003). Both autosomal dominant and autosomal recessive cases occur with mutations in α-actinin on chromosome 1q42.1 (Nowak et al., 1999). The clinical picture of nemaline myopathy is heterogeneous (Iannaccone and Castro, 2013; North et al., 2014; Ryan et al., 2001; Wallgren-Pettersson, 2005). Most common is early hypotonia succeeded by diffuse weakness of the arms and legs, mild weakness of the face and other bulbar muscles, and a dysmorphic appearance. The face is long and narrow, with abnormalities of the jaw that may be either prognathous or abnormally short. The feet are often high-arched, and kyphoscoliosis is common as the children grow older. The disorder is slowly progressive. In some patients, respiratory failure out of proportion to the general weakness may ensue. Cardiomyopathy also occurs. A severe infantile variety is fatal. These children have profound hypotonia and respiratory failure. Another form may have its onset in early adulthood and present with a mild proximal or predominantly distal weakness (Wallgren-Pettersson et al., 2007). No specific treatment for nemaline myopathy is available. Bracing and surgery have a role in treatment.

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Fig. 109.28 Central Core Disease. Unstained area in most fibers is characteristic of this illness (nicotinamide adenine dinucleotide dehydrogenase-tetrazolium reductase stain).

Fig. 109.29 Nemaline Myopathy. Although better demonstrated with the electron microscope, nemaline rods are also noted with histochemical reactions. Granular appearance of these fibers is due to the presence of many rods (modified Gomori trichrome stain).

In nemaline myopathy, EMG demonstrates the nonspecific myopathic changes. Serum CK levels may be normal or elevated. The muscle biopsy, in addition to demonstrating nemaline rods, often shows type 1 fiber predominance, selective atrophy of the type 1 fibers, and deficiency of type 2B fibers (Fig. 109.30). EM examination shows the characteristic rods. These are most often in the cytoplasm, but intranuclear rods also occur and equate with the severe infantile form (Goebel and Warlo, 1997).

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Fig. 109.30 Nemaline Myopathy. As in central core disease, nemaline myopathy shows predominance and atrophy of type 1 fibers. Note that the very smallest fibers in this biopsy are all type 1 (myosin adenosine triphosphatase stain, pH 9.4).

Congenital Fiber-Type Disproportion

Centronuclear Myopathy The term centronuclear myopathy applies to a group of diseases in which the pathological finding is the presence of fibers with internal nuclei (Iannaccone and Castro, 2013; North et al., 2014). The most common form is an X-linked and infantile presentation of severe extraocular, facial, and limb weakness that is often fatal due to respiratory failure (Wallgren-Pettersson, 2005). This disorder is also known as myotubular myopathy, as muscle biopsies show atrophic fibers with central nuclei resembling myotubes. Severe hypotonia and respiratory distress are the presenting features. The disorder is usually fatal during the first few months due to respiratory failure. The weakness is severe and includes weakness of the facial and neck muscles as well as the extraocular muscles. Ptosis and ophthalmoparesis occur. The ribs are thin, and there are contractures at the hips and less often at the knees and ankles. X-linked myotubular myopathy results from mutations in the MTM1 gene encoding for myotubularin-1 (Laporte et al., 1997). Occasional female carriers manifest less severe disease. An autosomal dominant form of centronuclear myopathy also exists. The disorder is milder, occurs later in life, and is less common than the severe X-linked form. Ptosis, extraocular weakness, and facial weakness may be present, and moderate limb weakness gives rise to some disability. Equinovarus deformity of the feet occurs. The autosomal recessive variety, which is also less common, seems to be intermediate in severity between the other varieties. Some autosomal dominant cases of centronuclear myopathy are associated with early involvement of distal muscles and caused by mutations in the DNM2 gene on chromosome 19p13.2 that encodes for dynamin-2 (Bitoun et al., 2005; Fischer et al., 2006). Of note, mutations in this gene cause CMT2B (Zuchner et al., 2005), explaining some of the overlapping features (distal weakness, mild sensory abnormalities). Laboratory studies show normal or slightly elevated serum CK concentrations. EMG demonstrates marked muscle membrane instability in the form of fibrillation potentials, positive sharp waves, complex repetitive discharges, and occasionally even myotonic discharges. Muscle biopsy demonstrates characteristic features. With the routine

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hematoxylin and eosin or trichrome stains, marked variability in the size of fibers occurs, most of which are small. In the center of many of these fibers is a large, plump nucleus resembling the myotube stage of muscle development. With the oxidative enzyme reaction, many of the fibers have a darkly staining central spot. Almost all the fibers have a pale staining area, with an ATPase reaction that runs through the middle of the fiber. Although this looks superficially like a core, most central cores are not visible with an ATPase stain. When viewed in longitudinal section, the fiber has a long central area containing nuclei spaced at intervals. The biopsy shares features of the other congenital disorders, with type 1 fiber predominance and often type 1 fiber atrophy or hypotrophy. The biopsy findings in the X-linked recessive illness appear similar. Although the muscle fibers superficially resemble myotubes, they are in fact quite different: hence the preferred term, centronuclear myopathy. The differentiation into well-marked histochemical fiber types and the cytoarchitecture of the fiber more resemble the adult fiber. Two fetal cytoskeletal proteins (vimentin and desmin), which are found in fetal myotubes, have been demonstrated in fibers from patients with myotubular myopathy by immunocytochemical studies. On occasion, the EEG shows a paroxysmal disturbance. Treatment includes respiratory and general supportive measures. Treatment of the severe infantile form requires balancing intervention against the very poor prognosis. The decision whether or not to provide life support for these children is a difficult one. Most die within the first 2 years.

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Children affected by congenital fiber-type disproportion are floppy at birth, with varying degrees of weakness. The weakness is diffuse and frequently involves the face and neck. Sometimes in early childhood, strength improves, but whether this represents an improvement in the disease or the child’s normal growth is uncertain. Contractures, particularly of the Achilles tendons, and congenital hip dislocation are common. Respiratory complications are common during the first 2 years of life, when the disease can be quite severe. As the children grow older, they remain weak and are short, with low weight. Accompanying the illness are various deformities of the feet, high-arched palate, and kyphoscoliosis. EMG shows myopathic potentials but no evidence of muscle membrane instability (i.e., no fibrillation potentials or positive sharp waves). The serum CK concentration may be normal to slightly elevated. Muscle biopsy is diagnostic; the characteristic feature is a marked disproportion between the size of type 2 and type 1 fibers. Muscle biopsy shows the features of type 1 fiber atrophy and predominance. The original suggestion that a 15% smaller mean diameter of type 1 fibers compared to type 2 fibers was diagnostic was incorrect. The diagnosis should only be made when the discrepancy between the type 1 and type 2 fibers is greater than 45% and when more than 75% of the fibers are type 1 (Fig. 109.31). The reason for this discrepancy in fiber size is unknown. Inheritance is autosomal dominant in approximately 40% of reported cases. This illness may represent nemaline myopathy without apparent rods, as some cases have been found with mutations in ACTA1 and TPN3 genes. Some patients have had mutations in the gene that encodes for selenoprotein N, which are also associated with multiminicore myopathy, congenital muscular dystrophy with rigid spine, and some cases of MFM.

Inflammatory Myopathies Inflammatory cell infiltrates may be seen on muscle biopsy in a wide range of myopathies and dystrophies. In many cases, this is presumably a secondary response of the immune system to the muscle fiber damage

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malignancy, prognosis, and expected response to various treatments. Contemporary classification schemes have incorporated these discoveries to an increasing degree. As there is not yet a perfect correlation between clinical, histopathological, and serological findings, there remains some controversy regarding appropriate categorization into strict categories of disease.

Dermatomyositis

Fig. 109.31 Congenital Fiber-Type Disproportion. The diagnosis requires a clear discrepancy between hypertrophic type 2 fibers and atrophic type 1 fibers, as demonstrated in this picture (myosin adenosine triphosphatase stain, pH 9.4).

induced by the underlying disorder. In the inflammatory myopathies, however, the disease process is a primary result of an abnormality of the immune system itself. DM, myositis associated with antisynthetase syndrome (ASS), PM, immune-mediated necrotizing myopathy (IMNM), and IBM are the most common inflammatory myopathies (Amato and Barohn, 2009a, 2009b). The underlying pathogenesis of these inflammatory myopathies is diverse. Inflammatory myositis can occur in isolation, as a paraneoplastic manifestation of malignancy, or in association with connective tissue disorders (overlap syndromes). When myositis occurs as part of another autoimmune disease (e.g., rheumatoid arthritis), the primary condition often overshadows the myopathy. Finally, viral, bacterial, and parasitic infections can directly affect muscle; much of the muscle damage in these cases arises from the resulting immune response. The classification of inflammatory myositis was initially based on criteria established by Bohan and Peter in 1975. Because IBM and IMNM were not yet understood to be distinct entities and because these criteria did not require muscle biopsy, the incidence of PM was overestimated and the disease likely overdiagnosed. Over time, distinct clinical and histopathological features have been described between these various disorders. Recent consensus classification schemas recognize these advances and allow for distinction between DM, PM, IBM, IMNM, and ASS (Allenbach et al., 2018; De Bleeker JL, Neuromuscul Disord, 2015; Hoogendijk, 2004). Equally important, however, an expanding array of pathological autoantibodies have been discovered in association with various myositis syndromes. Both myositis-specific antibodies (MSA)—seen only in the presence of an inflammatory myositis—and myositis-associated antibodies (MAA)— seen in myositis overlap syndromes with other autoimmune diseases— have been described. In many cases, a specific antibody can predict the underlying histopathology with high specificity and also predict clinical characteristics of the disease. In addition to securing a diagnosis, the identification of a specific autoantibody can offer the clinician important information about common associated manifestations of disease (e.g., interstitial lung disease [ILD] in ASS), risk of associated

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DM is an illness in which weakness is associated with a characteristic skin rash. It is the most common form of myositis and can present at any age from childhood through late adult life (Bendewald et al., 2010). The rash typically occurs prior to or with the onset of muscle weakness, although occasionally it will begin later. A “heliotrope rash” is characteristic—purplish discoloration of the skin over the cheeks and eyelids. An erythematous, macular rash may develop on the face, in a V-shaped distribution below the neck, the shoulders and upper back (shawl sign), or extensor surfaces of the elbows, knees, and knuckles (Gottron sign). The knuckles can also develop a papular rash (Gottron papules). The rash may spread widely over the body and be associated with edema of the skin, which frequently becomes scaly and weeping. Because the hallmark of the disease is the capillary abnormality, it may be helpful to use a hand lens to examine the skin around the nail beds. There, small hemorrhages and looped, dilated, and sometimes thrombosed capillaries may combine with avascular areas. The cuticle is discolored. In chronic long-standing DM of childhood, the skin changes may be more disabling than the muscle weakness. In the terminal stage, the skin may be a shiny, fragile, shell-like covering that cracks at the slightest movement. Soft-tissue calcification occurs in some patients as the disease progresses; it is usually late in the illness and is not necessarily an indication of active disease. Weakness is symmetrical and affects the proximal more than distal muscles of the arms and legs. Dysphagia affects up to 30%. Muscle pain may be noted but should not be the predominant feature of the disorder. The illness often follows a relapsing-remitting course, although occasionally the illness is clearly monophasic even to the point of recovering spontaneously without treatment. Muscle is not the only tissue involved in DM. There may be evidence of vascular abnormalities such as the Raynaud phenomenon. Cardiac involvement ranges from conduction defects to congestive cardiac failure secondary to cardiomyopathy. Interstitial pneumonitis and fibrosis may cause a nonproductive cough and respiratory distress. Chest radiographs show changes in the majority of patients, with patchy consolidation, particularly subpleural, and peribronchovascular thickening. The changes are reversible with treatment (Mino et al., 1997). Delayed gastric and esophageal emptying occurs in the illness, indicating an abnormality in the smooth muscle of the upper gastrointestinal tract. There is an increased risk for cancer in adults with DM. Approximately 10% to 15% of adults will develop a cancer within 2–3 years of presentation of the myositis (Olazagasti et al., 2015). Accordingly, all patients should undergo comprehensive screening. Breast, pelvic, testicular, and prostate examinations should be performed. We send complete blood count, electrolytes and renal function, urinalysis, and serum protein electrophoresis. We also obtain a CT scan of the chest, abdomen, and pelvis, a colonoscopy in all those over 50 or with gastrointestinal complaints, and mammography and pelvic ultrasound in women. The serum CK concentrations are often elevated in DM but can be normal in a third of cases, particularly in patients with a very indolent course. Serum CK levels do not necessarily reflect activity of the disease, so one might see a clinical exacerbation unaccompanied by marked changes in enzyme levels of patients whose illness appears quiescent and who have moderately elevated levels of CK. The CK levels may rise

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Fig. 109.32 Dermatomyositis. Short tau inversion recovery sequence on magnetic resonance imaging of the arm demonstrates hyperintensity consistent with muscle edema in affected muscles.

several weeks before a clinical relapse occurs. In approximately 10% of patients with a normal CK, the serum aldolase may be elevated. EMG demonstrates early recruitment of small polyphasic motor unit action potentials (MUAPs), often associated with increased insertional activity, fibrillation potentials, positive sharp waves, and complex repetitive discharges. When obtained, muscle MRI may show evidence of edema in affected muscles, best seen on short tau inversion recovery (STIR) sequences (Fig. 109.32). This is not specific for inflammatory myositis, but it may be helpful in selecting which muscle to biopsy. MSA are found in 60%–70% of patients with DM and include antibodies against Mi-2, melanoma differentiation protein 5 (MDA5), transcriptional intermediary factor 1-ϒ (TIF1-ϒ), and nuclear matrix protein 2 (NXP-2). Anti-Mi-2 occurs in 7%–30% (Pinal-Fernandez et al., 2015). Compared to other patients with DM, patients with anti-Mi-2 antibodies have a reduced risk of malignancy and more favorable response to treatment. By contrast, anti-TIF1-ϒ antibodies are seen in 14%–31% and are highly predictive of associated malignancy. The characteristic histological feature on muscle biopsy is perifascicular atrophy (a crust of small fibers surrounding a core of more normal-sized fibers deeper in the fascicle) (Fig. 109.33). Perifascicular atrophy is a rather specific abnormality and is typically seen only in DM and in some overlap syndromes (see later discussion). Importantly, perifascicular atrophy is not always appreciated (occurring in 80% of the lower limit of normal). Markedly reduced-amplitude SNAPs suggest CIP, unless there is an unrelated baseline neuropathy. EMG usually demonstrates prominent fibrillation potentials and positive sharp waves and early recruitment of myopathic MUAPs. Patients with severe weakness may be unable to volitionally recruit any MUAPs, which can make it difficult to distinguish CIM from CIP in patients who may have coincidental abnormal sensory conduction studies. Muscle biopsies reveal a wide spectrum of histological abnormalities, including type 2 muscle fiber atrophy with or without type 1 fiber atrophy, scattered necrotic muscle fibers, and, importantly, focal or diffuse loss of reactivity for myosin ATPase activity. EM reveals loss of thick filaments (myosin).

Endocrine Myopathies Myopathy can result from endogenous steroid hormone excess (i.e., Cushing syndrome) just the same as with exogenous corticosteroid administration. Additionally, myopathy can be seen in relation with thyroid and parathyroid diseases.

Hypothyroidism Patients with hypothyroidism develop proximal muscle weakness about one-third of the time (Duyuff et al., 2000). Cramps and myalgia are also common. Muscle symptoms are rarely the presenting complaint, with other systemic symptoms such as fatigue, cold intolerance, and weight gain typically also present. A distal, symmetric polyneuropathy can occur as a result of hypothyroidism, and carpal tunnel syndrome is common. Rhabdomyolysis has also been reported. Patients with muscle involvement may have delayed relaxation of the muscle stretch reflexes. Direct percussion of muscle with a reflex hammer can

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CHAPTER 109 Disorders of Skeletal Muscle produce painless local mounding (myoedema) in about one-third of patients; other patients have muscle hypertrophy (Salick and Perason, 1967). The serum CK is often elevated, but may be normal. Most cases occur with primary thyroid dysfunction, so thyroid stimulation hormone (TSH) should be elevated and thyroxine (T4) and triiodothyronine (T3) levels low. Needle EMG is frequently normal, though some patients may have myopathic motor unit potentials evident in severely weak muscles—especially when the CK is elevated. Muscle biopsy is rarely required, but when performed shows nonspecific findings including type 2 muscle fiber atrophy, type 1 muscle fiber hypertrophy, rare necrotic fibers, increased internalized nuclei, and vacuoles (Laylock and Pascuzzi, 1991). With correction of the hypothyroid state, muscle strength improves in the majority of patients.

Hyperthyroidism Thyrotoxic myopathy also produces proximal muscle weakness, typically more rapid in onset than with hypothyroidism (Kung, 2007). Muscle atrophy, particularly of the shoulder girdle, and scapular winging can occur. In severe cases, rhabdomyolysis has been reported. Myalgias and fatigue are common, like with hypothyroidism. Occasionally patients will develop bulbar or respiratory muscle weakness. Thyroid ophthalmopathy can occur in patients with Graves disease, leading to weakness of extraocular muscles and proptosis. Myasthenia gravis has been reported in association with Graves disease,

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leading to some diagnostic confusion. Eye closure weakness—present with myasthenia gravis and typically absent with Graves disease—as well as fluctuating symptoms can help distinguish. On examination, muscle strength reflexes may be brisk in contrast to hypothyroidism. Fasciculations and myokymia may also be noted. Serum CK values are commonly normal, as are NCS and EMG. With correction of hyperthyroidism, patients typically improve over months (Duyuff et al., 2000).

Rhabdomyolysis Rhabdomyolysis is a condition of acute and severe muscle fiber breakdown that leads to release of sarcoplasmic contents into the bloodstream, including myoglobin and potassium. Plasma myoglobin is filtered by the renal glomeruli but may precipitate in the renal tubules, producing acute renal failure. Potassium release into the bloodstream may cause cardiac arrest. The degree of muscle breakdown can cause profound muscle weakness and pain. Causes of rhabdomyolysis include crush injuries to limbs with vascular occlusion, metabolic myopathies such as CPT deficiency, and toxic myopathies such as those due to statin drugs (Nance and Mammen, 2015). However, in most cases of rhabdomyolysis, no underlying cause can be identified. Many of these patients have recurrent episodes of the condition. The complete reference list is available online at https://expertconsult. inkling.com/.

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110 Neurological Problems in the Newborn Jarred Garfinkle, Steven P. Miller

OUTLINE Neonatal Seizures, 2022 Pathophysiology, 2023 Etiology, 2024 Neonatal Epilepsy Syndromes, 2025 Diagnosis, Semiology, and Differential Diagnosis (see Chapter 91), 2025 Electroencephalography, 2026 Management, 2026 Prognosis and Progression Toward Epilepsy, 2027 Brain Injury in the Preterm Newborn, 2027 Intraventricular Hemorrhage, 2027 White Matter Injury, 2028 Gray Matter Injury, 2030 Cerebellar Hemorrhage, 2030 Hypoxic-Ischemic Injury in the Term Newborn, 2030 Etiology and Pathophysiology, 2030 Diagnosis, 2030 Neuroimaging, 2031 Management, 2032 Prognosis, 2032 Perinatal Stroke, 2032

Neurological problems in the newborn infant can arise from innate processes such as genetic abnormalities or disorders of nervous system development or can be the result of acquired brain injury from external insults. Both innate and acquired brain injury in the newborn have lifelong important impact on the developing person and his or her family (Moster et al., 2008). The increasing incidence of preterm delivery worldwide, currently estimated at 11%, and the improved survival of the sickest newborns require the neurologist to be aware of the neurological burden of perinatal and neonatal illness (Harrison and Goldenberg, 2016). More than half of very preterm newborns will have developmental problems ranging from attention-deficit/hyperactive disorder to cerebral palsy (Pascal et al., 2018). Almost half of neonates with hypoxic-ischemic encephalopathy (HIE) have neurodevelopmental sequelae as well (Jacobs et al., 2013). These developmental outcomes challenge the child, the family, and the community (Moster et al., 2008). The newborn, whether term or preterm, has a limited means of manifesting injury to the central nervous system (CNS). The adult brain manifests change in many domains with regional specificity, including cognition, behavior, speech, vision, and movement. In contrast, the neonatal brain is in a state of rapid development and most commonly reveals underlying brain dysfunction in two nonspecific ways: encephalopathy and seizures. In the preterm newborn, the neurological signs of significant injury can be even more subtle or not manifest at all.

Perinatal Arterial Ischemic Stroke, 2032 Cerebral Sinus Venous Thrombosis, 2032 Metabolic Brain Injury, 2033 Hypoglycemic Brain Injury, 2033 Inborn Errors of Metabolism, 2034 Hyperbilirubinemia, 2034 Infections in the Central Nervous System, 2035 Bacterial Meningitis, 2035 Viral Infections, 2035 Trauma to Extracranial, Central, and Peripheral Nervous System Structures, 2037 Intracranial Hemorrhage, 2037 Extracranial Hemorrhage, 2038 Skull Fractures, 2038 Spinal Cord Injury, 2038 Facial Paralysis, 2038 Brachial Plexus Injury, 2038 Neonatal Abstinence Syndrome and Antidepressant Exposure, 2039 Neonatal Abstinence Syndrome, 2039 Antidepressant Exposure, 2039

Advances in neurodiagnostic testing, and neuroimaging in particular, have enhanced our understanding of the pathophysiology of brain injury in the newborn. Digital electroencephalography (EEG) with bedside trending, such as amplitude-integrated EEG (aEEG), and remote access availability grant the clinical team a real-time window into brain function (Fig. 110.1). Neonatal neurology is a growing medical subspecialty with increasing numbers of dedicated multidisciplinary programs at academic institutions (Smyser et al., 2016). In addition to specific neuroprotective therapies, the increasing focus on the developing brain in the neonatal intensive care unit (NICU) may lead to improved outcomes via earlier recognition and treatment of neurological conditions (Bonifacio et al., 2011). A cooperative team effort often is the most effective approach to neurological problems in newborns. Many units also address fetal brain injury (Kirkham et al., 2018). This chapter reviews the practical aspects of diagnosis and management of neonatal neurological problems commonly encountered by practicing neurologists.

NEONATAL SEIZURES A seizure is defined clinically as a paroxysmal alteration in any neurological function accompanied by seizure activity identifiable on an EEG. Unlike the child and adult, in whom unprovoked seizures

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Fig. 110.1 Amplitude-Integrated Electroencephalography (aEEG) of a Neonate Demonstrating Seizures. The repetitive sudden rise in the lower margin of the aEEG trace (upper panel; marked in real-time with green bars) corresponds to seizures on the raw electroencephalography (EEG) trace in the lower panel of the image (corresponding to the red bar). Additional events which appear to be seizures on the aEEG, but which were not marked in real time, are indicated by green arrows. In this example, the seizures appear to be emanating from the left hemisphere. Notations at the top of the image were made in real time by the treating team to indicate what was transpiring at the bedside.

predominate, seizures in newborns are almost always acute symptomatic (Glass et al., 2016). They are more common in the first 28 days of life than in any other time of life and represent one of the most common manifestations of neonatal brain injury (Abend et al., 2018). The timing of onset of the seizures informs the etiology (Fig. 110.2).

Etiology of neonatal seizures by day of presentation Hypoxia-Ischemia Stroke:

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Intracranial hemorrhage or contusion Benign familial convulsions

Metabolic Disorders: Electrolytes, Glucose

Pathophysiology

Inborn errors of metabolism

Several developmental factors leading to excess excitation and reduced inhibition influence the high rate of acute-symptomatic seizures in the neonatal period. In adult neurons, γ-aminobutyric acid A (GABAA) receptor activation leads to chloride influx to produce membrane hyperpolarization and inhibition. In immature neurons, there is a net chloride efflux with GABAA receptor activation, which leads to membrane depolarization and excitability (Ben-Ari, 2014). The developmental fluctuations in neuronal chloride gradients are mediated largely by membrane ion transporters: NKCC1 leads to a high intracellular chloride concentration, whereas KCC2 acts as an active chloride extrusion pathway (Fig. 110.3). With increasing age, the expression of the KCC2 becomes dominant. These developmental changes in chloride influx/efflux may contribute to the often-disappointing response of neonatal seizures to GABA-agonist anticonvulsant medications such as phenobarbital. An understanding of the adverse consequences of neonatal seizures on the developing brain is emerging and informs the need to treat subclinical and refractory seizures (Fig. 110.4). Prolonged seizures may cause neuronal injury principally via disturbances in cerebral energy metabolism, with eventual diminution of energy supplies,

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Fig. 110.2 Common Etiologies of Neonatal Seizures. The most common etiologies of neonatal seizures are plotted by their most common day(s) of presentation. (Adapted from Miller, S.P., Ferriero, D.M., 2007. Neonatal brain injuries. In: Gilman, S. [Ed.], Neurobiology of Disease, first ed. Elsevier Academic Press, Burlington, p. 605.)

and excitotoxicity (Holmes, 2009). Recurrent, shorter seizures in animal models have not demonstrated neuronal injury but have been shown to mediate long-term morphological and physiological deficits, including suppression of neuronal stem cells (Holmes, 2009). There is also growing evidence that seizures in human newborns are associated with adverse neurobehavioral outcomes. Neonatal seizures, especially if frequent, intractable, or prolonged, are independently associated with further hypoxic-ischemic brain injury as measured by magnetic resonance (MR) spectroscopy and with later neurodevelopmental impairment (Glass et al., 2009; Miller et al., 2002).

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B Fig. 110.3 Schematic Diagram of the Developmental Alterations of Chloride Levels, The γ-Aminobutyric Acid (Gaba) Channel, and Chloride Cotransporters. (A) The intracellular chloride (Cl–) levels are higher in immature than adult neurons. (B) GABA depolarizes and excites immature neurons and inhibits adult ones. (Adapted from Ben-Ari, Y., 2014. The GABA excitatory/inhibitory developmental sequence: a personal journey. Neuroscience 279, 196.)

Etiology Most neonatal seizures are acute symptomatic and can follow a multitude of causes (see Fig. 110.2). The remainder relate to developmental brain abnormalities and neonatal epilepsy syndromes that are often of genetic origin. Determining the etiology, or etiologies, is important because it informs management and prognosis. HIE accounts for almost half of neonatal seizures in term newborns

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(Glass et al., 2016). In preterm newborns, HIE and intracranial hemorrhage each account for approximately one-third of the seizures, although the clinician should be alert for multiple concurrent etiologies (Glass et al., 2017). Congenital CNS abnormalities account for 5%–10% of neonatal seizures and require neuroimaging for diagnosis. Hypoxic-ischemic brain injury in the second and third trimesters of gestation can result

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Within hours-days

Encephalopathy Neonatal seizures

Seizures suspected in term or late preterm neonate: Confirm seizures with EEG or aEEG (where available) Check easily correctable causes: glucose, electrolytes.

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Neonatal brain injury

Cerebral palsy ? Global developmental delay Epilepsy Behavioral problems Fig. 110.4 Schematic of the Associations Between Neonatal Brain Injury, Neonatal Seizures, and Later Neurodevelopment. (Adapted from Garfinkle, J., Shevell, M.I., 2016. Neurodevelopmental outcomes of neonates with seizures. In: Nagarajan, L. [Ed.], Neonatal Seizures: Current Management and Future Challenges, first ed. Mac Keith Press, London, p. 164.)

Lorazepam 0.1 mg/kg IV

Lorazepam 0.1 mg/kg IV Consider continuous EEG monitoring if not already done Phenobarbital 20 mg/kg IV

in malformation of brain development (Inder et al., 1999). Seizures in the context of cerebral dysplasia are particularly refractory and usually progress towards epilepsy.

Phenobarbital 10 mg/kg IV

Neonatal Epilepsy Syndromes Neonatal epilepsy syndromes encompass genetic channelopathies and specific metabolic deficiencies that are increasingly recognized with next-generation genetic sequencing. Channelopathies can range from benign, with resolution of seizures and normal neurodevelopment, to severe early-onset epileptic encephalopathies. Benign familial neonatal epilepsy is an inherited autosomal dominant condition. When familial seizures are not identified, then the condition is termed benign neonatal seizures. Several gene loci which encode for voltage-gated channels, including KCNQ2, KCNQ3, and SCN2A, have been identified (Axeen and Olson, 2018). Seizure onset is usually in the first week of life, and seizures classically remit within the first year of life. In early infantile epileptic encephalopathy, seizures are often initially refractory. Some families retrospectively report rhythmic movements in utero. Some of the newborns are classified as having Ohtahara syndrome, a severe epileptic encephalopathy characterized clinically by intractable tonic seizures and burst suppression on EEG and caused by an increasing number of genetic abnormalities. Early myoclonic encephalopathy is another phenotype of early infantile epileptic encephalopathy featuring erratic focal myoclonus that shifts around the body in an asynchronous pattern, often with burst suppression pattern on EEG. Patients with early infantile epileptic encephalopathies may evolve into West or Lennox-Gastaut syndromes with age (Sanders et al., 2018). Sodium channel blockers, such as phenytoin and carbamazepine, are particularly effective in managing the channelopathies (Sanders et al., 2018; Sands et al., 2016). In the context of seizures of unknown etiology, treatable metabolic epileptic encephalopathies should be considered and appropriate therapy instituted pending diagnosis. These disorders include pyridoxine-responsive seizures and folinic acid–responsive seizures, which are both allelic to antiquitin (ALDH7A1) deficiency; pyridox(am)ine-5′phosphate oxidase deficiency secondary to homozygous mutations of PNPO; and 3-phosphoglycerate dehydrogenase deficiency responsive to serine supplementation (Saudubray and Garcia-Cazorla, 2018). Classically, the diagnosis of pyridoxine-responsive seizures was based on a response to a single large dose (e.g., 100 mg) of intravenous pyridoxine with concurrent EEG recording. However, the pyridoxine challenge is not sensitive and can induce apnea. As such, one strategy for suspected vitamin-responsive early-onset epileptic encephalopathies is to initiate broad treatment with folinic acid and pyridoxal phosphate for 3 days and to continue the therapy if there is a clinical improvement pending genetic test results (Fig. 110.5). Elevations of urinary α-aminoadipic semialdehyde (AASA) and serum or cerebrospinal fluid (CSF) pipecolic acid are nonspecific biomarkers for pyridoxine-dependent seizures (Ficicioglu and Bearden, 2011). F ECF

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Fig. 110.5 An Example Neonatal Seizure Management Algorithm Adapted From the Hospital for Sick Children (Toronto, Ontario, Canada). aEEG, Amplitude-integrated electroencephalography; IV, intravenous PLP, pyridoxal phosphate; PO, per os.

Many other inherited disorders can without specific treatments present with refractory neonatal seizures, such as nonketotic hyperglycinemia, peroxisomal biogenesis defects, respiratory chain disorders, sulfite oxidase deficiency, Menkes disease, and congenital disorders of glycosylation.

Diagnosis, Semiology, and Differential Diagnosis (see Chapter 91) Accurate diagnosis of neonatal seizures requires electrographic corroboration due to the difficulty in accurately identifying clinical seizures. Seizure manifestations in newborns differ from those in older individuals in that newborns generally do not have well-organized, generalized tonic-clonic seizures due to the immaturity of their synaptic connections. In addition, seizures in the newborn are often clinically silent and detected only on EEG; these seizures are referred to as subclinical seizures (Fig. 110.6; see later). In one study, only one-third of neonatal EEG seizures displayed clinical signs on simultaneous video recordings; only one-third of these clinical manifestations were recognized by experienced neonatal staff; and only one-quarter of clinically suspected seizures documented by staff had corresponding electrographic evidence of seizure activity (Murray et al., 2008). As such, EEG monitoring to identify seizures is an essential tool to avoid missing and undertreating seizures and to avoid overdiagnosing and overtreating seizures (Shellhaas et al., 2011). If continuous EEG is not available, then continuous aEEG

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can be used. aEEG is a simplified trend monitor that displays one or two channels of time-compressed, processed EEG signal on a semi-logarithmic scale (see Fig. 110.1). Compared with EEG, it is less sensitive but readily interpreted by trained bedside practitioners. The use of these brain-monitoring tools is a cornerstone of modern neonatal neurocritical care (Bonifacio et al., 2011). Clinical seizure semiologies have been classified by Volpe, and they are summarized in Table 110.1 (Abend et al., 2018). Seizure types are not specific for etiology, but some are seen more often with certain underlying conditions. For instance, focal clonic seizures in the term “newborn” are most commonly associated with focal cerebral infarction. Subtle and generalized tonic seizures do not consistently show concomitant electrographic discharges. In these cases the abnormal movements may represent nonepileptic brainstem release phenomena or seizure discharges in deep cerebral structures which are not transmitted to surface EEG. Nonepileptic movements must be distinguished from seizures. Physiological myoclonus, which occurs in healthy newborns, differs from myoclonic seizures, which often have a dismal outcome: the seizures are not evoked by stimuli, are nonsuppressible by touch, and occur with concomitant encephalopathy. Jitteriness, which is an exaggerated startle response, is often confused with clonic seizures, especially because both jitteriness and clonic seizures occur

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Fig. 110.6 Venn Diagram of Neonatal Seizures Classified According to Clinical And Electrographic Manifestations.

TABLE 110.1

from Volpe

Clinical Seizure Classification Manifestations and Key Points

Clinical Seizure Subtle

Clonic: focal or multifocal

Tonic: focal or generalized Myoclonic focal, multifocal, or generalized

Eye deviation, blinking, fixed stare Repetitive mouth and tongue movements Apnea, other autonomic phenomena Bicycling, other rhythmic limb movements Rhythmic movements of muscle groups Often represents a focal pathology Sustained flexion or extension of muscle groups Synchronous flexion jerks Must be distinguished from nonepileptic myoclonus

From Abend, N.S., Jensen, F.E., Inder, T.E., Volpe, J.J., 2018. Neonatal seizures. In: Inder, T.E., Volpe, J.J., Darras, B., de Vries, L., du Plessis, A., Neil, J., Perlman, J. (Eds.), Volpe’s Neurology of the Newborn. Elsevier.

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in similar underlying conditions, such as HIE, hypoglycemia, and drug withdrawal. The absence of associated ocular movements and autonomic changes (e.g., tachycardia, hypertension, and apnea) and the presence of stimulus sensitivity distinguish jitteriness from seizures. The predominant movement in jitteriness is tremor, in which the alternating movements are rhythmic and of equal rate and amplitude (Abend et al., 2018). In contrast, movements in clonic seizures have a fast and slow component. In addition, jitteriness stops when passively flexing the affected limb. Hyperekplexia is another abnormal movement that is nonepileptic. It is characterized by an exaggerated startle response and sustained tonic spasms in response to unexpected auditory, visual, and somesthetic stimuli and is caused by genetic mutations in genes involved in glycine neurotransmission (Shahar and Raviv, 2004).

Electroencephalography EEG and aEEG are necessary tools for the diagnosis of neonatal seizures. Continuous conventional EEG is currently recommended as the “gold standard” for diagnosis of neonatal seizures by the American Clinical Neurophysiology Society (Shellhaas et al., 2011). In most neonatal seizures, electrographic onset is focal or multifocal. Spread of the seizure within one hemisphere and secondary generalization to the contralateral hemisphere are uncommon, presumably due to the immature synapses in the newborn brain (Abend et al., 2018). Neonatal EEG seizures have (1) a sudden electrographic change; (2) repetitive waveforms that evolve in morphology, frequency, and/or location; (3) an amplitude of at least 2 µV; and (4) a duration of at least 10 seconds (Tsuchida et al., 2013). Fig. 110.6 illustrates the terminology used to describe clinical, electrographic, and subclinical seizures. Uncoupling refers to the phenomenon by which the clinical manifestations terminate while electrographic seizures persist, and commonly occurs in neonates after the administration of anticonvulsant medications (Scher et al., 2003). Electroclinical dissociation refers to the phenomenon by which the clinical expression of a seizure occurs without an electrical correlate (Weiner et al., 1991). Although electroclinical dissociation exists (e.g., seizures emanating from the mesial temporal lobe), it is not common. Sharp transients are normal in premature newborns and should not be confused with seizure activity. Similarly, the trace-alternant pattern of quiet sleep in normal=term infants, in which normal low-amplitude activity is preserved between bursts, must be distinguished from the abnormal burst-suppression pattern, in which long periods of voltage suppression or absence of activity are recorded between bursts of high-voltage spikes and slow waves (Andre et al., 2010). Interictal EEG has prognostic value: severe suppression of the background activity, whether interrupted by high-amplitude bursts or not, is associated with an abnormal outcome. Importantly, the severity of background disturbance is a more important predictor of seizure risk than are interictal epileptiform abnormalities in the neonate with brain injury (Glass et al., 2014).

Management Suspected neonatal seizures require urgent investigation for acute-symptomatic etiologies and management because prolonged and recurrent seizures are likely independently associated with brain injury and abnormal brain development, as discussed earlier. Glucose and electrolyte levels should be measured and any abnormality corrected. A full sepsis evaluation, including cultures of blood and CSF, should also be undertaken if feasible and empiric antibiotics started. Neuroimaging studies should proceed according to institutional availability; ultrasound of the head is usually readily available and can give diagnostic clues (Weeke et al., 2015).

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CHAPTER 110 Neurological Problems in the Newborn Genetic epilepsy syndromes are diagnosed with appropriate gene panels or whole exome sequencing. There is little in the way of evidence-based guidelines for the pharmacological management of neonatal seizures; nonetheless, treatment with anticonvulsant medications should be initiated once seizures are confirmed electrographically or if the clinical suspicion for seizures is sufficiently high. The World Health Organization (WHO) recommends phenobarbital as a first-line agent but other agents, such as phenytoin (or fosphenytoin) and benzodiazepines are acceptable alternatives and are all available intravenously (World Health Organization, 2011; Painter et al., 1999). Approximately half of seizures are controlled with a 20 mg/kg load of phenobarbital or phenytoin (Painter et al., 1999). Benzodiazepines such as lorazepam or midazolam have the advantage of a short half-life and can be particularly useful when seizures are suspected based on clinical observation alone but unconfirmed by EEG or aEEG. The use of these medications as a first-line agent may obviate the need for further therapy in neonates in whom seizures do not recur or, are later shown, via neuromonitoring, not to have any epileptic correlate. Levetiracetam is increasingly being used as well despite limited safety and efficacy data (Ahmad et al., 2017). A recent randomized controlled trial showed that levetiracetam was less effective than phenobarbital for the treatment of neonatal seizures (Sharpe et al., 2020). If seizures are not controlled after repeated loading doses of standard medications, titration of a midazolam infusion may be indicated. An example of an abridged seizure management algorithm is provided in Fig. 110.5, but individual institutions should develop their own.

Prognosis and Progression Toward Epilepsy The major determinant of prognosis following neonatal seizures is the underlying etiology (see Fig. 110.4). Of newborns with seizures who survive their acute injury, 25%–70% will go on to have subsequent neurodevelopmental impairments (Uria-Avellanal et al., 2013). The frequency of epilepsy following neonatal seizures is between 10% and 30% (Pisani et al., 2015). A relatively high frequency of infantile spasms has been observed among survivors of neonatal seizures (Garfinkle and Shevell, 2011). The decision regarding maintenance antiepileptic medications after NICU discharge relates mostly to the likelihood of developing postneonatal epilepsy balanced with the potential long-term toxicity of the therapy. In most acute symptomatic seizures, the seizures remit within a few days of life. Currently, it is unknown if continuing antiepileptic treatment for up to several months is helpful or harmful. The rationale for using antiepileptic drugs at discharge is to decrease the likelihood of seizure recurrence. In the presence of risk factors for later epilepsy, antiepileptic medication may be warranted. These risk factors include status epilepticus, severe hypoxic-ischemic brain injury, and the use of more than a single antiepileptic medication to adequately control the neonatal seizures (Garfinkle and Shevell, 2011; Pisani et al., 2015). Importantly, there are theoretical concerns that some treatment strategies for neonatal seizures could be toxic to the developing brain, and, as such, it may be judicious to withhold maintenance antiepileptic medication in the absence of these risk factors for later epilepsy (Jansen, 2018).

BRAIN INJURY IN THE PRETERM NEWBORN The brain of the preterm newborn is in a state of rapid development and is susceptible to four overarching and overlapping forms of preterm brain injury: intraventricular hemorrhage (IVH), white matter injury (WMI), gray matter injury, and cerebellar hemorrhage. The neurodevelopmental impact of preterm brain injury is substantial and lifelong. Among contemporary cohorts of children born very preterm, (i.e., at