Comprehensive Board Review in Neurology [1st ed.] 9781604064704, 1604064706, 1588904067, 9781588904065, 9783131429711, 3131429712

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Comprehensive Board Review in Neurology Mark K. Borsody

~ Thieme

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Comprehensive Board Review in Neurology

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Comprehensive Board Review in Neurology

Mark K. Borsody, M.D., Ph.D. Director Northern Neurosciences, Inc. Dearborn, Michigan

Thieme New York • Stuttgart

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Thieme Medical Publishers, Inc. 333 Seventh Ave. New York, NY 10001 Executive Editor: Timothy Hiscock Editorial Assistant: David Price Vice President, Production and Electronic Publishing: Anne T. Vinnicombe Production Editor: Print Matters, Inc. Sales Director: Ross Lumpkin Associate Marketing Director: Verena Diem Chief Financial Officer: Peter van Woerden President: Brian D. Scanlan Compositor: Compset, Inc. Printer: Everbest Printing Co. Library of Congress Cataloging-in-Publication Data Borsody, Mark K. Comprehensive board review in neurology/Mark K. Borsody. p. ; cm. ISBN 1-58890-406-7 (US-HC)—ISBN 3-13-142971-2 (GTV-HC) 1. Neurology—Examinations, questions, etc. I. Title. [DNLM: 1. Nervous System Diseases—Examination Questions. WL 18.2 B738c 2006] RC356.B67 2006 616.80076—dc22 2006044639 Copyright ©2007 by Thieme Medical Publishers, Inc. This book, including all parts thereof, is legally protected by copyright. Any use, exploitation, or commercialization outside the narrow limits set by copyright legislation without the publisher’s consent is illegal and liable to prosecution. This applies in particular to photostat reproduction, copying, mimeographing or duplication of any kind, translating, preparation of microfilms, and electronic data processing and storage. Important note: Medical knowledge is ever-changing. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy may be required. The authors and editors of the material herein have consulted sources believed to be reliable in their efforts to provide information that is complete and in accord with the standards accepted at the time of publication. However, in view of the possibility of human error by the authors, editors, or publisher of the work herein or changes in medical knowledge, neither the authors, editors, or publisher, nor any other party who has been involved in the preparation of this work, warrants that the information contained herein is in every respect accurate or complete, and they are not responsible for any errors or omissions or for the results obtained from use of such information. Readers are encouraged to confirm the information contained herein with other sources. For example, readers are advised to check the product information sheet included in the package of each drug they plan to administer to be certain that the information contained in this publication is accurate and that changes have not been made in the recommended dose or in the contraindications for administration. This recommendation is of particular importance in connection with new or infrequently used drugs. Some of the product names, patents, and registered designs referred to in this book are in fact registered trademarks or proprietary names even though specific reference to this fact is not always made in the text. Therefore, the appearance of a name without designation as proprietary is not to be construed as a representation by the publisher that it is in the public domain. Printed in China 54321 TMP ISBN 1-58890-406-7 978-1-58890-406-5 GTV ISBN 3-13-142971-2 978-3-13-142971-1

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To Dr. Juan J. Cayaffa, professor emeritus of the Department of Neurology at the Northwestern Memorial Hospital. A neurologist could have no better teacher, and a man no better role model.

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Contents

Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .xi 1.

Neuroanatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1 Jose Rafols, Gregory Van Stavern, and Edwin M. Monsell

2.

Vascular Diseases of the Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .55 Renee Bailey Van Stavern

3.

Seizures and Epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .80 Jagdish Shah and Demian Naguib

4.

Disorders of Myelination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .104 Rana Zabad

5.

Tumors of the Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .119 Jeffrey Raizer

6.

Headache and Pain Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .137 M. Maher Fakhouri

7.

Behavioral Neurology and Psychiatry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .154 Randall R. Benson, Prasanth Manthena, and David Kemp

8.

Movement Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .183 Edwin B. George

9.

Diseases of the Nerves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .203 Nancy J. Cao

10.

Diseases of the Muscles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .230 Demian Naguib

11.

Infections of the Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .249 Alexandros C. Tselis

12.

Developmental and Metabolic Diseases of the Nervous System . . . . . . . . . . . . . . . . . . . . . . . . .269 Alexander G. Bassuk

13.

Systemic Diseases Affecting the Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .293 Jayant Khitha

Last Head 1 Contents

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .ix

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .303

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In the inner cover of this medical text the reader will find buried among the copyright and library cataloguing information a disclaimer, one stating something to the effect that “medicine is a rapidly changing science.” What an understatement! The hands of science have only recently touched medicine; nonetheless, medicine is undergoing a thorough reshaping by this most merciless of sculptors. It is this rapid change in the field of medicine, as well as the breadth and depth of its existing knowledge base, that requires us as physicians to set about organizing the available information in order to master it. Not incidentally, physicians must take board examinations exactly because medicine is such an immense and rapidly changing discipline. As difficult as it may be to believe from where you, the potential reader of this review book, find yourself, there are many good reasons to require physicians to take—and periodically retake—board examinations. I began organizing my personal notes on the field of neurology five years ago, when I was a resident at the Northwestern Memorial Hospital. Doing so was mostly force of habit, but early on I structured the notes so that I could use them in preparation for the American Board of Psychiatry and Neurology (ABPN) written examination. As my notes developed and the possibility of publishing them as a review book became a reality, I was fortunate enough to find experts in every subsection of neurology and in the related areas of psychiatry and medicine who diligently worked on these notes-cum-chapters to pare them down, fill them out, and otherwise tune them up. These experts were

also most helpful with developing the numerous tables and with identifying key diagrams and neuroimaging slides that you will find in this review book; such organizational items are intended to easily summarize large amounts of material for the time-pressed reader. Additionally, an excellent young pathologist, Dr. Chisa Yamada, kindly provided important pathology slides and assisted with the description of key histopathological abnormalities of common neurological disorders. With the assistance of these experts (whom I acknowledge deservedly as editors), I am confident that we have assembled the most comprehensive and up-to-date review book possible. Of course no book would be of much value if there were only a single copy of it stashed away in the author’s study. I am indebted to the forethought of the people of Thieme Medical Publishing, who were quick to recognize the importance of a comprehensive board review book in neurology and who have been immensely supportive of its development. In particular, I would like to thank Thieme’s Executive Editor, Mr. Timothy Hiscock, who has been a sound shepherd of this review book from its inception. I am already looking forward to working on subsequent editions with this wonderful crew. To that end, I trust that you, the reader, will help by sending me your questions or comments. Now, on to the book. Study hard!

Last Head 1 Preface

Preface

Mark Borsody http//www.northern–neurosciences.com

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Editor Mark K. Borsody, M.D., Ph.D. Director Northern Neurosciences, Inc. Dearborn, Michigan

General Editor of Pathology Chisa Yamada, M.D. Department of Pathology Montefiore Medical Center Bronx, New York

David Kemp, M.D. Research Fellow Bipolar Disorder Research Center Case Western Reserve University Cleveland, Ohio Jayant Khitha, M.D. Department of Cardiology Louisianna State University Health Sciences Center–Shreveport Shreveport, Louisianna

Contributors

Prasanth Manthena, M.D. Department of Neurology Northwestern University Feinberg School of Medicine Chicago, Illinois

Alexander G. Bassuk, M.D., Ph.D. Assistant Professor Departments of Pediatrics and Neurology Northwestern University Feinberg School of Medicine Chicago, Illinois

Edwin M. Monsell, M.D., Ph.D. Professor Department of Otolaryngology—Head and Neck Surgery Wayne State University School of Medicine Detroit, Michigan

Randall R. Benson, M.D. Assistant Professor Department of Neurology Wayne State University School of Medicine Detroit, Michigan

Demian Naguib, M.D., Ph.D. Department of Neurology Wayne State University School of Medicine Detroit, Michigan

Nancy J. Cao, M.D., Ph.D. Department of Neurology Wayne State University School of Medicine Detroit, Michigan

Jose Rafols, Ph.D. Professor Department of Anatomy and Cell Biology Wayne State University School of Medicine Detroit, Michigan

M. Maher Fakhouri, M.D. Assistant Professor Department of Neurology Wayne State University School of Medicine Detroit, Michigan

Jeffrey Raizer, M.D. Assistant Professor Department of Neurology Northwestern University Feinberg School of Medicine Chicago, Illinois

Edwin B. George, M.D., Ph.D. Assistant Professor Department of Neurology Wayne State University School of Medicine Detroit, Michigan

Jagdish Shah, M.D. Associate Professor Department of Neurology Wayne State University School of Medicine Detroit, Michigan

Last Head 1 Contributors

Contributors

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Contributors

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Alexandros C. Tselis, M.D., Ph.D Assistant Professor Department of Neurology Wayne State University School of Medicine Detroit, Michigan

Renee Bailey Van Stavern, M.D. Assistant Professor Department of Neurology Wayne State University School of Medicine Detroit, Michigan

Gregory Van Stavern, M.D. Assistant Professor Departments of Neurology and Ophthalmology Wayne State University School of Medicine Detroit, Michigan

Rana Zabad, M.D. Hotchkiss Brain Institute University of Calgary Calgary, Canada

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1 Neuroanatomy

Note: Significant diseases are indicated in bold and syndromes in italics.

1.

Important gyri, lobes, and Brodmann areas (Fig. 1–1)

2.

Types of cortical neurons (Fig. 1–2)

3.

a.

projection neurons: pyramidal and fusiform neurons

b.

interneurons: stellate and granule cells, horizontal cells of Cajal

Chemoanatomy a.

b.

afferents i.

corticocortical fibers and thalamocortical fibers (glutamate, aspartate)

ii.

projections from the nucleus basalis of Meynert (acetylcholine), hypothalamus (histamine, orexin/hypocretin), and brainstem (norepinephrine, serotonin, dopamine)

efferents i.

4.

Cerebral Cortex

I. Cerebral Cortex

all use glutamate and aspartate

Subtypes of cortex a.

cytoarchitectonic subtypes i.

isocortex: exhibits the six typical layers (1) homotypical isocortex: the six layers are proportionate (2) heterotypical isocortex: certain layers are enlarged, for example, the (a) primary motor cortex (Brodmann area 4) exhibits an enlarged layer 5 due to oversized pyramidal cells that project into the corticospinal tract {Betz cells}

A

B

Figure 1–1 Important gyri, lobes, and Brodmann areas. (A) lateral surface; (B) medial surface. (From Duus P, Topical Diagnosis in Neurology. Stuttgart, Germany: Georg Thieme; 1998:276, Fig. 8.23. Reprinted by permission.)

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(b) primary visual cortex (Brodmann area 17) exhibits a pronounced outer line of Baillarger in layer 4 {band of Gennari} that is thalamocortical afferents ii.

mesocortex: exhibits five or six poorly defined layers, located at transition between isocortex and allocortex (e.g., parahippocampal gyrus)

iii. allocortex: exhibits only three layers; includes the inferior and mesial temporal lobes (hippocampal formation) b.

general functional subtypes i.

primary motor and sensory areas

ii.

monomodal association areas

1 Neuroanatomy

(1) monomodal motor association areas: receive input from the primary and monomodal association sensory areas, and project to the primary motor area (2) monomodal sensory association areas: receive input from the primary sensory area, and project to the heteromodal association areas and primary motor area

Figure 1–2 Types of cortical neurons. (From Duus P, Topical Diagnosis in Neurology. Stuttgart, Germany: Georg Thieme; 1998:262, Fig. 8.11. Reprinted by permission.)

iii. heteromodal association areas: receive input from monomodal association areas; project to other heteromodal association and paralimbic areas, and the basal ganglia iv.

limbic and paralimbic areas

A. Motor Systems 1.

Primary motor cortex (Brodmann area 4) a.

somatotopic organization (Fig. 1–3)

b.

lesions strictly limited to Brodmann area 4 produce focal paralysis with hypotonia, mild hyperreflexia, and a partial Babinski sign (i.e., upgoing first toe only) i.

c. 2.

stimulation causes simple flick-like focal movements involving a few agonist and antagonist muscles

Monomodal motor association areas: share the precentral sulcus with the primary motor cortex, and extend rostrally onto the superior, middle, and inferior frontal gyri a.

premotor area (lateral surface of Brodmann area 6): prepares the body posture for subsequent complex limb movements; acts via the rubrospinal, tectospinal, and reticulospinal tracts i.

b.

2

extending the lesion into the premotor area (lateral surface of Brodmann area 6) produces the typical “clasp knife” spasticity of the antigravity muscles (upper extremity flexors and lower extremity extensors), pronounced hyperreflexia, and a complete Babinski sign (i.e., upgoing first toe with fanning of the other toes)

shares the homunculus of the primary motor cortex: the frontal eye fields (Brodmann area 8) are located anterior to head representation

supplementary motor area (medial surface of Brodmann area 6): prepares and initiates complex limb movements; likely exhibits its own homunculus independent of that of the premotor area and primary motor cortex i.

lesions cause

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B

A

Figure 1–3 Sensory (A) and motor (B) homunculi. Note the proximity of the thumb to the forehead. (From Duus P, Topical Diagnosis in Neurology. Stuttgart, Germany: Georg Thieme; 1998:273, Fig. 8.20. Reprinted by permission.)

Cerebral Cortex

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(1) global akinesia with speech arrest that develops into hypokinesia (contralateral  ipsilateral), reduced speech, and reduced facial expression; chronically, patients will exhibit only poor hand coordination (2) ideomotor apraxia, which may be associated with a contralateral alien hand phenomenon characterized by unconscious reflexive movements ii. 3.

stimulation causes bilateral posturing movements, contralateral head and body rotation, and vocalizations {salutary seizures}

Subcortical projections a.

corticobulbar tract: the ventral division travels with the corticospinal tract and synapses in the facial nucleus; the dorsal division travels closer to the medial lemniscus and synapses in other cranial nerve nuclei and the reticular formation

b.

corticospinal tract: composed of fibers not only from the primary motor cortex (25%) and monomodal motor association cortex (30%) but also the primary somatosensory cortex (30%) and superior parietal lobule (Brodmann areas 5 and 7; 15%) i.

terminates in the cervical spinal cord (55%), thoracic spinal cord (20%), and lumbosacral spinal cord (25%)

ii.

the majority (80%) of the corticospinal tract decussates at cervicomedullary junction (upper extremity fibers decussate rostral to the lower extremity fibers) (1) the rest of the corticospinal tract does not decussate until it arrives at its terminal cervical and upper thoracic spinal cord levels (ventral corticospinal tract)

B. Somatosensory Systems 1.

Primary sensory cortex (Brodmann areas 3-1-2) a.

subdivided according to sensory modality i.

Brodmann area 3a receives deep sensation from muscle spindles and Golgi tendon organs

ii.

Brodmann area 3b receives superficial sensation from exteroceptors and cutaneous receptors

3

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iii. Brodmann areas 1 and 2 receive deep and superficial sensation including subcutaneous tissues b.

somatotopic organization: similar to the motor homunculus, but less well defined and may extend caudally into Brodmann areas 5 and 7 i.

c.

lesions cause loss of proprioception (but not vibration sensation), poor localization of stimuli {topagnosia}, difficulty with two-point discrimination, reduced object recognition through touch {astereognosis}, tactile hallucinations, rapid fatigability of prolonged sensory stimulation, and paresthesias i.

1 Neuroanatomy

d. 2.

face and body are bilaterally represented; limbs are unilaterally represented

primary modality sensory loss is pronounced with postcentral gyrus lesions that involve the posterior insula and underlying white matter

stimulation produces numbness and paresthesias, and often a sensation of movement

Secondary sensory cortex (supramarginal gyrus; Brodmann area 40): Posterior to the inferior part of the primary somatosensory cortex a.

exhibits bilateral inputs with contralateral predominance, and is somatotopically organized into a separate homunculus that may be related to pain sensation

3.

Unimodal somatosensory association area (Brodmann area 5): Involved in recognition of object shape by tactile sensation {stereognosis}

4.

Subcortical afferents: anterolateral system/spinothalamic tract, dorsal columns, and trigeminal pathways terminate in the ventroposteromedial and ventroposterolateral thalamic nuclei that then project to the primary sensory cortex

C. Special Sensory Systems 1.

Vision (see p. 37) and hearing (see p. 48)

2.

Vestibular sensation (see p. 50)

3.

Taste (Brodmann area 43): Adjacent to the primary somatosensory tongue representation and the insular cortex motor areas for salivation and gastrointestinal motility a.

4.

distorted taste perception {dysgeusia} is poorly localized and usually is caused by zinc or vitamin A deficiency

Olfaction: represented by bilateral projections from the olfactory nerves to the piriform cortex and amygdala via lateral olfactory stria, and to the orbitofrontal cortex overlying the septal nuclei via the medial olfactory stria; no olfactory bulb projections enter the anterior perforated substance in humans a.

distorted odor perception {parosmia} is usually caused by injury to the olfactory nerves from head trauma or by psychiatric illness (e.g., depression)

b.

olfactory hallucinations can be caused either by injury to the olfactory nerves or by seizures in the mesial temporal lobe or uncus that involve the amygdala (Box 1.1)

D. Heteromodal Association Areas 1.

Frontal heteromodal association area/prefrontal cortex: involves all the cortex located anterior to the monomodal motor association areas a.

4

unlike other heteromodal association areas, the prefrontal cortex i.

projects to the amygdala and caudate

ii.

receives indirect projections from the hippocampus through the dorsomedial thalamus and direct projections from the cingulate gyrus and hypothalamus

Box 1.1 Other Types of Hallucinations Visual—Formed hallucinations from posterior temporal lobe or mesencephalon (i.e., peduncular hallucinosis) dysfunction or in reaction to vision loss {Bonnet’s syndrome}, which have hallucinations in the area of vision loss; unformed hallucinations with occipital lobe dysfunction Auditory—Formed hallucinations from superior temporal gyrus dysfunction; unformed hallucinations from pontine dysfunction, usually in the presence of hearing loss Gustatory—from frontoparietal cortex dysfunction

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Table 1–1 Frontal Lobe Syndromes Effects of unilateral damage

Effects of bilateral damage

Dorsolateral

Dominant: ↓ verbal intellect and memory; perseveration Nondominant: ↓ visuospatial intellect and memory

Global intellectual impairment (dementia)

Ventromedial

Dominant: labile emotions, sociopathy, environmental dependency (i.e., the presence of an object induces its use); speech apraxia, gait apraxia Nondominant: sociopathy, environmental dependency

Sociopathy, environmental dependency

Anterior cingulate

Inability to perform tasks or make decisions {abulia}

Akinetic mutism

Orbitofrontal

Disinhibited behavior

b.

Cerebral Cortex

Prefrontal cortex region

lesions: in addition to the injured part of the prefrontal cortex, the depth of the lesion and the age at which the patient was injured will also affect the symptoms (Table 1–1) i.

Bruns’ frontal lobe ataxia/marché à petits pas of Dejerine—wide-based, slow, short-stepped gait with flexed posture and frequent freezes; can progress to inability to stand (1) caused by lesions anywhere in frontal lobes that are often bilateral and multifocal

2.

Parietal heteromodal association areas: Located in the superior and inferior parietal lobules a.

dominant-sided lesions produce (Box 1.2) i.

alexia

ii.

Gerstmann’s syndrome—classically involves agraphia, finger agnosia, acalculia, and left-right confusion; lesions are located on the angular gyrus (Brodmann area 39)

Box 1.2 Large dominant-sided inferior parietal lobule lesions can cause an acquired illiteracy.

iii. contralateral tactile neglect and spatial inattention iv. b.

somatotopic ideomotor apraxia

nondominant-sided lesions produce i.

contralateral tactile neglect and spatial inattention, which may be so severe that the patient does not recognize the deficit {anosognosia}

ii.

constructional and dressing apraxias

iii. spatial disorientation iv.

impersistence; inattention; static confusional state/encephalopathy

E. Language Areas 1.

Dominant hemisphere language areas a.

Broca’s area: located in the inferior frontal gyrus, and includes the pars opercularis (Brodmann area 44; a monomodal motor association area) (Box 1.3) and the pars triangularis (Brodmann area 45; a heteromodal association area) i.

lesions produce (1) Broca’s aphasia—classically involves Broca’s area, the mouth representations of the primary motor and somatosensory cortices, and the underlying white matter (a) symptoms include nonfluent speech that is slow and agrammatic as well as dysarthric, and impaired repetition; writing is minimal and agrammatic

Box 1.3 Bilateral damage of Brodmann area 44 that extends into the inferior parietal lobe causes loss of voluntary eye, face, oropharynx, and tongue movements (an apraxia).

5

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(2) aphemia—a pure anarthria caused by lesions strictly limited to Broca’s area (i.e., not involving the primary motor and somatosensory cortices or the underlying white matter); may also be caused by bilateral lesions of the corticobulbar tracts b.

Wernicke’s area i.

includes posterior superior and middle temporal gyri, planum temporale (Brodmann area 42; a monomodal auditory association area), and heteromodal association areas of the parietal lobe (angular and supramarginal gyri; Brodmann areas 39 and 40)

ii.

lesions cause Wernicke’s aphasia (1) characterized by excessive speech of normal cadence and prosody associated with impaired naming, comprehension, and repetition, and the presence of paraphasias and neologisms; writing is similarly excessive with paraphasias and neologisms

1 Neuroanatomy

(2) impairment of comprehension can be particularly pronounced with specific subjects, thereby giving the false appearance of a fluctuant deficit c.

secondary language areas (i.e., the cortex surrounding Broca’s and Wernicke’s areas): lesions produce the transcortical aphasias because they isolate the primary language areas without directly injuring them; all have preservation of repetition i.

subtypes of transcortical aphasias (1) transcortical motor aphasia—generally caused by lesions anterior or superior to Broca’s area, or by lesions in the supplementary motor area (2) transcortical sensory aphasia—can be caused by lesions surrounding Wernicke’s area, but otherwise is usually poorly localized (3) mixed transcortical aphasia—caused by large areas of dominant hemisphere injury that spare the perisylvian regions (e.g., as in watershed infarction or dementias)

d.

subcortical connections of Broca’s and Wernicke’s areas: lesions produce i.

conduction aphasia—caused by disconnection of Broca’s and Wernicke’s areas, most commonly the result of a subcortical white matter lesion that interrupts the arcuate fasciculus (in the superior longitudinal fasciculus; and/or the extreme capsule (1) symptoms: isolated loss of repetition with occasional paraphasic errors

ii.

2.

anomia—generally has no localizing value when mild, but significant anomia may reflect lesions in the basal temporal lobe that interrupt hippocampal projections to Wernicke’s area

Nondominant hemisphere language areas a.

areas related to the variation of pitch, intonation, melody, rhythm, and loudness of speech {prosody} i.

affective prosody—involves the expression of mood and emotion in speech; caused by lesions in the nondominant hemisphere in areas that are anatomical and functional parallels to Broca’s and Wernicke’s areas of the dominant hemisphere (1) affective prosody is most commonly observed in psychiatric diseases (e.g., motor and sensory aprosodies in schizophrenia, motor hyperprosody in mania)

ii.

6

propositional prosody—defines a phrase as a question or a statement; can occur after lesions of either hemisphere

b.

areas related to gesturing that accompanies speech {kinesia}: poorly localized

c.

areas related to singing: an acquired inability to sing {amelodia} is caused by lesions of the posterior inferior frontal lobe or anterior parietal lobe

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amelodia/amusia, which is the inability to recognize music (e.g., a melody); amusia is usually caused by superior temporal gyrus lesions on either side

1.

Paralimbic cortex: collects inputs from heteromodal association areas, monomodal association areas, and limbic areas (hippocampal formation and amygdala); projects primarily to the hippocampal formation

2.

Paralimbic cortex includes a.

anterior and posterior cingulate gyrus

b.

parahippocampal gyrus (entorhinal cortex and piriform/periamygdaloid cortex)

c.

insular and orbitofrontal cortex

d.

temporal poles: lesions cause i.

Kluver-Bucy syndrome—occurs only after bilateral anterior temporal cortex destruction, usually from temporal lobectomy; does not have to involve the amygdala or hippocampus to produce all of its symptoms

Box 1.4

(1) symptoms (Box 1.4)

Placidity, hypersexuality, and hyperorality are the classic triad that occurs in animal experiments.

(a) placidity (b) hypersexuality

Cerebral Cortex

F. Paralimbic Cortex

(c) hyperorality and increased manual exploration, which likely reflects an inability to recognize objects by vision alone {visual agnosia} (d) memory impairment, dementia (e) hyperphagia ii.

rage—caused by bilateral anterior and inferior temporal lesions, usually due to trauma or herpes encephalitis

G. Limbic Areas 1.

Hippocampal formation: includes the hippocampus, dentate gyrus, and subiculum a.

afferent and efferent connections: the circuit of Papez (Fig. 1–4)

b.

intrinsic hippocampal connections (Fig. 1–5)

c.

functions: memory formation, learning, and regulation of emotional behavior

d.

pathophysiology—transient global amnesia i.

an unknown type of neurological dysfunction, likely involving bilateral mesial temporal lobes

ii.

epidemiology: common only in patients  50 years old; associated with a history of migraine

iii. symptoms: short-term anterograde and retrograde memory loss with preserved immediate recall and long-term memory; often develops acutely after exertion or excitement (1) patient has a normal level of arousal and attention, and no of other neurological signs iv.

diagnostic testing: none are necessary to establish the diagnosis

Figure 1–4 The circuit of Papez. (From Duus P, Topical Diagnosis in Neurology. Stuttgart, Germany: Georg Thieme; 1998:206, Fig. 5.20. Reprinted by permission.)

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Alveus

fimbria Mossy fibers

CA3

field

Projections to granular cells of the dentate gyrus

CA2

field

Perforating tract

CA1

field

1 Neuroanatomy

Dendritic branches of pyramidal neurons

Figure 1–5 Intrinsic hippocampal connections. (From Kahle W, Color Atlas/Text of Human Anatomy, Vol. 3: Nervous System and Sensory Organs. 4th ed. Stuttgart, Germany: Georg Thieme; 1993:221, Fig. A. Reprinted by permission.)

Schaffer collaterals

(1) electroencephalogram (EEG): can rule out nonconvulsive temporal lobe seizures (2) magnetic resonance imaging (MRI) may exhibit increased diffusionweighted imaging signal in the mesial temporal lobes v.

treatment: none specific

vi. prognosis: gradual return of memory over 12–24 hours; recurs in 20% of patients 2.

Amygdala a.

subdivisions i.

corticomedial amygdala: interconnected with the olfactory bulb via the lateral olfactory tract, the hypothalamus, and the septum via the stria terminalis

ii.

basolateral amygdala: interconnected with the hippocampal formation, ventral basal ganglia (limbic loop, see Table 1–2), and basal forebrain

iii. central amygdala: interconnected reciprocally with brainstem autonomic centers (e.g., solitary nucleus)

Table 1–2 The Five Major Basal Ganglia—Thalamocortical Loops

8

Thalamic relay nuclei

Function

GPe,i, SNR

Ventral anterior and ventral lateral

Initiating voluntary movement, postural reflexes, muscle tone

Caudate, putamen (anterior)

Gpi, SNR superior colliculus

Dorsomedial

Generation of voluntary saccades

Dorsolateral prefrontal

Caudate (head)

GPe,i

Dorsomedial

? Cognitive functions

Orbitofrontal

Orbitofrontal, ventromedial, frontal

Caudate, putamen (anterior)

GPe,i

Dorsomedial

? Cognitive functions

Limbic

Cingulate gyrus, hippocampus, amygdala

Nucleus accumbens

GPe,i

Dorsomedial

Mood, emotional behavior, motivation

Loop*

Cerebral cortex input

Input nuclei

Output nuclei

Motor

Primary motor, monomodal motor association, primary somatosensory

Putamen (posterior)

Ocular motor

Frontal eye field (Brodmann area 8)

Dorsolateral prefrontal

*All loops receive dopamine from the substantia nigra pars compacta except for the limbic loop, which receives dopamine from the ventral tegmental area. Abbreviations: GPe, globus pallidus externus; GPi, globus pallidus internus; SNR, substantia nigra reticulata.

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functions i.

olfactory sensory processing and integration of olfactory-visceral reflexes

ii.

coordination of emotional behavior and autonomic nervous system responses

iii. association of memories with their emotional content c.

lesions generally produce a loss of aggressive behavior; stimulation produces fear or defense reactions

II. Subcortical White Matter Corona radiata/Centrum semiovale a.

pathophysiology i.

leukoaraiosis: can be part of, but is not identical to, vascular dementia or Binswanger’s disease (1) lesion types include (Fig. 1–6) (a) irregular white matter abnormalities, typically scattered about randomly (i)

Figure 1–6 Leukoaraiosis. (From Hosten N, Liebig T, CT of the Head and Spine. Stuttgart, Germany: Georg Thieme; 2002:31, Fig. 1.33b. Reprinted by permission.)

histology: resembles ischemia

(b) periventricular white matter caps and halos (i)

b.

histology: resembles demyelination (not ischemia), with subependymal gliosis and breakdown of the underlying ependyma of the ventricles

internal capsule (Fig. 1–7) i.

pathophysiology: the striatocapsular syndrome, typically caused by infarction from occlusion of a lenticulostriate artery; symptoms include (1) hemiparesis (95%), which is often the only symptom {pure motor syndrome} (Box 1.5) (2) hemi-sensory loss (60%) (3) aphasia or neglect (60%)

c.

Subcortical White Matter

1.

association fibers i. ii.

short association fibers/“U” fibers: short-range cortical–cortical projections

Box 1.5 Differentiate striatocapsular syndrome from primary motor cortex lesions that may allow reflex movements of the apparently paralyzed limb (mediated by monomodal motor association areas).

long association fibers (Fig. 1–8) (1) cingulum: connects the temporal and prefrontal heteromodal cortices with the cingulate gyrus (2) uncinate fasciculus: connects the temporal and prefrontal heteromodal cortices

Figure 1–7 Internal capsule. (From Greenberg MS, Handbook of Neurosurgery. 3rd ed. Greenberg Press; 1994:114, Fig. 23.12. Reprinted by permission.)

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Cingulum

Superior longitudinal fasciculus

Superior frontooccipital fasciculus

Inferior frontooccipital fasciculus

1 Neuroanatomy

A Figure 1–8 Long association fibers. (A) Lateral view; (B) transected hemisphere at the level of the insula. (Left, from Mumenthaler M, Neurological Differential Diagnosis. 2nd ed. Stuttgart, Germany: Georg Thieme;

(3) superior longitudinal fasciculus: connects the parietal and temporal lobes with the frontal lobe; includes the arcuate fasciculus, lesions of which cause conduction aphasia (4) inferior longitudinal fasciculus: connects the occipital cortex with the inferior temporal and fusiform gyri; important for the ventral occipitotemporal neural network, which is involved in face and object recognition (the “what” pathway) (5) superior occipitofrontal fasciculus: interconnects all the lobes; important for the dorsal parietofrontal neural network, which is involved in spatial orientation (the “where” pathway) (6) inferior occipitofrontal fasciculus: connects the inferior temporal, fusiform, and lingual gyri with the frontal lobe d.

commissures i.

corpus callosum: regions of the cortex project through the corpus callosum to symmetric regions in the contralateral hemisphere, and occasionally to other regions; fibers originate from cortex layer 3 (1) pathophysiology (a) transection of the corpus callosum: symptoms are generally detectable only by specific testing, and include (i)

inability to name objects or read words presented in the visual hemifield of the nondominant hemisphere

(ii) inability to name objects felt by the nondominant hand (iii) inability to write with the nondominant hand (iv) impaired spatial construction skills with the dominant hand (v) callosal alien hand syndrome—discoordination of simultaneous voluntary hand movements ii.

anterior commissure: connects the caudal orbitofrontal, anterior temporal, and parahippocampal cortices as well as the contralateral olfactory nerve to the piriform cortex for bilateral olfactory representation

iii. posterior commissure: carries fibers of the medial longitudinal fasciculus, posterior thalamus, pretectal nuclei, mesencephalic accessory ocular motor nuclei, and superior colliculi iv.

10

B

1992:49, Fig. 18 and right, from Kahle W, Color Atlas/Text of Human Anatomy, Vol. 3: Nervous System and Sensory Organs. 4th ed. Stuttgart, Germany: Georg Thieme; 1993:247, Fig. D. Reprinted by permission.)

hippocampal commissure: minimal size and function in humans

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Putamen Caudate Internal capsule

Cingulate gyrus Globus pallidus Extreme capsule underneath the insula

Superior temporal gyrus

Claustrum

Olfactory cortex (see enlargement) Septum pellucidum above the fornices

Figure 1–9 The basal forebrain posterior to the nucleus accumbens demonstrating the olfactory cortex, septal nuclei, and ventral basal ganglia (inferior to the anterior commissure). (From Kahle W, Color Atlas/Text of Human Anatomy, Vol. 3: Nervous System and Sensory Organs. 4th ed. Stuttgart, Germany: Georg Thieme; 1993:201, Fig. B; 211. Reprinted by permission.)

Basal Ganglia

Anterior commissure

III. Basal Forebrain (Fig. 1–9) 1.

2.

Septal region: Includes a.

septal nuclei: the lateral septal nucleus receives input from the medial olfactory stria, the hypothalamus, and the hippocampus via the fimbria-fornix, and relays that information to the medial septal nucleus; projections from the medial nucleus (acetylcholinergic as well as GABAergic) go to the hippocampus via the fornix and to the brainstem via the medial forebrain bundle

b.

nucleus of the diagonal band of Broca, which provides acetylcholinergic innervation to the hippocampus as do the septal nuclei

c.

nucleus accumbens: the equivalent of the caudate and putamen for a limbic basal ganglia loop (Table 1–2); receives dopaminergic afferents from the ventral tegmental area and is involved in positive reinforcement and craving behaviors

d.

islets of Calleja, which have a poorly defined function

Nucleus basalis of Meynert: Similar to the septal nuclei but provides acetylcholinergic innervation to the cortex (particularly pronounced in limbic and paralimbic areas) and extrinsic cholinergic innervation to the striatum (although 80% of striatal acetylcholine is intrinsic) and not to the hippocampus; functions in memory formation and retrieval

IV. Basal Ganglia (Fig. 1–10) 1.

Striatum: Includes the caudate, putamen, and nucleus accumbens; some also include the claustrum a.

neuron types: the motor striatum (caudate and putamen) and the limbic striatum (nucleus accumbens) are cytologically identical i.

spiny neurons: project from the striatum to the globus pallidus and substantia nigra (1) nondopaminergic inputs to the spiny neurons terminate on the tips of their spines; dopaminergic inputs terminate on the spine bases, thereby modulating the efficiency of the nondopaminergic inputs

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(2) subtypes (a) type I spiny neurons: contain GABA and enkephalin, and express D2 receptors; act in the indirect pathway from the putamen (b) type II spiny neurons: contain GABA, substance P, and dynorphin, and express D1 receptors; act in the direct pathway from the putamen ii.

aspiny neurons: the interneurons of the striatum

Caudate Stria terminalis and thalamostriate vein

Septum pellucidum

Fornices Thalamus Postcentral gyrus

Pineal

Habenula at the end of the stria medullaris

(1) subtypes

1 Neuroanatomy

(a) type I aspiny neurons: contain GABA (b) type II (large) aspiny neurons: contain acetylcholine (c) type III aspiny neurons: contain somatostatin and neuropeptide Y b.

effects of lesions

Superior and inferior colliculi

Figure 1–10 Superficial view of the diencephalic roof. (From Kahle W, Color Atlas/Text of Human Anatomy, Vol. 3: Nervous System and Sensory Organs. 4th ed. Stuttgart, Germany: Georg Thieme; 1993:207, Fig. B. Reprinted by permission.)

i.

caudate lesions cause contralateral choreoathetosis, abulia, and behavioral disinhibition

ii.

putamen lesions cause (1) contralateral hemidystonia (70%)  hemichorea or hemiparkinsonism (2) hypophonic dysarthria with a transcortical motor aphasia-like language impairment due to bradykinesia (3) impairment of short-term memory (4) contralateral tilting and falling (in lesions that involve the globus pallidus)

2.

Globus pallidus: contains large motor-type neurons and interneurons a.

3.

Substantia nigra: lesions produce contralateral parkinsonism; subdivisions include a.

pars compacta (dopaminergic): has a predominantly afferent function in the basal ganglia loops; projects to the striatum via the nigrostriatal dopaminergic pathway

b.

pars reticulata (GABAergic): has a predominantly efferent function in the basal ganglia loops; projects to the ventral anterior and ventral lateral nuclei of the thalamus

4.

Ventral tegmental area: projects to the nucleus accumbens via the mesolimbic dopaminergic pathway; analogous to the substantia nigra for the limbic striatum

5.

Subthalamic nucleus a.

12

unilateral lesions cause contralateral hemidystonia and/or hemiparkinsonism, abulia, and short-term memory loss; bilateral lesions may also cause akinetic mutism

lesions cause hypotonia and continuous flailing movements of the extremities sparing the face due to uncontrollable contractions of the proximal musculature {ballismus} i.

ballismus typically involves the contralateral half of the body {hemiballismus}, and may involve only a single extremity {monoballismus}

ii.

ballismus is a violent type of chorea, and it may resolve over time into chorea

iii. ballismus may occur with lesions elsewhere in the basal ganglia, thalamus, or motor cortex, although these forms are generally milder than that caused by subthalamic nucleus lesions

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Thalamus

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Figure 1–11 Coronal section of the thalamus at the level of the mammillary bodies. (From Kahle W, Color Atlas/Text of Human Anatomy, Vol. 3: Nervous System and Sensory Organs. 4th ed. Stuttgart, Germany: Georg Thieme; 1993:163, Fig. B. Reprinted by permission.)

(1) transient dysfunction of the basal ganglia may underlie a rapidly reversible form of hemiballismus that occurs during hyperglycemia iv.

6.

treatment: antipsychotic medications that have antagonist properties on D2 receptors (i.e., not clozapine); stereotactic lesioning or deep brain stimulation of the internal globus pallidus or ventral anterior– ventral lateral thalamus

General circuitry: See p. 12 (Table 1–2) a.

output projections (GABAergic) from the globus pallidus and substantia nigra reticulata to the (Box 1.6) i.

thalamus via ansa lenticularis and the lenticular and thalamic fascicles

ii.

subthalamic nucleus

Box 1.6 Ansa lenticularis also carries ascending cerebellar projections to ventral lateral thalamic nucleus.

V. Thalamus (Fig. 1–11) 1.

Functional divisions (Fig. 1–12) a.

cortical relay nuclei i.

anterior nuclei group (AG): functions in memory processing, learning, and attention (1) subcortical afferents: hippocampus and mammillary bodies via mammillothalamic tract (part of the circuit of Papez)

Box 1.7

(2) bilateral lesions cause

Caused by dominant-side lesions of the anterior limb of internal capsule  head of caudate nucleus and/or putamen Thalamic nuclei: dorsomedial nucleus or ventral nuclei group, which usually produces a mixed transcortical aphasia sparing reading and writing.

(a) anterograde amnesia, when they occur in conjunction with bilateral lesions of the dorsomedial thalamic nuclei (b) antero- and retrograde amnesia {Korsakoff’s syndrome}, when they occur in conjunction with bilateral mammillary body and mammillothalamic tract lesions ii.

Subcortical Aphasias

ventral nuclei group (Box 1.7) (Box 1.8) (1) ventral anterior nuclei

Box 1.8

(2) ventral lateral nuclei: afferents involve not only globus pallidus and substantia nigra reticulata, but cerebellum as well

Ventral anterior nuclei and ventral lateral nuclei are the motor nuclei of ventral nuclei group.

(a) lesions cause contralateral

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1 Neuroanatomy

To cingulate gyrus Dorsomedial nucleus

Anterior nucleus

Anterior ventral and lateral nucleus (from globus pallidus and substantia nigra pars reticulata)

Pulvinar (superior colliculus)

Ventroposterolateral nucleus, from medial lemniscus, spinothalamic tract

From cerebellum

Taste

Lateral geniculate body (optic nerve)

Medial geniculate body (inferior colliculus)

Figure 1–12 Functional divisions of the thalamus. (From Duus P, Topical Diagnosis in Neurology. Stuttgart, Germany: Georg Thieme; 1998:275, Fig. 8.22. Reprinted by permission.)

(i)

hemiataxia, usually with hemiparesis and/or sensory loss from involvement of nearby structures; develops acutely after injury

(ii) intention tremor: develops several weeks after injury (iii) dystonia: develops several months or years after injury (3) lateral geniculate (see p. 14) (Box 1.9) (4) medial geniculate (5) ventral posterior nuclei (a) ventral posterolateral nucleus has distinct areas for proprioception (i.e., the shell of the nucleus) and cutaneous (i.e., the core) inputs from body (b) ventral posteromedial nucleus receives trigeminal inputs for facial sensation and inputs from the solitary tract nucleus via the solitary tract conveying taste (c) lesions cause (i)

chiro-oral syndrome—symptoms include the contralateral loss of all sensory modalities and paresthesias of the mouth, tongue, and hand 1.

14

face, trunk, and proximal extremities are bilaterally represented (with a contralateral preference) in the ventral posterior thalamus, and so their sensation is preserved in unilateral lesions

Box 1.9 Lateral geniculate, medial geniculate, and posterior lateral nuclei: sensory nuclei of the ventral nuclei group

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(ii) tactile neglect—symptoms include contralateral neglect to touch that can be so severe with nondominant thalamus lesions that it approximates an anosognosia (iii) Dejerine-Roussy syndrome/anesthesia dolorosa (Box 1.10) 1.

generally develops weeks or months after the initial lesion; occasionally develops acutely after injury

2.

symptoms: burning pain that may be continuous or triggered by innocuous stimuli, and that is aggravated by emotional stress; sensory loss (proprioception  other modalities; deep sensation  cutaneous sensation) a.

3.

Dejerine-Roussy syndrome rarely occurs with lesions in the primary somatosensory cortex.

threshold for pain is paradoxically increased in the affected regions

treatment: thalamotomy of the intralaminar thalamic nuclei

association nuclei i.

Box 1.11

dorsomedial nucleus (Box 1.11) (1) specific afferents are from limbic structures (ventral basal ganglia, amygdala, hippocampal formation) and hypothalamus

The dorsomedial nucleus is injured during Wernicke–Korsakoff syndrome even more than the mammillary bodies.

(2) bilateral lesions cause

Thalamus

b.

Box 1.10

(a) hypersomnolence with reduced non-REM sleep (b) akinetic mutism, coma (c) anterograde amnesia, when they occur in conjunction with bilateral anterior thalamic lesions (d) Klein-Levin syndrome—symptoms include recurrent episodes lasting several days or weeks of compulsive eating, sexual disinhibition, hypersomnia with normal sleep structure, and impaired memory (i)

likely involves some simultaneous dysfunction of the posterior hypothalamus

(ii) more common in adolescent boys, and spontaneously remits in adulthood (iii) treatment: lithium, valproate ii. c.

d.

intralaminar thalamic nuclei (ITN): connections involve i.

rostral nuclei: reticular formation → ITNr → entire telencephalon and diencephalon

ii.

caudal nuclei: reticular formation → ITNc → motor telencephalon and diencephalon

reticular thalamic nucleus (RTN): forms a thin shell on the lateral surface of the thalamus i.

2.

3.

pulvinar has poorly defined visual and language functions

connections: reticular formation, collaterals of thalamocortical projections (particularly from intralaminar thalamus group), and cortex → RTN → all thalamic nuclei and reticular formation

Chemoanatomy: glutamate and aspartate are released from all thalamic nuclei except the reticular thalamic nucleus, which is GABAergic Vascular anatomy (Fig. 1–13)

Figure 1–13 Vascular anatomy of the thalamus. (From Duus P, Topical Diagnosis in Neurology. Stuttgart, Germany: Georg Thieme; 1998:188, Fig. 5.8. Reprinted by permission.)

15

1 Neuroanatomy

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A

B

Figure 1–14 The hypothalamus in sagittal (A) and coronal (B) views. Panel A shows only the medial hypothalamus. Arrows in panel A correspond to the cross-sections in panel B. (From Duus P, Topical Diagnosis

in Neurology. Stuttgart, Germany: Georg Thieme; 1998:194, Fig. 5.13; 195, Fig.5.14. Reprinted by permission.)

VI. Hypothalamus 1.

2.

General functions

Box 1.12

a.

controls the autonomic nervous system and the endocrine system (Box 1.12)

b.

maintains visceral activity, metabolic activity, and body temperature

Autonomic Effects of Stimulation

c.

participates in goal-directed behavior and motivation, affective behavior (particularly aggressive behaviors), and sleep–wake cycling

Parasympathetic effects: Preoptic region (medial hypothalamus), supraoptic region (medial hypothalamus) Sympathetic effects: Mammillary region (medial hypothalamus), lateral hypothalamus

Subdivisions (Fig. 1–14) a.

lateral hypothalamus: a “reward” center that likely mediates pleasurable sensations; regulates thirst (by means of vasopressin secretion from the paraventricular and supraoptic nuclei of the supraoptic region) and hunger and food-motivated behaviors (Table 1–3)

b.

medial hypothalamus: divided into i.

preoptic region (1) median preoptic nucleus: a sexually dimorphic nucleus

Table 1–3 Neurogenic Syndromes of Water Imbalance

16

Syndrome

Abnormality

Symptoms and signs

Cause

Treatment

Syndrome of inappropriate ADH secretion (SIADH)

↑ ADH

Hypotonic hyponatremia, ↓ Urination, ↑ Urine osmol and [Na]

AIDS (35%), any type of surgery, hypothalamic injury, systemic tumor

Water restriction, hypertonic saline, demeclocycline

Cerebral salt wasting syndrome

-↑ Sympathetic activity? -Circulating natriuretic factors?

Hypotonic hyponatremia, Polydipsia, ↑ urination, ↓ urine osmol, ↑ urine [Na], ↓ vascular volume

Nonspecific neurological injury

Salt supplements, fludrocortisone

Diabetes insipidus (central type)

↓ ADH

Polydipsia,↑ urination; weight loss with fluid restriction; urine does not concentrate

Hypothalamic injury (50%), including trauma; idiopathic (50%)

Allow free access to water; desmopressin, vasopressin; thiazides

Psychogenic polydipsia

Psychiatric

Polydipsia,↑ urination; rarely hyponatremia; urine concentrates

Schizophrenia, chronic alcoholism

Clozapine

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(2) medial preoptic nucleus: regulates body temperature and febrile responses (Box 1.13) (3) lateral preoptic nucleus: promotes sleep onset, and inhibits brain regions that are necessary for maintaining arousal by GABAergic and galanin projections ii.

supraoptic region (1) neurohormonal/magnocellular nuclei (paraventricular and supraoptic nuclei): project to the posterior pituitary where they directly release hormones

Box 1.13 Responses involved in body temperature regulation include: Heat loss (preoptic region): vasodilation; sweating, panting; decreased metabolism Heat production (posterior nucleus): vasoconstriction; shivering, piloerection; increased metabolism

(2) suprachiasmatic nucleus: the pacemaker of circadian rhythms (e.g., sleep–wake cycle, body temperature, cortisol and growth hormone release) (a) receives direct input from the retina; projects predominantly to the preoptic region and neurohormonal nuclei

iii. tuberal region (1) ventromedial nucleus: inhibits feeding behaviors together with the arcuate nucleus; opposed by the lateral hypothalamus (Box 1.14) (2) hormonal/parvocellular nuclei, which includes the ventromedial and arcuate nuclei: project to the median eminence where they release hormones into the portal system that then influence anterior pituitary hormone release (Table 1–4) (3) dorsomedial nucleus, tuberal nucleus iv.

mammillary region (1) mammillary bodies: receives projections from the hippocampus via the postcommissural fornix

Box 1.14 Froehlich’s Syndrome Symptoms—Obesity, failure of sexual development, and polyuria, occurring mostly in boys Cause—Hypothalamic lesions producing multiple releasing hormone deficiencies Differential diagnosis—Prader–Willi syndrome

Hypothalamus

(b) lesions cause irregular timing of sleep–wake behaviors; otherwise a normal amount of time is spent in each sleep phase

(a) serves in the circuit of Papez for memory formation; one of the chief sites of atrophy in Wernicke–Korsakoff syndrome (2) posterior nucleus: a “punishment” center that likely mediates negative affect; also involved in (a) inducing and maintaining wakefulness by diffuse histamine projections (b) initiating rage and fighting behaviors (c) regulation of the sympathetic nervous system

Table 1–4 Hypothalamic and Anterior Pituitary Hormones Hypothalamic hormone

Effect on pituitary hormones

Pituitary hormone target

Target tissue hormones

Thyrotropin-releasing hormone (TRH)

() TSH

Thyroid

T3, T4

Growth hormone releasing hormone (GHRH)

() GH

Whole body

n/a

Corticotropin releasing hormone (CRH)

() ACTH

Adrenal cortex

Glucocorticoids, adrenocorticoids

Gonadotropic-releasing hormone (GnRH)

() LH () FSH

Testes, ovaries

Sex steroids

Somatostatin

() GH () Prolactin

Whole body Breast

n/a

Dopamine

() Prolactin

Breast

n/a

Oxytocin

n/a

Smooth muscle in uterus and mammary gland

n/a

Vasopressin/antidiuretic hormone (ADH)

n/a

Distal renal tubule

n/a

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1 Neuroanatomy

(3) posterolateral nucleus: induces and maintains wakefulness by diffuse orexin/hypocretin projections 3.

Connections (Fig. 1–15)

4.

Vascular supply a.

anterior hypothalamus: recurrent artery of Huebner

b.

middle hypothalamus: thalamotuberal branches from posterior communicating artery

c.

posterior hypothalamus: thalamoperforating branches of posterior cerebral artery

VII. Cerebellum 1.

Types of cerebellar neurons (Fig. 1–16) a.

A

molecular layer i.

Purkinje neurons: have a flat dendritic field that is organized perpendicular to the long axis of folia (1) receive excitatory inputs from granular cells, which send parallel fibers that pass perpendicularly through the dendritic field of the Purkinje neurons (2) send inhibitory GABAergic projections to the deep cerebellar nuclei and directly to the lateral vestibular nucleus

ii.

interneurons (stellate cells, basket cells): all are GABAergic and inhibitory on the Purkinje neurons; all are excited by parallel fibers from the granular cells

B Figure 1–15 Afferents (A) and efferents (B) of the hypothalamus. (Refer to Figure 1–14 for nuclei labels.) (From Duus P, Topical Diagnosis in Neurology. Stuttgart, Germany: Georg Thieme; 1998:196, Figs. 5.15, 5.16. Reprinted by permission.)

iii. Bergman glia: form shells around the Purkinje cell bodies, exposing only synaptic sites; also serve to guide granule cell migration during development b.

granular layer i.

granular cells: each granular cell receives input from a single mossy fiber in a multisynaptic complex {glomerulus} that also involves inhibitory Golgi neuron inputs

ii.

Golgi neurons: receive input from parallel fibers, but unlike Purkinje neurons they exhibit a three-dimensional dendritic field that extends into the molecular layer (1) send inhibitory projections to the glomeruli

2.

General afferent fibers a.

18

cerebellar relay nuclei i.

inferior olivary complex: sends glutamatergic projections to Purkinje neurons and Golgi cell dendrites {climbing fibers} (Box 1.15)

ii.

pontine nuclei and arcuate nuclei (ectopic pontine nuclei), which in turn receive projections from the motor cortex {corticopontine tract}

Box 1.15 Pontine nuclei arcuate nuclei, and all sensory inputs form mossy fiber inputs (glutamate) to the granular layer glomeruli

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sensory inputs i.

spinal cord via spinocerebellar tracts

ii.

medial and inferior vestibular nuclei

iii. vestibular division of CN VIII directly iv. c.

modulatory inputs: pedunculopontine tegmental nucleus (acetylcholine); locus coeruleus (norepinephrine); ventral tegmental area (dopamine); medullary raphe nuclei (serotonin)

Efferents from the deep cerebellar nuclei: outputs are glutamatergic except for some of the projection to the inferior olivary nucleus, which is GABAergic a.

fastigial nucleus: contralateral  ipsilateral projections to the vestibular nuclei and pontomedullary reticular formation {uncinate fasciculus} via the inferior cerebellar peduncle (juxtarestiform body)

b.

interposed nuclei (globose, emboliform): contralateral projections to the red nucleus via the superior cerebellar peduncle

c.

dentate nucleus: contralateral projections via the superior cerebellar peduncle to the thalamus (ventrolateral nuclei and a small part of the ventroposterolateral nucleus), the ocular motor and accessory ocular motor nuclei, and the pontomedullary reticular formation

4.

Efferents from direct projections: The flocculus and the vermis of the anterior cerebellar lobule project directly to vestibular nuclei

5.

Subdivisions based on function (Fig. 1–17) a.

b.

c.

Figure 1–16 Types of cerebellar neurons and basic connections of the cerebellum. (From Duus P, Topical Diagnosis in Neurology. Stuttgart, Germany: Georg Thieme; 1998:166, Fig. 4.3. Reprinted by permission.)

vestibulocerebellum (includes the flocculus, nodulus, and uvula): regulates postural reflexes, equilibrium, and autonomic nervous system activity i.

principal afferents are from the vestibular nuclei and the vestibular part of CN VIII

ii.

output is to the fastigial nucleus; the flocculus also has a direct output to the vestibular nuclei

spinocerebellum (includes the anterior cerebellar lobe, simple lobule, and vermis and paravermal areas of the biventer lobule): involved in the maintenance of muscle tone i.

principal afferents are from the spinocerebellar tracts and precerebellar nuclei of the reticular formation (see p. 29)

ii.

output is to the interposed nuclei (emboliform and globose nuclei); the vermis of anterior cerebellar lobe also has direct output to the vestibular nuclei

pontocerebellum (includes the superior and inferior semilunar lobules of the cerebellar hemispheres): involved in the coordination of voluntary movements i.

principal afferents are from the pontine nuclei

ii.

output is to the dentate nucleus

6.

Vascular supply (Fig. 1–18)

7.

Pathophysiology: the classic cerebellar syndromes a.

Cerebellum

3.

tactile, auditory, and visual inputs by poorly defined routes

rostral vermis syndrome—symptoms include gait ataxia with some limb ataxia (mostly in the lower extremities), but rarely hypotonia, nystagmus, or dysarthria i.

typical cause: atrophy from chronic alcoholism

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Simple lobule

Superior semilunar lobule

1 Neuroanatomy

A

B Figure 1–17 Dorsal (A) and ventral (B) views of the cerebellum. (From Duus P, Topical Diagnosis in Neurology. Stuttgart, Germany: Georg Thieme; 1998:165, Figs. 4.1, 4.2. Reprinted by permission.)

b.

caudal vermis syndrome—symptoms include gait ataxia without limb ataxia, axial disequilibrium, nystagmus, and a rotated head posture i.

c.

hemispheric syndrome—symptoms include ipsilateral limb ataxia and dysarthria; does not have nystagmus, but may have ocular dysmetria i.

d.

typical cause: infarction

pancerebellar syndrome—symptoms include bilateral symptoms of the other three types of cerebellar syndromes i.

8.

typical cause: midline tumors, posterior fossa surgery

typical cause: infection, paraneoplastic syndromes

Pathophysiology: the uncommon cerebellar syndromes a.

symptoms include an oropharyngeal apraxia causing dysphagia, mutism, and an inability to open the eyes; also may exhibit urinary retention i.

typical cause: surgical removal of midline cerebellar tumors (1) typically develops 1–3 days after surgery (2) symptoms generally improve but may leave residual dysarthria

b.

cerebellar fits/diencephalic autonomic seizures—symptoms include transient decerebrate rigidity occurring most commonly in comatose patients with intracranial mass lesions located in the posterior fossa; often are mistaken for seizures i.

c.

20

typical cause: transient episodes of increased intracranial pressure, which likely cause periods of mesencephalic dysfunction

cerebellar cognitive-affective syndrome—symptoms include slowed decision making, personality changes (disinhibited or blunted), and impaired spatial and language abilities i.

typical cause: pancerebellar diseases

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Brainstem

A

Box 1.16 Cerebellar Peduncles

B Figure 1–18 Vascular anatomy of the cerebellum. (A) Midline view; (B) Inferior view. (From Duus P, Topical Diagnosis in Neurology. Stuttgart, Germany: Georg Thieme; 1998:173, Figs. 4.8, 4.9. Reprinted by permission.)

VIII. Brainstem A. Mesencephalon 1.

Motor output centers a.

eye movements: oculomotor nucleus, trochlear nucleus

b.

red nucleus i.

has connections with (Box 1.16) (1) motor cortices (2) cerebellar deep nuclei: dentate nucleus (parvocellular red nucleus); interposed nuclei (magnocellular red nucleus) (3) inferior olivary complex

Superior cerebellar peduncle/brachium conjunctivum: ✧ Afferents from the ventral spinocerebellar tract, red nucleus, tectum, and modulatory inputs ✧ Efferents to the red nucleus (from interposed nuclei) and thalamus (from dentate nucleus) Middle cerebellar peduncle: Exclusively carries afferents from the pontine nuclei Inferior cerebellar peduncle: Restiform body: Carries afferents from the inferior olivary nucleus, dorsal spinocerebellar tract from Clarke’s column (exteroceptors from below T1), lateral cuneate nucleus from fasciculus cuneatus (exteroceptors from above T1), and arcuate nuclei Juxtarestiform body: Carries bidirectional connections with the vestibular nuclei

(4) spinal cord ii.

pathophysiology: palatal myoclonus

Box 1.17

(1) classically develops several months after lesions of the central tegmental tract, although 25% of cases are idiopathic; lesions elsewhere in the triangle of Mollaret (Box 1.17) just cause intention tremor

Triangle of Mollaret—Bidirectional connections between ipsilateral red nucleus, ipsilateral inferior olivary complex, and contralateral dentate nucleus

21

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(2) symptoms (a) bilateral palatal myoclonus and the perception that is a clicking sound at 2–3 Hz from the eustachian tube opening caused by tensor veli palatini contractions (innervated by CN V3); both are continuous during sleep, unlike virtually all other movement disorders (b) pendular nystagmus (30%) that is often vertical and asymmetric; head and/or extremity tremor (10%); uncontrollable vocalizations and spasmodic dysphonia caused by laryngeal myoclonus (3) diagnostic testing: MRI may show hypertrophy of inferior olivary nucleus more than 3 weeks after injury to the central tegmental tract

1 Neuroanatomy

2.

Other centers a.

accessory ocular motor nuclei

b.

dopaminergic nuclei i.

substantia nigra pars compacta: forms the nigrostriatal dopaminergic pathway to the caudate and putamen

ii.

ventral tegmental area: forms (1) mesocortical dopaminergic pathway to the frontal lobe, anterior cingulate gyrus, and mesial temporal lobe (2) mesolimbic dopaminergic pathway to the nucleus accumbens, amygdala, and septal nuclei

3.

c.

substantia nigra pars reticulata

d.

mesencephalic reticular formation

e.

inferior colliculus

Pathophysiology: The anterior mesencephalic syndromes (Fig. 1–19) a.

Weber’s syndrome—symptoms include ipsilateral CN III palsy (pupil-involving) with contralateral hemiplegia; caused by lesions of the cerebral peduncles

b.

Claude’s syndrome—symptoms include ipsilateral CN III palsy (usually partial) with contralateral ataxia; lesion involves fibers of CN III and the dentato-rubro-thalamic tract as it decussates after leaving the superior cerebellar peduncle, but not always the red nucleus, which sits immediately superior to the dentato-rubrothalamic tract

c.

Benedikt’s syndrome—symptoms include ipsilateral CN III palsy with contralateral dyskinesias (parkinsonian tremor, chorea, athetosis); caused by lesions involving the red nucleus, medial substantia nigra, and fibers of CN III

d.

von Monakow’s syndrome—symptoms include ipsilateral CN III palsy with contralateral hemisensory loss for vibratory and position sense; caused by lesion involving the fibers of CN III and the medial lemniscus

e.

peduncular hallucinosis i.

22

symptoms (1) formed visual hallucinations involving bizarre, vivid characters and objects that are often cartoonish in nature; hallucinations are recognized as such by the patient, and are purely visual in nature

Figure 1–19 Anterior mesencephalic syndromes. (From Tsementis SA, Differential Diagnosis in Neurology and Neurosurgery. Stuttgart, Germany: Georg Thieme; 2000:171, Fig. 15a. Reprinted by permission.)

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(2) disrupted sleep–wake cycles (3) occasionally CN III palsy ii.

f.

specific lesions have been located bilaterally in the medial substantia nigra pars reticulata; symptoms may relate to dysfunction of the mesencephalic reticular formation with disinhibition of dream generation

top-o’-the-basilar syndrome i.

symptoms (1) somnolence, coma (2) amnesia (3) visual and ophthalmologic dysfunction: hemianopia or complete vision loss; Anton’s syndrome, Balint’s syndrome, Parinaud’s syndrome (see pp. 43, 45) (4) peduncular hallucinosis

4.

caused by occlusion of the basilar tip, leading to infarction of the tegmentum, medial thalamus, and parietal and occipital lobes; may be unilateral or bilateral

g.

midbrain locked-in syndrome—symptoms are as per pontine locked-in syndrome (quadriparesis, anarthria) except that no voluntary eye movements are preserved; caused by bilateral lesions of the cerebral peduncles

h.

hemiparkinsonism, contralateral to lesions of the substantia nigra pars compacta

i.

hemiplegia

Brainstem

ii.

Dorsal mesencephalon syndromes a.

b.

Nothnagel’s syndrome—symptoms include ipsilateral ataxia, vertical gaze palsy, and ipsilateral CN III palsy; caused by lesions in the pretectum involving the fibers of CN III and the superior cerebellar peduncle (Box 1.18) ophthalmologic syndromes (see p. 44)—Parinaud’s syndrome, syndrome of the Sylvian aqueduct, retraction nystagmus, vertical one-and-a-half syndrome

Box 1.18 Different than Claude’s syndrome, which has contralateral ataxia

B. Pons (Fig. 1–20) 1.

2.

Motor output centers a.

motor trigeminal nucleus: innervates mostly the muscles of mastication and tensor tympani and tensor veli palatini muscles via CN V3

b.

abducens nucleus (see p. 45)

c.

facial nucleus: lower motoneurons for the upper face muscles (i.e., auricular, occipital, frontalis, and corrugator supercilii muscles) are positioned dorsal to those of the other facial muscles i.

the muscles of the upper face receive bilateral innervation from the corticobulbar tract, sparing the upper face from paralysis after unilateral upper motoneuron lesions

ii.

involuntary facial movements involve projections from the basal ganglia, hypothalamus, and thalamus that do not travel in the internal capsule

Sensory input centers a.

principal trigeminal nucleus: receives ipsilateral ascending fibers of CN V that convey large-fiber sensory information from the face; most efferent projections of the principal trigeminal nucleus decussate immediately and ascend along the side of the contralateral medial lemniscus to the ventral posteromedial thalamus, although some trigeminal fibers ascend to the thalamus ipsilaterally, which allows unilateral thalamic lesions to spare facial sensation (as in the chiro-oral pattern of sensory loss)

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1 Neuroanatomy

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Figure 1–20 Anatomy of the pons. (A) Upper pass; (B) Lower pass. (From Tsementis SA, Differential Diagnosis in Neurology and Neurosurgery. Stuttgart, Germany: Georg Thieme; 2000:172, Fig. 15b; 173, Fig. 15c. Reprinted by permission.)

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Table 1–5 Other Trigeminal Reflexes Ciliospinal reflex

Pinching the neck skin causes pupil dilation

Corneal reflex

Corneal touch causes blinking

Corneomandibular reflex

Corneal touch causes jaw movement and blinking, only becomes unmasked with frontal lobe lesions (i.e., a frontal release sign)

Glabellar/blink reflex

Tapping on the supraorbital ridge causes blinking

b.

4.

Other centers a.

locus coeruleus (see p. 48)

b.

auditory nuclei (see p. 48): nucleus of the lateral lemniscus, nucleus of the trapezoid body, superior olivary nucleus

Pathophysiology: the ventral pontine syndromes a.

ataxic-hemiparesis/clumsy hand-dysarthria syndrome—symptoms include contralateral ataxia and weakness, dysarthria, and nystagmus i.

classically a pontine lesion, but can also occur with thalamocapsular or internal capsule/basal ganglia lesions

ii.

may involve ipsilateral sensory loss, typically in the face, which is strongly indicative of a lesion in the thalamus

Brainstem

3.

mesencephalic trigeminal nucleus: contains the primary sensory neurons for the muscle spindles and Golgi tendon organs of the masticatory muscles; forms monosynaptic connection with the motor trigeminal nucleus to produce the jaw jerk reflex (Table 1–5)

iii. usually the weakness is worse in the lower extremity, and the ataxia is worse in the upper

5.

b.

Millard-Gubler syndrome—symptoms include ipsilateral facial weakness, horizontal diplopia from CN VI palsy, and contralateral weakness of the upper and lower extremities; caused by lesions involving the facial nucleus, CN VI fibers, and the corticospinal tract

c.

ventromedial pontine syndrome/Raymond’s syndrome—as per MillardGubler syndrome, but may also involve ipsilateral ataxia with middle cerebellar peduncle involvement and ipsilateral facial hemisensory loss with CN V root involvement

d.

pseudobulbar palsy—dysarthria, dysphagia, uni- or bilateral facial weakness, extremity weakness, and emotional behaviors often without conscious perception of the emotion; caused by bilateral injury of the corticobulbar fibers that disconnects brainstem motor nuclei from the cortex

e.

pontine locked-in syndrome—symptoms include weakness in all extremities, aphonia due to bilateral corticobulbar tract injury, and bilateral loss of horizontal eye movements with preservation of vertical eye movements; caused by bilateral ventral pontine lesions that involve the corticospinal and corticobulbar tracts, and bilateral CN VI fibers

f.

hemiplegia—has a tendency to affect parts of the corticospinal tract (e.g., a single limb) because it is divided by the pontine nuclei

Pathophysiology: the dorsal pontine syndromes a.

Marie-Foix syndrome—symptoms include contralateral hemiparesis, ipsilateral ataxia, and a variable loss of small-fiber sensation; caused by lesions of the corticospinal tract, middle cerebellar peduncle, and spinothalamic tract

b.

Foville’s syndrome—symptoms include ipsilateral facial weakness and lateral rectus weakness; caused by lesions involving the facial nucleus and abducens nucleus

c.

Raymond-Gestan syndrome—symptoms include ipsilateral ataxia, contralateral pan-modal sensory loss, ipsilateral facial weakness, and horizontal diplopia from ipsilateral lateral rectus weakness; lesions involve the middle cerebellar peduncle, medial lemniscus and spinothalamic tract, facial nucleus or CN VII fibers, and abducens nucleus

d.

internuclear ophthalmoplegia, one-and-a-half syndrome (see p. 45)

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C. Medulla (Fig. 1–21) 1.

Motor output centers a.

hypoglossal nucleus: unilateral lesions cause ipsilateral tongue weakness and dysphagia  dysarthria; bilateral tongue weakness may obstruct the airway i.

b.

dorsal motor nucleus of the vagus: sends parasympathetic efferents to the heart, lungs, GI tract, and other abdominal viscera; viscerotopically organized

c.

nucleus ambiguus: innervates muscles that are derived from the branchial arches, which includes masticatory, facial, pharynx, and larynx muscles

1 Neuroanatomy

2.

upper motoneuron lesions causing tongue weakness are rare

i.

the cranial portion of the nucleus ambiguus innervates the soft palate (except tensor veli palatini [CN V-3]), oropharynx, and laryngeal muscles (via the recurrent laryngeal and pharyngeal branches of CN X)

ii.

spinal portion of nucleus ambiguus (C1–5 levels) innervates the sternoclidomastoid and trapezius muscles

Sensory input centers a.

vestibular and cochlear nuclei

b.

nucleus cuneatus and gracilis: receives the large fiber sensory input (from C2–T6 spinal cord levels via the fasciculus cuneatus, and from below T6 spinal cord level via the fasciculus gracilis); efferents decussate and ascend to the ventroposterolateral nucleus of the thalamus

c.

spinal trigeminal nucleus: receives the descending projections of CN V (for facial pain and temperature sensation) and general somatic afferents via CN V, VII, IX, X i.

d.

facial sensory representation is divided according to CN V branch as well as into an onion-skin pattern (Fig. 1–22)

solitary tract nucleus i.

the rostral half of the solitary tract nucleus receives taste sensory fibers carried by CN VII, IX, X

ii.

the caudal half of the solitary tract nucleus receives sensory inputs related to cardiovascular function, respiration, and GI function that are carried by CN IX and X (1) blood pressure sense is from carotid body and sinus (via CN IX), and blood chemosensation from the aortic body and sinus (via CN X)

e.

26

Figure 1–21 Anatomy of the medulla. (A) Midline medulla; (B) Inferior medulla. (From Tsementis SA, Differential Diagnosis in Neurology and Neurosurgery. Stuttgart, Germany: Georg Thieme; 2000:174, Fig. 15d; 175, Fig. 15e. Reprinted by permission.)

area postrema: chemosensitive for both intravascular blood and intraventricular cerebrospinal fluid; involved in triggering the vomiting reflex by either direct irritation or after irritation of thoracoabdominal CN X fibers i.

the only paired circumventricular organ

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Brainstem

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Figure 1–22 The onion-skin pattern of CN V sensory innervation. (From Mumenthaler M, Neurological Differential Diagnosis. 2nd ed. Stuttgart, Germany: Georg Thieme; 1992:144, Fig. 54. Reprinted by permission.)

3.

Other centers a.

inferior olivary complex: composed of the principal and accessory olivary nuclei i.

afferents (1) cerebral cortex via the corticospinal tract (2) red nucleus via the central tegmental tract (3) deep cerebellar nuclei, including some GABAergic projections (4) spinoolivary tract that arises from all levels of the spinal cord

ii.

efferents (to contralateral  ipsilateral targets) (1) cerebellar hemispheres and deep cerebellar nuclei (principal olivary nuclei) (2) cerebellar vermis (accessory olivary nuclei)

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b.

arcuate nuclei: essentially are ectopic pontine nuclei (i.e., cerebellar relay nuclei) that send afferents to that cerebellum via the inferior cerebellar peduncle

c.

perihypoglossal nuclei, which are accessory ocular motor nuclei (see p. 44)

Pathophysiology: The medullary syndromes a.

hemiplegia cruciata/cruciate paralysis—symptoms include ipsilateral lower extremity and contralateral upper extremity weakness, wherein the upper extremity weakness is worse than the lower extremity weakness; also may involve respiratory impairment, hypotension, sensory loss in the neck and posterior head, facial sensory loss in an onion-skin pattern (from spinal trigeminal nucleus injury; and/or lower cranial neuropathies (CN IX–XI) i.

1 Neuroanatomy

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caused by lesions of the lateral aspect of the corticospinal tract decussation where upper extremity fibers decussate rostral to the lower extremity fibers

b.

ventromedial medullary syndrome/Dejerine’s syndrome—symptoms include contralateral upper and lower extremity weakness sparing the face, ipsilateral weakness of the tongue, and ipsilateral loss of vibratory and position sense; caused by lesions involving the corticospinal tract, anterior CN XII fibers, and medial lemniscus

c.

dorsolateral medullary syndrome/Wallenberg’s syndrome i.

symptoms (1) ipsilateral: Horner’s syndrome; ataxia; loss of small-fiber sensation in the face; transient facial pain; weakness of the palate, larynx, and pharynx causing dysarthria and dysphonia (2) contralateral: loss of small-fiber sensation in body (3) hiccups

ii.

d.

caused by lesions of the lateral ponto-mesencephalic junction, usually vertebral artery infarction more so than posterior inferior cerebellar artery (PICA) infarction

hemimedullary syndrome/Babinski-Nageotte syndrome—the combination of ventromedial and dorsolateral medullary syndromes

D. Reticular Formation 1.

Anatomy: a diffuse group of intrinsic brainstem and diencephalic neurons of varying size and shape that are separated by myelinated axons projecting in all directions {reticulum}; extends from the caudal medulla through the pons and mesencephalon into the diencephalon up to the posterior hypothalamus and thalamus (midline, intralaminar, and reticular nuclei)

2.

Subdivisions and key nuclei a.

mesencephalic reticular formation i.

dorsal raphe nucleus: sends serotonergic projections to most of the forebrain and basal ganglia; many neurons colocalize serotonin with substance P

ii.

pedunculopontine tegmental nucleus (acetylcholinergic): related to basal ganglia circuits

iii. ventral tegmental area (dopaminergic): related to the nucleus accumbens b.

pontine reticular formation i.

28

locus coeruleus: supplies norepinephrine to most of the brain and spinal cord except for the hypothalamus and the preganglionic sympathetic neurons of the spinal cord intermediolateral cell column, which receive adrenergic innervation from the medulla (1) degenerates in conditions that affect other pigmented neurons (e.g., Parkinson’s disease) or in dementing disorders (e.g., Alzheimer’s disease)

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nucleus reticularis pontis: controls convergent and divergent eye movements and forms the ventral reticulospinal tract

iii. paramedian pontine reticular formation c.

medullary reticular formation (Box 1.19) i.

lateral reticular nucleus

ii.

medullary raphe nuclei (pallidus, obscurus, magnus): forms serotonergic projections to the diencephalon, brainstem, and spinal cord, but not to the telencephalon; many neurons colocalize serotonin with substance P or galanin

Box 1.19 The paramedian pontine reticular formation and the lateral reticular nuclei are also known as the precerebellar nuclei of the reticular formation, which form mossy fiber inputs to the cerebellum.

iii. nucleus gigantocellularis

4.

Afferents a.

spinoreticulothalamic tract, which carries poorly localizable pain sensation to the intralaminar thalamic nucleus and reticular formation

b.

corticospinal and corticobulbar tracts

c.

sensory and autonomic brainstem nuclei; fastigial nucleus; hypothalamus

Efferents a.

sensory and motor brainstem nuclei; cerebellum

b.

ventral and lateral reticulospinal tracts

c.

i.

ventral reticulospinal tract: formed by projections from the nucleus reticularis pontis; has ipsilateral projections that are generally excitatory upon spinal motoneurons

ii.

lateral reticulospinal tract: formed by projections from the nucleus gigantocellularis; has ipsilateral and contralateral projections that are inhibitory upon spinal motoneurons, causing atonia during REM sleep

Spinal Cord

3.

spinal cord: nucleus raphe magnus reduces pain sensation via projections to the spinal trigeminal nucleus and posterior horn of spinal cord (endogenous analgesic systems) i.

the nucleus raphe magnus is regulated by the periaqueductal gray, which is itself regulated by the hypothalamus and amygdala

d.

autonomic control centers

e.

ascending reticular activating system (ARAS) and non-ARAS sleep centers

IX. Spinal Cord 1.

Long tracts (Fig. 1–23) a.

anterior funiculus i.

spinothalamic tract/anterolateral system: formed by axons of secondorder neurons located in the contralateral Rexed laminae I, VI, and VII, which decussate as they ascend a few spinal cord levels (1) fibers are arranged somatotopically in the spinal cord and also by modality (pain fibers are located anteriorly, temperature fibers are located posteriorly) (2) carries localizable pain sensation; the spinoreticulothalamic tract carries poorly localizable pain sensation and terminates in the reticular formation and intralaminar nuclei of the thalamus

ii.

anterior corticospinal tract

iii. medial longitudinal fasciculus: carries descending fibers to the cervical and upper thoracic spinal cord from the motor nuclei of the ocular muscles, nuclei of the auditory pathway, and vestibular nuclei (all of which control head positioning) iv.

vestibulospinal tracts (see p. 50): facilitates extensor antigravity muscle tone

v.

ventral and lateral reticulospinal tracts

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lateral funiculus i.

lateral corticospinal tract (see p. 3): composed of projections from the (1) primary motor cortex (Brodmann area 4) and supplementary motor area and premotor cortex (Brodmann area 6), which terminate in the anterior horn (2) primary somatosensory cortex (Brodmann areas 3,1,2): terminates in Rexed lamina IV; modulates ascending sensory input

1 Neuroanatomy

ii.

rubrospinal tract: decussates immediately after leaving the red nucleus; projects to the anterior horn only in the upper cervical spinal cord levels

iii. spinocerebellar tracts: carry unconscious proprioception, exteroception, and somatosensory information Figure 1–23 Long tracts of the spinal cord. (From Duus P, Topical Diagnosis in Neurol(1) dorsal spinocerebellar tract: ogy. Stuttgart, Germany: Georg Thieme; 1998:20, Fig. 1.21. Reprinted by permission.) originates in the ipsilateral dorsal nucleus of Clarke that receives sensory inputs from spinal cord levels below T1; projects to the anterior cerebellar lobe via the inferior cerebellar peduncle

(2) ventral spinocerebellar tract: originates in contralateral Rexed laminae V–VII (lumbosacral levels), projects to the anterior cerebellar lobe via the superior cerebellar peduncle 2.

3.

Posterior funiculus: The dorsal columns, that is, the fasciculus gracilis (from lower thoracic, lumbar, and sacral spinal cord) and fasciculus cuneatus (from the spinal cord above T6) a.

both fasciculi are arranged somatotopically and according to modality (pressure and vibration are superficial, proprioception and touch are deep)

b.

carry sensation for conscious proprioception, vibration, and discriminative touch (e.g., two-point discrimination, stereognosis, textures)

Gray matter a.

dorsal horn: important laminae include i.

substantia gelatinosa (Rexed lamina II): contains interneurons that release opioid agonists thereby limiting release of substance P from pain-sensitive dorsal root fibers (1) supraspinal pain modulation is provided by descending norepinephrine fibers from the pontine A7 nucleus (not the locus coeruleus) and serotonergic fibers from the nucleus raphe magnus

ii.

nucleus proprius (Rexed lamina III and IV): GABAergic interneurons

iii. lamina V projects into the spinothalamic tract (with laminae I and VII) b.

intermediate zone (Rexed lamina VII) i.

30

intermediolateral cell column: receives descending excitatory aminergic input from medullary C/A2 and A5 aminergic nuclei, and inhibitory serotonergic input from the medullary raphe nuclei

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ii.

c.

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Clarke’s column: located medial to the intermediolateral cell column between T1 and L3 spinal cord levels; relays proprioceptive and tactile sensory inputs from spinal cord levels below T1 (from the trunk and lower limbs) to the cerebellum through the dorsal spinocerebellar tract

anterior horn (Rexed lamina VIII, IX) i.

motoneurons (1) subtypes (a) -I motoneurons: have large cell bodies; innervate fatigable and fatigue-resistant fast-twitch muscle fibers (b) -II motoneurons: have small cell bodies; innervate fatigueresistant slow-twitch muscle fibers

Figure 1–24 Somatotopic organization of the spinal gray matter. (From Kahle W, Color Atlas/Text of Human Anatomy, Vol. 3: Nervous System and Sensory Organs. 4th ed. Stuttgart, Germany: Georg Thieme; 1993:47, Fig. C. Reprinted by permission.)

(c)  motoneuron/fusimotor neurons: have very small cell bodies; innervate the intrafusal muscle fibers of the muscle spindles (2) somatotopic arrangement of motoneurons (Fig. 1–24)

ii.

Spinal Cord

(3) modulated by excitatory fibers from locus coeruleus and inhibitory fibers from the medullary raphe nuclei interneurons: all are inhibitory, and use glycine  GABA (1) Ia “reciprocal” interneurons: receive direct excitatory input from sensory Ia (glutamate) muscle spindle afferents of the agonist muscle, and serve to inhibit the motoneurons of the antagonist muscle (e.g., during rapid contraction) (2) Renshaw cells: innervated by excitatory acetylcholinergic collaterals of the agonist muscle motoneurons, and serve to inhibit those same motoneurons {recurrent inhibition} and the Ia interneurons of the antagonist muscles (i.e., increases antagonist tone) (3) Ib interneurons: receive direct excitatory input from the sensory Ib afferents of the Golgi tendon organs of the agonist muscle and from cutaneous sensory receptors, and serves to inhibit the agonist muscle (e.g., to limit the force of exploratory touch) 4.

Vascular supply (Fig. 1–25): Not continuous along the whole length of the spinal cord, allowing for watershed infarctions

5.

Pathophysiology: incomplete spinal cord injuries a.

b.

central cord syndrome—symptoms include bilateral weakness in the upper  lower extremities because of involvement of the medial corticospinal tracts (which place fibers to the upper extremity medially) and the lower motoneurons of the cervical spinal cord i.

caused by neck hyperextension that compresses the spinal cord between an anterior osteophytic bone or herniated disk and the posterior ligamentum flavum; the pathological process is not necessarily infarction, but may involve traumatic injury and demyelination

ii.

differentiate from cruciate paralysis by the presence of lower motoneuron-type weakness, the absence of facial sensory loss, and the absence of cranial nerve injury

anterior cord syndrome—symptoms include bilateral weakness, loss of pain and temperature sense below the level of lesion, and impaired bowel and bladder control; proprioception, vibration, and light touch are preserved i.

caused by lesions of the entire cord except the dorsal columns

ii.

may develop painful dyesthesias below the level of lesion

Figure 1–25 Vascular anatomy of the spinal cord. (From Rohkamm R, Color Atlas of Neurology. Stuttgart, Germany: Georg Thieme; 2004:23).

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Table 1–6 Conus Medullaris and Cauda Equina Syndromes Conus medullaris syndrome

Cauda equina syndrome

Caused by lesions at L1-2

Caused by lesions at L4-5 or L5-s1

Symptoms include

Symptoms include

Symmetric weakness

Asymmetric weakness

Symmetric saddle anesthesia for small fiber sensation

Asymmetric saddle anesthesia involving all modalities Decreased knee reflex

Bowel and bladder incontinence, developing early

Bowel and bladder retention developing late

1 Neuroanatomy

Normal knee reflex

c.

posterior cord syndrome—symptoms include loss of proprioception and vibratory sense below the level of lesion, and complete sensory loss in the dermatome at the level of the lesion (i.e., also involving small fiber sensation); caused by lesions of the dorsal columns

d.

Brown-Sequard/hemisection syndrome—symptoms include ipsilateral sensory loss for vibration and proprioception, ipsilateral hemiplegia, and contralateral loss of pain and temperature sensation; touch is generally preserved due to representation in multiple bilateral ascending tracts i.

e.

pain and temperature sensory loss tends to occur 1–2 levels below the level of vibration and proprioception loss because the projections of the second-order sensory neurons of the spinothalamic tracts ascend a few levels as they decussate

conus medullaris and cauda equina syndromes (Table 1–6)

X. Cranial Nerves 1.

Anatomy a.

CN II (see p. 39); CN III, IV, VI (see p. 44)

b.

CN VII: (Fig. 1–26)

c.

CN XI: (Fig. 1–27)

2.

Cranial nerve ganglia (Table 1–7)

3.

Specific disorders of cranial nerves a.

optic neuritis ischemic optic neuropathy (see p. 38)

b.

trigeminal neuralgia, glossopharyngeal neuralgia

c.

hemifacial spasm—symptoms include irregular, repetitive contractions of the muscles of half of the face (including the platysma) that are induced by voluntary facial movements; often begins in the orbicularis oculi, and spreads to the other facial muscles over time

d.

32

i.

caused by compressive lesions of CN VII (e.g., tumor, basilar artery aneurysm) or as a complication of a resolving Bell’s palsy

ii.

treat with antiepileptic drugs (carbamazepine) or surgical decompression

Bell’s palsy—there is generally no hyperacusis; loss of the stapedius reflex does not cause hyperacusis to normal sounds; principles of neurologic localization do not apply in Bell’s palsy; involvement of the stapedius or GSPN (dry eye) is an indication of greater severity of the lesion, not an indication of location of the lesion; the entire nerve is inflamed; the greatest degree of compression seems to be in the labyrinthine segment, where the fallopian canal is the narrowest i.

epidemiology: increased risk in diabetics but not during pregnancy

ii.

symptoms: retroauricular pain that precedes facial weakness by 1–2 days; the facial weakness is relatively acute in onset but it increases over 2–5-day period (1) associated symptoms (hyperacusis, loss of taste sensation) occur depending upon the segment of CN VII involved (Fig. 1–26)

Figure 1–26 Fiber components of CN VII and the nervus intermedius. Damage in different segments of the nerve (numbered 1–5) causes different neurological symptoms because of the involved nerve branches. The greater petrosal nerve carries parasympathetics to the lacrimal and nasal glands. The stapedius nerve acts to dampen the tympanic membrane oscillation. The chorda tympani carries taste sensation from the anterior tongue. (From Duus P, Topical Diagnosis in Neurology. Stuttgart, Germany: Georg Thieme; 1998:113, Fig. 3.35. Reprinted by permission.)

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Figure 1–27 Course of CN XI. (From Duus P, Topical Diagnosis in Neurology. Stuttgart, Germany: Georg Thieme; 1998:130, Fig. 3.43. Reprinted by permission.)

Table 1–7 Cranial Nerve Ganglia Cranial nerve and ganglia

Carries

To

CN III Ciliary ganglion

Parasympathetics from the Edinger–Westphal nucleus

Pupil constrictor muscle, ciliary muscles for lens accommodation

CN V Gasserian ganglion

General facial sensation

Principle and spinal trigeminal nuclei

Parasympathetics from the superior salivatory nucleus via the greater petrosal nerve

Lacrimal and nasal glands

Submandibular ganglion

Parasympathetics from the superior salivatory nucleus via the chorda tympani

Submandibular and sublingual glands

Geniculate ganglion

General sensation from the external auditory meatus, pinna, and mastoid; taste sensation from anterior tongue

Principle and spinal trigeminal nuclei Rostral solitary tract nucleus

Vestibular sensation from hair cells in ampula of the semicircular canals, and macula of utricle and saccule auditory sensation from the cochlear

Vestibular nucleus and cerebellar vermis

Hair cells

Cochlear nuclei

CN VII Pterygopalatine ganglion

CN VIII Vestibular/Scarpa’s ganglion

Organ of Corti CN IX Otic ganglion

Parasympathetics from the inferior salivatory nucleus

Parotid gland

Superior ganglion

Taste sensation from the posterior tongue; general sensation from the posterior tongue and oropharynx

Rostral solitary tract nucleus; spinal trigeminal nucleus

Inferior ganglion

As per superior ganglion Chemoreception and baroreception from the carotid body and sinus

As per superior ganglion; caudal solitary tract nucleus

General sensation from the external auditory canal, pinna, oropharynx, and larynx

Spinal trigeminal nucleus

As per superior ganglion Nonpainful visceral sensation

As per superior ganglion Solitary tract nucleus

CN X Superior/jugular ganglion Inferior/nodose ganglion

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Table 1–8 Cranial Nerve Syndromes Syndrome

CN involved

Location of lesion

Typical cause

Foix

III, IV, V-1, VI

Sphenoid fissure

Mass lesions, aneurysm

Tolosa-Hunt

III, IV, V-1, VI; sympathetics

Cavernous sinus or superior orbital fissure

Idiopathic granulomatous disease, sinus thrombosis, or aneurysm

Gradenigo

V, VI

Petrous apex

Idiopathic inflammatory disease

Vernet

IX, X, XI

Jugular foramen

Mass lesions

Collet-Sicard

IX, X, XI, XII

Around the occipital condyle

Mass lesions

Villaret

IX, X, XI, XII; sympathetics

Around the occipital condyle

Mass lesions involving the internal carotid artery

1 Neuroanatomy

iii. treatment: protection and lubrication of the ipsilateral eye; 4–10-day course of prednisone  antiherpetic drug (acyclovir, famcyclovir), started within 1 week of symptomatic onset (1) no evidence in support of CN VII decompression surgery iv.

prognosis: 75% recover within 3 weeks; better outcomes occur in cases with partial weakness and a rapid recovery of taste (1) increased tone of the facial muscles after CN VII regeneration may give the appearance that the facial palsy was on the opposite side (2) facial synkinesis—aberrant regeneration of CN VII fibers that innervate the wrong target, often producing unintentional blinking, twitching, tearing, or snarling

4.

Cranial nerve syndromes (Table 1–8)

XI. Autonomic Nervous System 1.

2.

3.

Urination a.

motor innervation (Fig. 1–28)

b.

sensory innervation: diffuse innervation by sympathetic and parasympathetic afferents, which are sensitive mostly to distension; somatic innervation of the external sphincter is provided by the pudendal nerve

Sexual function a.

erection: mediated by parasympathetic motor fibers from the intermediolateral cell column of the S2-4 spinal cord via the pelvic splanchnic nerves {nervi erigentes}

b.

ejaculation: mediated by sympathetic motor fibers from the intermediolateral cell column of the L2–4 spinal cord via the hypogastric nerves

Pathophysiology a.

the syndrome of autonomic dysreflexia—caused by hyperactive visceral reflexes that are triggered by noxious stimuli applied to the skin or viscera below the level of the spinal cord lesion (e.g., intestinal or bladder distention, urinary tract infection, bladder catheterization, bed sores); occurs with spinal cord lesions above T6 i.

symptoms: the simultaneous occurrence of (1) hypertension (from splanchnic vasoconstriction) and reflex bradycardia (2) profuse sweating, piloerection, and skin flushing above the spinal cord level (3) pupillary dilatation (4) erection and ejaculation; bowel and bladder incontinence

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b.

bladder dysfunction (Table 1–9)

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XII. Ventricle System and Cerebrospinal Fluid (CSF) Pathophysiology a.

traumatic lumbar puncture: differentiate from subarachnoid hemorrhage by declining red blood cell count in sequential tubes, a RBC–WBC (white blood cell) ratio  700 to 1, the absence of xanthochromia, the presence of clotting blood, and a protein level elevated no more than 1 mg/1000 RBCs

b.

intracranial pressure/Lundberg waves: reflect arterial and venous pressure, and the respiratory cycle i.

Lundberg A waves: high amplitude increases in CSF pressure lasting  5 minutes, generally associated with increases in blood pressure

ii.

Lundberg B waves: mid-amplitude increases in CSF pressure lasting  5 minutes, associated with cyclic breathing

Ventricle System and Cerebrospinal Fluid (CSF)

1.

iii. Lundberg C waves: low amplitude increases in CSF pressure lasting  30 seconds occurring on top of Lundberg A waves; unknown significance c.

pediatric hydrocephalus (see Ch. 12)

d.

adult hydrocephalus: symptoms include dementia similar to that of bilateral frontal lobe dysfunction, usually without apraxia, agnosia, or aphasia i.

general diagnostic testing: neuroimaging (1) requires temporal horns  2-mm wide, as well as one of the following (a) compressed Sylvian fissures, interhemispheric fissures, and cerebral sulci (b) frontal horn (FH)/internal diameter (ID) at the frontal horn level  0.5 (c) frontal horn/maximal intracranial diameter  0.3 {Evan’s ratio} (2) nonspecific radiographic findings: frontal horn ballooning (“Mickey Mouse” ventricles); transependymal edema; upward bowing of the corpus callosum on sagittal sections

ii.

pathophysiology: normal pressure hydrocephalus/Hakim-Adams syndrome

Figure 1–28 Motor innervation of the bladder. (From Mumenthaler M, Neurological Differential Diagnosis. 2nd ed. Stuttgart, Germany: Georg Thieme; 1992:57, Fig. 157. Reprinted by permission.)

(1) a communicating hydrocephalus that does not involve increased intracranial pressure; potential mechanisms include dilation caused by transiently increased intracranial pressure and/or altered elastic properties of the ventricle walls (2) epidemiology: more common in males  60 years old

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Table 1–9 Bladder Dysfunction Type

Lesion site

Pattern of urination

Upper motoneuron/ spastic bladder

Between the frontal lobes and the pons

Bladder contracts during filling instead of relaxing; poor emptying

Bladder dyssynergy

Below the pons but above the conus

Simultaneous detrussor and internal sphincter contraction causes ureter reflux, poor emptying, and overflow incontinence

Lower motoneuron/ flaccid bladder

Lower motoneurons

Retention with poor emptying

Sensory paralytic bladder

Afferent sensory fibers, dorsal columns, or spinothalamic tracts

Retention with overflow incontinence; preserved voluntary urination

Bladder areflexia

Acute spinal shock; caudal equina or conus medullaris injury

Unrestricted bladder distention causes overflow incontinence and retention

(3) symptoms (in order of appearance) (a) gait disturbance: Bruns’ frontal lobe ataxia (see p. 5) (b) dementia (60%): predominant short-term memory impairment (c) urinary incontinence from a spastic bladder; urinary urgency may precede incontinence (4) specific diagnostic testing: no test exhibits high diagnostic accuracy (a) lumbar puncture (i)

demonstrates normal pressure but continuous CSF pressure monitoring may exhibit Lundberg B waves or transient pressures  20 mm Hg

(ii) symptoms must improve with large-volume CSF drainage (iii) measurement of resistance with fluid infusion into subarachnoid space is correlated with symptoms but is not predictive of shunting outcome (b) radionuclide cisternography: retention of contrast in the ventricles  24 hours after administration is not useful for establishing the diagnosis or predicting the clinical response to shunting (c) MRI CSF flow study: absence of CSF flow near the cerebral aqueduct does not predict the clinical response to shunting (5) treatment: low-pressure ( 3-mm opening pressure) ventriculoperitoneal shunt (a) patient should be sat upright slowly over several days after placement (b) lumboperitoneal shunts generally results in overshunting and have high complication rates (6) prognosis: incontinence and gait generally improve more than dementia (a) responsiveness to shunting is prediced by (i)

the presence of the classic triad of symptoms

(ii) clinical improvement after lumbar puncture (iii) opening pressure  7 mm Hg (iv) the presence of high transient pressures on continuous CSF pressure monitoring (v) the absence of ischemic changes on MRI

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iii. hydrocephalus ex vacuo—dilation of the ventricular system due to brain atrophy that can be either diffuse or focal

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Figure 1–29 Photoreception in the retina. (From Koolman J, Rohm KH, Color Atlas of Biochemistry. Stuttgart, Germany: Georg Thieme; 1996:326. Reprinted by permission.)

XIII. Neuroophthalmology A. The Sensory Visual System 1.

Retina a.

vision reception (Fig. 1–29)

b.

subtypes of retinal fiber bundles (Fig. 1–30)

c.

pathophysiology: retinal fiber loss causes i.

decreased visual acuity with papillomacular bundle injury

ii.

scotomata (Box 1.20) (1) scotomata from papillomacular bundle injury (Fig. 1–31): central, centrocecal (a central scotoma that connects to the blind spot), or paracentral scotoma (2) scotomata from arcuate bundle injury (Fig. 1–32): all connect with the physiological blind spot

Box 1.20 Failure of defect to connect to the blind spot suggests the lesion is retro-chiasmatic.

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1 Neuroanatomy

illopap cular ma ndle bu

Figure 1–30 Retinal fiber bundles. (From Duus P, Topical Diagnosis in Neurology. Stuttgart, Germany: Georg Thieme; 1998:83, Fig. 3.11. Reprinted by permission.)

Figure 1–31 Papillomacular bundle injuries cause paracentral (A), central (B), or centrocecal (C) scotomata.

(a) Bjerrum/arcuate/scimitar scotoma (b) Seidel scotoma: caused by lesions in the proximal arcuate bundle (c) nasal step of Ronne: caused by lesions in the distal arcuate bundle (d) isolated scotoma in Bjerrum’s area: caused by lesions in the intermediate part of the arcuate bundle (3) scotomata from nasal bundle injury: wedge-shaped/ quadrantic temporal scotoma that connects to the blind spot but does not necessarily respect the horizontal meridian (Fig. 1–32) d.

2.

diagnostic testing: the electroretinogram, which measures the electrical potential measured from the retina in response to a series of flashing lights; the electrical potential is generated by the ganglion cell layer, and is reduced by ganglion cell loss (e.g., optic neuropathies)

Optic disc: The collection of retinal ganglion cell projections (still unmyelinated); normally forms the blind spot located in the temporal visual field a.

blood supply: the circle of Zinn-Haller, which is formed by the short posterior ciliary arteries, choroid arteries, and pial arterial network

b.

pathophysiology i.

scotoma and loss of visual acuity (as per retinal fiber bundle injuries)

ii.

papilledema: caused by transmission of elevated intracranial pressure along the subarachnoid space of CN II, or else by elevated pressure central retinal vein; takes  24 hours to develop after elevation of intracranial pressure

Figure 1–32 Arcuate bundle injuries cause an isolated scotoma within the Bjerrum region (A), an altitudinal defect/fat Bjerrum scotoma (B), the Bjerrum scotoma (C), nasal step of Ronne (D), and the Seidel scotoma (E). Nasal bundle injury causes a temporal field defect (F).

(1) generally is asymptomatic unless long-standing and severe, wherein it may cause visual blurring and/or loss of acuity iii. anterior ischemic optic neuropathy (AION)—caused by ischemia of the optic disc and the most anterior portion of the optic nerve, wherein the ischemia is exacerbated by swelling of the ischemic neural tissue; usually from diseases of the short posterior ciliary arteries

38

(1) subtypes: both are common only in women  50 years old and in Whites

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(a) arteritic AION: ischemia is the result of giant cell arteritis or other vasculitides (b) non-arteritic AION: not related to giant cell arteritis, but rather to classic stroke risk factors; congenitally small discs may also predispose the patient to ischemia of the anterior optic nerve (i)

Optic nerve a.

subdivisions i.

intraocular segment (1-mm length): unmyelinated and therefore smaller diameter

ii.

intraorbital segment (25-mm length): passes through the annulus of Zinn formed by the tendinous origins or the superior, inferior, and medial recti muscles (1) normally exhibits a sinusoidal course in the orbit; a straight course suggests tension caused by proptosis, and it may cause tenting of the posterior globe

iii. intracanalicular segment (10-mm length): optic nerve turns medially and passes through optic canal; the dura of the optic nerve fuses with the periosteum, so the subarachnoid space of brain is continuous with the subarachnoid space of the optic nerve (all three layers of the dura are present in the orbit) iv.

4.

Neuroophthalmology

3.

symptoms: painless (90%) vision loss that often develops during sleep; papilledema that can be limited to a segment of the optic disc {sectorial disc edema} and that is often associated with retinal flame hemorrhages

intracranial segment (15-mm length)

b.

blood supply: extracranial optic nerve is supplied by the ophthalmic artery; intracranial optic nerve is supplied by the middle cerebral artery (MCA) and the anterior communicating artery (ACA) (Fig. 1–33)

c.

pathophysiology i.

decreased visual acuity and scotomata (as for retinal fiber bundles)

ii.

optic neuritis

Optic chiasm a.

fiber decussation i.

Wilbrand’s knee: an anterior deflection of the decussating fibers from the inferior nasal retina into the terminal part of the contralateral optic nerve; accounts for a superior temporal field cut contralateral to an optic nerve injury (Fig. 1–30)

ii.

fibers from macula cross in posterior part of chiasm

Figure 1–33 The intracranial segment of CN II. (From Rohkamm R, Color Atlas of Neurology. Stuttgart, Germany: Georg Thieme; 2004:13. Reprinted by permission.)

b.

blood supply: ACA, MCA, and posterior communicating artery

c.

pathophysiology: almost invariably caused by mass lesions (e.g., pituitary tumors, suprasellar meningiomas, aneurysms) i.

lesions posterior to the chiasm do not decrease visual acuity (except for bilateral injury to the poles of the occipital cortex that represent the macula)

ii.

scotomata and field cuts (1) anterior chiasmal lesions {junctional scotoma} (Fig. 1–34): ipsilateral vision loss (from optic nerve injury) and a contralateral superior temporal scotoma (from Wilbrand’s knee) (2) lesions in the body of the chiasm: bitemporal hemifield scotomata

39 Figure 1–34 The junctional scotoma.

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(3) lateral chiasmal lesion: produces a nasal hemianopia; rarely occurs bilaterally 5.

Optic tracts a.

contains the postchiasmal ipsilateral temporal and contralateral nasal retinal projections to the lateral geniculate nucleus

b.

a small projection avoids lateral geniculate nucleus and terminates in the suprachiasmatic nucleus of the supraoptic hypothalamic region, superior colliculus, and pretectal nucleus i.

nongeniculate projections are responsible for (1) setting circadian rhythms (2) blind sight: the ability to respond to visual stimuli without the conscious perception of sight (i.e., cortical blindness)

1 Neuroanatomy

(3) pupil reaction to light c.

blood supply: anterior choroidal branch of the MCA

d.

pathophysiology: homonymous visual field deficits that are poorly matched in shape between eyes but that still respect the vertical meridian; congruity of the visual field deficits increases as the bilateral visual projections become more organized along the length of the optic tract i.

6.

lesions do not decrease visual acuity, but there is a relative afferent pupillary defect in the eye ipsilateral to lesion (i.e., in the eye with the temporal field defect)

Lateral geniculate nucleus a.

subdivisions i.

subdivisions according to the type of vision (1) magnocellular/M pathway: important for motion and stereopsis, but provides low spatial resolution; synapses in geniculate layers 1–2, projects to visual cortex layer 4C (2) parvocellular/P pathway: important for fine spatial resolution and color vision; synapses in layers 3–6, projects to visual cortex layer 4C

ii.

subdivisions according to eye of origin of the nerve fibers: fibers from the ipsilateral eye synapse in geniculate layers 2,3,5; fibers from the contralateral eye synapse in layers 1,4,6

iii. subdivisions according to the position of the nerve fibers in the retina: incoming nerve fibers of the optic tract are rotated 90° nasally (e.g., superior retina nerve fibers synapse medially in the lateral geniculate); outgoing nerve fibers from the lateral geniculate rotate another 90° nasally (e.g., the medial lateral geniculate projections synapse inferiorly in the visual cortex) b.

c. 7.

i.

lateral portion: anterior choroidal branch of the MCA

ii.

medial portion: posterior lateral choroidal branch of the posterior cerebral artery (PCA)

pathophysiology: sectoranopias, which still exhibits significant incongruity (Fig. 1–35)

Optic radiations a.

40

blood supply

the projections of the lateral geniculate are divided into fibers carrying information from the superior and inferior quadrants of the retina i.

superior retinal quadrant projections from the lateral geniculate are carried straight posterior along the mesial parietal cortex before reaching the occipital lobe

ii.

inferior retinal quadrant projections from the lateral geniculate must wrap anterior in front of the temporal horn before passing posterior toward the occipital cortex {Meyer’s loop}

Figure 1–35 Sectoranopias from anterior choroidal artery infarction (A) and lateral choroidal artery infarction (B).

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b.

8.

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pathophysiology: large lesions in Meyer’s loop cause superior homonymous quadrantic (“pie in the sky”) field defects, whereas small lesions cause scotoma-like defects; lesions in the mesial parietal lobe cause inferior homonymous quadrantic field defects (a defect that is more likely to be caused by occipital lobe lesions)

Primary visual cortex (Brodmann area 17/visual area I) a.

b.

representation of visual fields on the primary visual cortex i.

visual field representation is completely inverted on the occipital cortex (e.g., the superior visual field is below calcarine fissure; the inner retina (macula) is represented on the outermost occipital cortex)

ii.

macular retina has disproportionately large area of representation on the visual cortex

blood supply i.

outside of macular region: calcarine artery branch of the PCA

ii.

macular region/pole of occipital cortex: in addition to the PCA, it may receive collaterals from the meninges that could account for the sparing of macular vision that can occur after bilateral occipital lobe infarcts

c.

pathophysiology: highly congruous visual field defects; vision loss does not involve neglect, asymmetry of optokinetic nystagmus, or loss of blinking to threat

d.

diagnostic testing i.

A

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visual evoked potentials (VEP): the potential derived from occipital cortex caused by stimulation of the retina (e.g., with a strobe light or reversal of a checkerboard pattern) (Fig. 1–36)

B

Figure 1–36 The right (A) and left (B) eye VEP from a patient with optic neuritis. Delay in the P100 potential and a loss of amplitude are noted in the affected left eye.

41

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(1) requires time-locked averaging, which averages-out the background EEG signal (2) VEP predominantly tests macular vision because the macula has a disproportionately large cortical representation and is closer to the electrode (3) VEP uses (a) multiple sclerosis: prolonged latency of the positive-deflection at 100 ms (P100) can be considered as a subclinical demyelinating event, although it also occurs with other demyelinating diseases (e.g., vitamin B12 deficiency, spinocerebellar degeneration)

1 Neuroanatomy

(b) optic neuropathy: reduced P100 amplitude is suggestive of ischemia, although it can also represent nerve compression or toxic neuropathies (c) factitious disorders: normal VEP and electroretinogram make the subjective complaint of vision loss highly suspect 9.

Association visual cortex a.

subdivisions i.

Brodmann area 18/visual area II

ii.

Brodmann area 19/visual area III

iii. Brodmann area 36/visual area IV iv. b.

Brodmann area 37/visual area V: involved in the perception of motion {kinetopsia}, which may also involve visual area III

pathophysiology i.

achromatopsia (Box 1.21): caused by lesions in visual area IV (occipitotemporal junction of the fusiform and lingual gyri) (1) hemiachromatopsia often occurs with a superior quadrantopsia and/or prosopagnosia (2) color vision is also compromised early in disorders of the optic nerve and chiasm (particularly red perception) and may persist even if acuity returns

ii.

akinetopsia: the inability to perceive moving objects in the contralateral visual hemifield, which suddenly appear when they become stationary; caused by lesions of visual area V

iii. visual neglect: the inability to perceive visual stimuli in the affected visual field when subjected to bilateral stimulation, but without outright vision loss; typified by patient complaints of running into objects on the neglected side (1) associated with abnormal optokinetic nystagmus, and with abnormal drawing and copying abilities when the lesion is in the nondominant hemisphere (2) caused by lesions in Brodmann areas 18 or 19/visual areas II or III iv.

prosopagnosia: the inability to recognize familiar faces; usually caused by bilateral lesions of the fusiform gyrus, although it may also occur with large injuries in the nondominant temporal lobe (e.g., as in progressive prosopagnosia, a subtype of frontotemporal lobar degeneration)

v.

Anton’s syndrome—the denial of complete blindness (i.e., anosognosia for blindness) with confabulation (1) caused by lesions that produce complete vision loss (typically bilateral medial occipital lobe lesions, although the lesions may be in the anterior visual system) in conjunction with (a) bilateral lateral occipitoparietal cortex lesions (visual areas II and III)

42

(b) thalamic lesions, as in the top-o’-the-basilar syndrome

Box 1.21 Blue/yellow deficits occur early in glaucoma.

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(c) any metabolic encephalopathy (2) diagnostic testing: EEG exhibits loss of alpha rhythms that return with vision vi. Balint’s syndrome—caused by bilateral lesions of the lateral occipitoparietal cortex, typically watershed infarction (1) symptoms (a) simultanagnosia: the inability to integrate an entire visual field (b) ocular ataxia: clumsiness of voluntary movements that are guided by vision

(d) neglect of the peripheral visual fields (causing apparent tunnel vision), or an altitudinal visual field neglect

B. The Ocular Motor System 1.

Ocular motor cranial nerves (Fig. 1–37) a.

pathophysiology i.

isolated CN III palsy (1) risk of aneurysm (typically from the posterior communicating artery or distal basilar) is high when complete loss of parasympathetic function (e.g., ptosis and mydriasis) is accompanied by at least some ocular motor dysfunction

Neuroophthalmology

(c) ocular apraxia: the inability to voluntarily direct gaze with saccadic eye movements

(a) high-risk patients should be evaluated immediately for aneurysm regardless of exam findings (b) patients who are not at high risk should be reevaluated within a few days to determine if parasympathetic dysfunction has developed, which would make them high risk

Dorello’s canal

(2) other causes (a) pupil-sparing CN III palsy: diabetic neuropathy, atherosclerosis, vasculitis (e.g., giant cell arteritis)

Figure 1–37 Entry of CN III, IV, V, and VI into the cavernous sinus. (From Duus P, Topical Diagnosis in Neurology. Stuttgart, Germany: Georg Thieme; 1998:88, Fig. 3.16. Reprinted by permission.)

(b) pupil-involving CN III palsy: tumors (chordoma, meningioma) ii.

isolated CN IV palsy: caused by trauma (40%), nerve infarction (20%), or mass lesion (10%)

iii. isolated CN VI palsy: in adults, usually caused by ischemia; in children, usually caused by viral infection 2.

Oculomotor nucleus (Fig. 1–38) a.

Edinger-Westphal nucleus: contains the parasympathetic neurons that innervate the pupillary sphincter muscle and the ciliary bodies that perform lens accommodation

Figure 1–38 The oculomotor nucleus. (From Duus P, Topical Diagnosis in Neurology. Stuttgart, Germany: Georg Thieme; 1998:87, Fig.3.15. Reprinted by permission.)

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3.

4.

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b.

convergence movements involving both medial rectus muscles are coordinated by interneurons located within the medial rectus subdivision of the oculomotor nucleus

c.

pathophysiology: lesions of the oculomotor nucleus impair the ipsilateral ocular muscles innervated by CN III except for the superior rectus, which is contralaterally innervated; ptosis occurs only with lesions of the central caudal subdivision of the oculomotor nucleus, and is always bilateral

Trochlear nucleus: Efferent fibers decussate in the medullary velum and innervate the contralateral superior oblique muscle, which acts to move the eye downward when it is fully adducted a.

lesions cause extorsion of the affected eye and head tilting to the opposite shoulder

b.

test for CN IV palsy in the presence of CN III palsy by having the patient attempt to look downward with the affected eye in abduction, which should produce a clockwise rotation of the eye if CN IV is functional

Abducens nucleus (Box 1.22) a.

types of neurons include i.

motoneurons projecting to the ipsilateral lateral rectus muscle

ii.

neurons projecting to the contralateral oculomotor nucleus via the medial longitudinal fasciculus; these neurons are regulated by the paramedian pontine reticular formation (PPRF) to direct horizontal conjugate eye movements (1) nucleus reticularis pontis of the pontine reticular formation coordinates the oculomotor and abducens nuclei during convergence and divergence

b.

pathophysiology i.

internuclear ophthalmoplegia (1) symptoms: lack of contralateral eye adduction during conjugate lateral gaze, but not during convergence; nystagmus in both eyes (greater in abducted eye) during conjugate lateral gaze (2) caused by lesions of the medial longitudinal fasciculus in the pons, which is often bilateral due to the close proximity of the two fasciculi

ii.

5.

one-and-a-half syndrome—caused by lesions of both the medial longitudinal fasciculi and the abducens nucleus (an intranuclear ophthalmoplegia); symptoms include bilateral inability to adduct the eyes during conjugate lateral gaze and ipsilateral lateral rectus muscle weakness

Accessory ocular motor nuclei a.

mesencephalic accessory ocular motor nuclei i.

rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF): regulates vertical conjugate eye movements (1) neurons controlling upward gaze (often specifically called the nucleus of the posterior commissure) project through the tectum (i.e., dorsal to the aqueduct) to the oculomotor and trochlear nuclei, therefore they are more sensitive to pineal masses causing Parinaud’s syndrome (2) neurons controlling downward gaze project through the tegmentum (i.e., ventral to the aqueduct) to the oculomotor and trochlear nuclei

ii.

interstitial nucleus of Cajal: involved in maintaining vertical gaze

iii. pretectal nucleus: regulates pupil light reaction; receives direct optic nerve input (1) pathophysiology: Argyll-Robertson pupil, which is a functional elimination of the light reaction circuit without impairment of pupil constriction during accommodation iv.

44

b.

nucleus of Darkschewitsch, which has an unknown function

pontine and medullary accessory ocular motor nuclei

Box 1.22 Near Triad Reflex ✧ Convergence ✧ Lens accommodation ✧ Pupil constriction

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paramedian pontine reticular formation (PPRF): irregulates horizontal conjugate eye movements acting via abducens nucleus (1) excitatory burst neurons initiate saccode (2) inhibitory burst neurons suppress contralateral abducens nucleus (3) omnipause neurons block burst neurons and prevent saccodes

ii.

perihypoglossal nuclei: have poorly defined roles in conjugate eye movements; not related to tongue movements

iii. nucleus prepositus hypoglossi: involved in maintenance of horizontal gaze along with the medial vestibular nucleus iv.

pathophysiology involving the accessory ocular motor nuclei i.

Parinaud’s syndrome—caused by pineal-region masses or hydrocephalus that injures the pretectal region (1) symptoms include (a) supranuclear upgaze palsy, but preserved oculocephalic and oculovestibular-induced upgaze (b) eyelid retraction {Collier’s sign} and lid lag with downgaze {setting sun sign} (c) loss of convergence and accommodation (d) Argyll-Robertson pupil

Neuroophthalmology

c.

nucleus interpositus and the nucleus of Roller, which have unclear functions

(e) convergence spasm and retraction nystagmus (f) skew deviation ii.

syndrome of the Sylvian aqueduct—Parinaud’s syndrome also with a downgaze palsy

iii. vertical one-and-a-half syndrome—symptoms include bilateral upgaze palsy and ipsilateral monocular downgaze palsy; caused by poorly localized pretectal lesions iv.

skew deviation/vertical strabismus—symptoms include the perception of tilting of the visual fields, which is often compensated for by a head tilt (1) caused by an imbalance in the vestibular input from lesions anywhere in the vestibular complex, vestibular division of CN VIII, or brain regions dealing with vestibular sensation including cortex; can also be seen with diffuse intracranial processes (e.g., elevated intracranial pressure, metabolic encephalopathy) (a) variance of the skew deviation in different gaze positions suggests medullary lesion (b) slowly alternating skew deviation suggests a mesencephalic tectal lesion

6.

Superior colliculus: controls saccadic eye movements via projections to the PPRF and riMLF, and regulates gaze fixation on visual targets

7.

Cerebellum: coordinates ballistic eye movement and braking during saccades a.

vermis and superior cerebellar peduncle lesions produce hypermetric contralateral saccades and hypometric ipsilateral saccades, which is the opposite of what fastigial nucleus lesions produce

b.

flocculus lesions impair ipsilateral smooth pursuit movements and the ability to maintain gaze fixation after a saccade

8.

Pulvinar (thalamus): involved in the maintenance and shifting of visual attention; promotes contralateral saccadic eye movements

9.

Ocular motor circuit of the basal ganglia (see Table 1–2): acts selectively to gait all types of saccadic eye movements

10. Cortical gaze centers a.

frontal eye field (Brodmann area 8): directs intentional saccades and pursuit movements contralaterally; has separate neurons for selecting the new eye position and for actually moving the eyes

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lesions cause ipsilateral gaze preference acutely, which resolves within days

parietal eye field (Brodmann area 39 in the angular gyrus): directs unconscious saccades toward novel objects in the visual field, and mediates reflex pursuit of a visual target; visual area III of the occipital cortex may assist in reflex pursuit movements as well i.

the right parietal eye field is involved in bilaterally directed saccades whereas the left parietal eye field is involved only in contralaterally directed saccades, although lesions or either side cause an ipsilateral gaze preference

c.

supplementary motor cortex (Brodmann area 6): involved in the generation of multi-step saccadic eye movements, and in suppressing unconscious saccades

d.

pathophysiology i.

1 Neuroanatomy

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gaze deviation: oculocephalic/oculocaloric testing determines if the gaze limitation observed during voluntary eye movements can be overcome by involuntary brainstem mechanisms (i.e., the vestibular system); if a gaze palsy can be overcome by oculocephalic/oculocaloric testing, it is caused by a lesions above the brainstem (i.e., a supranuclear gaze palsy)

11. Localizable nystagmus syndromes (Fig. 1–39) 12. Inherited ocular motor disorders a.

Kearns-Sayre syndrome i.

pathophysiology: usually caused by a large deletion in the mitochondrial genome; sporadic inheritance, unlike other mitochondrial diseases (1) number of mitochondria in a cell may be increased as a compensatory reaction to their poor function (2) severity of symptoms is proportionate to the number of affected mitochondria

Vestibular nystagmus

46

Brun’s nystagmus

Figure 1–39 Localizable nystagmus lesions. Other localizable nystagmus includes: Retraction nystagmus → mesencephalon tegmentum; seesaw nystagmus → diencephalon; upbeat nystagmus → medulla lesion; downbeat nystagmus → cervicomedullary junction (i.e., Chiari

Cerebellar nystagmus

malformation); periodic alternating nystagmus → cervicomedullary junction  cerebellum; ocular bobbing → pons. (From Mumenthaler M, Neurological Differential Diagnosis. 2nd ed. Stuttgart, Germany: Georg Thieme; 1992:71–73, Fig. 24a–c,g,i,k,o. Reprinted by permission.)

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symptoms: develops in childhood (1) progressive ophthalmoplegia (2) retinitis pigmentosa (3) sensorineural hearing loss (4) weakness, myalgias, and spasticity (5) mental retardation (6) cardiac arrhythmia; endocrinopathy from hypothalamic dysfunction; short stature

iii. diagnostic testing: muscle biopsy demonstrates ragged red fibers on light microscopy and distorted mitochondria on electron microscopy; cerebrospinal fluid analysis demonstrates increased protein and decreased folate levels iv. b.

treatment: multivitamin supplementation

Leigh’s disease i.

ictal nystagmus

subtypes: usually autosomal recessive inheritance, rarely maternal; due to (1) pyruvate dehydrogenase deficiency (25%): the enzyme normally converts pyruvate to citrate in the Kreb’s cycle, and is located in the mitochondrion

Neuroophthalmology

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(2) cyclooxygenase deficiency (25%) (3) mitochondrial respiratory chain complex I (25%) or V (15%) deficiencies (4) point mutations in the mitochondrial genome (rare) ii.

seesaw nystagmus

histology: necrosis of the basal ganglia and periaqueductal gray

iii. symptoms: onset is usually in infancy; may have a progressive or episodic course (1) apnea, particularly sleep apnea (one of the few causes of central sleep apnea) (2) ophthalmoplegia (mostly with cyclooxygenase deficiency) (3) ataxia; spasticity (4) peripheral neuropathy Heimann-Bielschowsky phenomenon from monocular vision loss

(5) seizures (only with complex V deficiency) (6) retinitis pigmentosa (only with complex V deficiency) iv.

diagnostic testing (1) lactate and pyruvate are elevated only after glucose challenge (2) enyzme and genetic analysis

v.

treatment: carnitine, coenzyme Q10, and B-complex vitamin supplementation

Figure 1–39 (Continued).

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1 Neuroanatomy

Transverse temporal/Heschl’s gyrus and monomodal auditory association area (Brodmann area 42) on the planum temporale

Medial geniculate body

Thalamus

Brachium of the inferior colliculus

Superior olivary nucleus

Inferior Colliculus Anterior cochlear nucleus Pons

Commissure of the inferior colliculus Nucleus of the lateral lemniscus Lateral lemniscus

Cochlear portion of CN VIII Posterior cochlear nucleus

Nucleus of the trapezoid body Posterior acoustic stria

Trapezoid body

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Medulla Figure 1–40 The auditory system. (From Kretschmann HJ, Weinrich W, Neurofunctional Systems. Stuttgart, Germany: Georg Thieme; 1998:56, Fig. 28. Reprinted by permission.)

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XIV. Neurotology A. Auditory System (Fig. 1–40) 1.

End organs: The cochlea and the organ of Corti, which are innervated by the acoustic part of CN VIII (Fig. 1–41)

2.

Superior olivary nucleus: Regulates the stapedius and tensor tympani acoustic reflexes that are activated in response to intense acoustic stimulation; innervation is bilateral, therefore hyperacusis does not occur with pontine lesions (Box 1.23)

3.

stapedius acoustic reflex: acts to dampen the oscillation of the ossicles; fibers are carried by CN VII, which accounts for the hyperacusis of CN VII injury (e.g., Bell’s palsy)

b.

tensor tympani acoustic reflex: acts to increase the tension on the tympanic membrane; fibers are carried by the mandibular branch of CN V. Potentials are used for screening for retrocochlear disease (vestibular schwannoma), for infant hearing screening, and for estimation of auditory thresholds in persons not able to cooperate for behavioral testing (e.g., infants, young children, malingering). The interpretation for retrocochlear diagnosis requires behavioral audiometry

CN VIII also sends cholinergic fibers to the organ of Corti to modulate sensitivity.

Neurotology

a.

Box 1.23

Diagnostic testing: brainstem auditory evoked potentials (BAER) a.

unilateral ear stimulation (e.g., with a click) produces electrical potentials in the central nervous system that can be measured over the brainstem (with a contralateral mastoid or earlobe electrode) and the auditory cortex i.

potentials are labeled sequentially, not according to latency (Fig. 1–42); potentials poorly relate to specific brainstem auditory nuclei (1) potentials I and II correlate with CN VIII (2) potential III is certainly generated within the brainstem

Figure 1–41 The inner ear. (From Duus P, Topical Diagnosis in Neurology. Stuttgart, Germany: Georg Thieme; 1998:115, Fig. 3.35A. Reprinted by permission.)

(3) potential VI is generated in the upper mesencephalon, likely the medial geniculate nucleus

B. Vestibular System 1.

2.

End organs: innervated by the vestibular part of CN VIII a.

semicircular canals: sensitive to angular acceleration; only innervated at the distal enlargements (ampula)

b.

utricle and saccule: sensitive to linear acceleration; only innervated at their maculae

c.

Scarpa’s ganglion: bipolar neurons that form the vestibular part of CN VIII

Vestibular nuclei: located at the pontomedullary junction at the floor of the 4th ventricle a.

subdivisions (Table 1–10) i.

ii.

the medial vestibulospinal tract projects to the contralateral cervical and thoracic spinal cord, and functions in coordination of head and eye positioning the lateral vestibulospinal tract projects to the entire ipsilateral spinal cord, but particularly to the extensor musculature (i.e., for antigravity postures)

Figure 1–42 Brainstem auditory evoked potential and sequential potentials. (From Poser CM et al., The Diagnosis of Multiple Sclerosis. Stuttgart, Germany: Georg Thieme; 1984:121, Fig.1. Reprinted by permission.)

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Table 1–10 Vestibular Nuclei Nucleus

Afferents from Scarpa’s ganglion

Receives cerebellar projections from

Efferents go to

Superior

Semicircular canals

Flocculonodulus, uvula

Ocular motor nuclei*

Medial

Semicircular canals

Flocculonodulus, uvula

Ocular motor nuclei,* cerebellar cortex, medial vestibulospinal tract

Lateral

Utricle

Anterior vermis, fastigial nucleus

Lateral vestibulospinal tract

Inferior

Saccule

Fastigial nucleus

Ocular motor nuclei,* cerebellar cortex, lateral vestibulospinal tract

1 Neuroanatomy

*Includes accessory ocular motor nuclei.

b.

vestibular thalamus: there is no clear target for vestibular inputs, although a thalamic intermediary is very likely

c.

vestibular cortex: vestibular sensation is likely represented in i.

Brodmann area 2v, located adjacent to the inferior edge of the lateral surface of Brodmann area 2 in the parietal lobe

ii.

Brodmann areas 41 and 42, adjacent to the primary auditory cortex in the temporal lobe

C. Neurotology Pathophysiology 1.

Hearing loss a.

conductive hearing loss—occurs with pathological process of the external acoustic meatus or middle ear structures; produces a uniform hearing loss across all frequencies that is usually associated with low-frequency tinnitus; conductive hearing losses are equal in all frequencies or may involve the low frequencies mostly; tinnitus is usually not present, but may be of any perceived frequency i.

b.

sensorineural hearing loss—caused by diseases of the cochlea more commonly than injury to CN VIII; produces hearing loss in the high-frequency ranges, and exhibits decreased sensitivity to low and mid-intensity sounds but increased sensitivity to high-intensity sounds; usually associated with high-frequency tinnitus; there are many patterns of SNHL; flat and high frequency patterns are more common; a low frequency SNHL is characteristic of cochlear hydrops i.

c.

the Rinne test produces a louder sound with bone conduction than with air conduction, and the Weber test lateralizes to the diseased ear

the Rinne test produces a louder sound with air conduction than with bone conduction, and the Weber test lateralizes to the normal ear

treatment i.

glucocorticoids (typically prednisone 1 mg/kg for 7 days) for rapid hearing loss; for sudden sensorineural hearing loss, after otolaryngic and audiologic evaluations

ii.

hearing aids, for either type of hearing loss

iii. corrective surgical procedures for conductive hearing loss 2.

Tinnitus—Associated with some degree of hearing loss in 95% of cases (Box 1.24) a.

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generally tinnitus is only perceived by the affected individual; tinnitus that can be perceived by the examiner usually relates to muscular contractions of the nasopharynx (e.g., palatal myoclonus) or is transmitted from the carotid artery; tinnitus of vascular origin may be due to mild benign intracranial hypertension, primary or metastatic tumors, intracranial or extracranial vascular lesions

Box 1.24 Tinnitus is not the same as otoacoustic emissions, which are sounds that are normally produced by the outer hair cells of the cochlea in response to an auditory stimulus.

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treatment i.

masking sounds (e.g., white noise generators) to interrupt the tinnitus

ii.

hearing aids for hearing loss

iii. antidepressants, alprazolam iv. a.

pure word deafness/auditory agnosia—caused by injury to the dominantside monomodal auditory association cortex i.

reading and writing are intact, therefore it is not an aphasia

ii.

comprehension of nonverbal sounds are intact

b.

impaired ability to understand nonverbal sounds occurs with injury to nondominant monomodal auditory association area

c.

cortical auditory hallucinosis—tend to be formed hallucinations with identifiable sounds, in contrast to pontine auditory hallucinosis i.

4.

biofeedback and stress management

Other abnormalities of hearing

poorly localizes to the superior temporal gyrus in the dominant hemisphere; typically occur in the context of temporal lobe seizures in conjunction with other types of hallucinations (olfactory, gustatory) (Box 1.25)

d.

paracusis—distortions in the perception of timbre, tone, or loudness in the presence of otherwise normal hearing; can occur with lesions anywhere in the temporal lobe

e.

diplacusis—a difference in perception of sound between the two ears that causes a single sound to be heard as two separate sounds; most commonly a cochlear injury

f.

hyperacusis—the perception of abnormal growth of loudness, which typically occurs with loss of outer hair cells, e.g., classic Meniere’s disease (Box 1.26)

Vertigo: Distinguishing central versus peripheral vertigo (Table 1–11) a.

benign paroxysmal positional vertigo (BPPV) i.

Box 1.25 Pontine auditory hallucinosis—Poorly formed sounds that are more complex than just tinnitus (e.g., ringing, buzzing); caused by poorly localized injuries that do not interfere with BAEPs

Neurotology

3.

Box 1.26 Hyperacusis is most commonly caused by injury to the cochlea.

pathophysiology: caused either by movement of free otoliths in a semicircular canal (usually the posterior), or else by accumulations of basophilic material in the cupula of a semicircular canal that cause it to bend when the head is in certain positions; not caused by having the head in any particular position; caused by an angular acceleration in the plane of the semicircular canal that has the lesion

Table 1–11 Central versus Peripheral Vertigo Feature*

Central vertigo

Peripheral vertigo

Hearing loss

Rare

Common

Ocular responses to caloric testing

Symmetric

Asymmetric, except for BPPV

Nystagmus without vertigo

Yes

No

Ataxia without vertigo

Yes

No

Types of nystagmus

Bidirectional; vertical; pure horizontal is common; direction can be variable

Unidirectional, torsional, rarely pure horizontal, consistent direction

Effect of visual fixation on nystagmus

None

Reduces nystagmus

Habituation

No

Yes

*The severity, exacerbation by movement, nausea, and tinnitus are not reliable distinguishing features. Vertigo may occur in isolation with brainstem injuries or in conjunction with only hearing loss due to infarction of the internal auditory artery (a branch of the anterior inferior cerebellar artery). Abbreviation: BPPV, benign paroxysmal positional vertigo.

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(1) 15% of cases develop after head trauma, and 15% develop after viral labyrinthitis (i.e., after a period of more intense vertigo) (2) increased incidence in patients with Meniere’s disease ii.

symptoms: episodes of vertigo lasting  1 minute that are provoked by certain movements (lying down, turning over in bed, flexing or extending the head), although exacerbation by movement is nonspecific for all vertiginous disorders; vertigo typically develops several seconds after the provoking movement (1) episodes tend to be more severe after awakening (2) in the elderly, BPPV may last only a few seconds and be provoked only by head turning

iii. diagnostic testing

1 Neuroanatomy

(1) Dix-Hallpike maneuver: produces  1-minute episodes (typically  15 seconds) of nystagmus with a latency of a few seconds; the nystagmus is predominantly torsional but also has a vertical component (a) sitting upright after the maneuver also causes symptoms and reverses the direction of the nystagmus (b) repeating the maneuver causes acclimation that requires several minutes to fatigue (c) unlike all other causes of vertigo, the nystagmus fast phase is toward the side of the bad ear; the nystagmus is torsional and geotropic, i.e., the upper part of the eye in the fast component beats toward the ground when the affected side of the head is moved into the Dix-Hallpike position (2) caloric testing: normal iv.

treatment (in order of preference) (1) repositioning maneuvers (a) Epley maneuver: improves symptoms in 95% of cases within 1 week; decreases the 6-month recurrence rate to 5% (b) Seamont maneuver: improves symptoms in 90% of cases within 1 month; decreases the 6-month recurrence rate to 5% (2) antiemetics; vestibular suppressants (meclizine, benzodiazepines, amitriptyline) (3) habituation exercises (4) surgical treatments, for medically refractory cases (a) occlusion of the posterior semicircular canal (b) transection of vestibular part of CN VIII as it connects with the posterior semicircular canal

v.

b.

prognosis: episodes typically occur intermittently over a period of several weeks before spontaneously resolving, although BPPV may be a chronic condition in the elderly; without repositioning treatment, 25% resolve within 1 month

Meniere’s disease i.

pathophysiology: may be caused by endolymphatic distention {hydrops} that follows rupture of the membranous labyrinth, which ultimately causes cochlear hair cell death (1) endolymphatic hydrops and cochlear hair cell loss are not always associated with the symptoms of Meniere’s disease, and may also occur after traumatic inner ear injury, labyrinthitis, or syphilis infection (2) obvious cochlear hair cell loss occurs only in advanced Meniere’s disease; such cases also exhibit degeneration of other inner ear structures (e.g., atrophy of the cristae and the tectorial membrane)

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(3) exhibits rare autosomal dominant and recessive inherited forms

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symptoms (1) episodic symptoms (a) tinnitus (generally low-pitched) and fullness in the ear, which sometimes precede the symptoms of vertigo and hearing loss by a few hours (b) vertigo, lasting from 20 minutes to hours (c) sensorineural hearing loss predominantly in the lowfrequency range that resolves over a period of a few hours (2) chronic symptoms (present between episodes) (a) sensorineural hearing loss (low  high frequencies): may actually precede the onset of episodic symptoms (b) mild ataxia late in the disease course; disequilibrium subjectively is more prominent than observable ataxia

iii. diagnostic testing (1) audiometry demonstrates sensorineural hearing loss, characteristically in low frequencies (2) caloric testing sometimes demonstrates a reduced sensitivity of the diseased ear to irrigation in cases of unilateral disease iv.

treatment (1) low-salt diet (2) medical therapy

Neurotology

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(a) episodic treatment: meclizine (Antivert), antiemetics (b) prophylaxis: diuretics (3) surgical therapy for medically refractory cases (a) intratympanic gentamicin (b) selective vestibular nerve section (c) endolymphatic sac procedures: usually decompression or endolymphatic fluid shunting into the mastoid (d) labyrinthectomy, if all hearing is already lost v.

prognosis: 40% will develop some symptoms in the other ear within 5 years, although only 10% will develop the full Meniere’s syndrome in the second ear (1) recurrence of episodes is highly variable and cases often involve periods of remission (2) definitive spells usually end when the hearing loss reaches approximately 70 dB and 50% word recognition

c.

vestibular neuronitis i.

pathophysiology: likely caused by viral infection of the vestibular part of CN VIII, because it occurs in epidemics; associated with mumps, measles, Epstein-Barr, and herpes zoster viruses

ii.

symptoms: continuous vertigo, typically developing after an upper respiratory tract infection and a prodromal period involving the sensation of disequilibrium; does not involve hearing loss (unlike labyrinthitis)

iii. diagnostic testing: caloric testing demonstrates reduced sensitivity of the diseased ear to irrigation

d.

iv.

treatment: meclizine (Antivert) and antiemetics for 2–3 days to weeks, followed by vestibular rehabilitation

v.

prognosis: spontaneous resolution over several days to weeks; rarely recurs, but inducible vertigo may persist for weeks

labyrinthitis i.

pathophysiology: caused by infection of the labyrinth (either bacterial or viral) or by erosion from chronic middle ear inflammation (e.g., from a cholesteatoma)

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1 Neuroanatomy

Table 1–12 Other Diseases Associated with Vertigo Disease

Key features

Vertigo associated with seizures

Vertigo lasts a few seconds. Vertigo is part of an aura, usually with other types of sensations. Usually it is the sensation of linear movement, but may be rotational. Seizures are complex partial with a focus in the superior temporal lobe.

Cervical vertigo

Associated with pain in neck, usually due to trauma. May be caused by position-dependent flow reduction through the vertebral arteries.

Migraine

Adult migraine: 20% have vertigo associated with headaches; 10% report episodic vertigo between headaches. Recurrent episodes of transient vertigo in children may develop into classic migraine. Caloric testing is normal and symmetric.

Head trauma/vestibular concussion

Heterogeneous group of ill-defined central and peripheral disorders. Often related to for temporal bone fractures.

ii.

symptoms (1) continuous vertigo, which is exacerbated by sneezing or the Valsalva maneuver (likely because of the development of a perilymph fistula) (2) severe sensorineural hearing loss (3) occasional meningitis-like symptoms

iii. diagnostic testing: temporal bone CT demonstrates bone erosion, mastoiditis, or abscesses; lumbar puncture to evaluate for meningitis iv.

treatment (1) medical: antibiotics for an identifiable infection (2) surgical: myringotomy or mastoidectomy for abscess drainage; removal of middle ear masses

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e.

medications causing vertigo: aminoglycosides, antiepileptics, antihypertensives, sedatives

f.

other diseases associated with vertigo (Table 1–12)

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2 Vascular Diseases of the Nervous System Note: Significant diseases are indicated in bold and syndromes in italics.

1.

2.

3.

Ischemic Stroke

I. Ischemic Stroke Subtypes: considering all ischemic strokes a.

30% are likely due to small artery occlusion

b.

30% are likely due to large artery thromboembolism

c.

20% are likely due to cardioembolism

d.

20% are due to other mechanisms or are cryptogenic

Epidemiology: ischemic stroke accounts for 80% of all strokes a.

age: the most predictive factor for stroke

b.

sex: male predominant disease until age  75

c.

race: Blacks and Hispanics have higher stroke rates

Risk factors: identification of a risk factor that may have caused the stroke (e.g., atrial fibrillation) does not obviate the need to evaluate the patient for other possible risk factors a.

previous stroke, either clinical or radiographic

b.

transient ischemic attack (TIA): 10% 90-day stroke risk, and 25% 90-day risk of TIA, stroke, or myocardial infarction i.

stroke risk is highest within 24–48 hours of TIA, which supports the recommendation of hospital admission and aggressive evaluation of TIA patients

c.

intracranial atherosclerosis: 7%/year stroke risk; higher incidence in Blacks, Asians, and Hispanics

d.

hypertension: systolic pressures  140 mmHg and diastolic pressures  90 mm Hg are independent risk factors for stroke, and stroke risk is proportionate to the degree of hypertension

e.

carotid stenosis: the degree of stenosis is proportionate to stroke risk in both symptomatic and asymptomatic patients

f.

heart disease (Box 2.1) i.

atrial fibrillation (1) overall stroke risk  6%/year; stroke risk is higher in chronic atrial fibrillation or atrial fibrillation due to thyroid disease (a) 1%/year stroke risk in patients  65 years old without other risk factors (can be treated with aspirin if need be)

Box 2.1 Cardiovascular Procedure Stroke Risks ✧ Angiography  1% ✧ Coronary artery bypass graft  2% ✧ Thoracic aorta operation  7% (higher

incidence in emergent operations)

(b) 7–18%/year stroke risk in patients with at least one other stroke risk factor (must use Coumadin) (2) stroke risk is highest at the time of onset of atrial fibrillation; conversion to sinus rhythm without anticoagulation is also high risk (3) atrial enlargement without fibrillation is also a stroke risk factor ii.

congestive heart failure: stroke risk  4%/year

iii. myocardial infarction: wall motion abnormalities (particularly of the anterior wall) allow intracardiac thrombus formation that is a source of emboli

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valve abnormalities (stenosis, calcification, valve replacement) or the presence of coagulant material adherent to a valve (echogenic “strands”) (1) mitral valve prolapse is unlikely to be a cause of stroke (2) stroke risk for mechanical valves is greater than for bioprosthetic valves

2 Vascular Diseases of the Nervous System

v.

patent foramen ovale: may allow a paradoxical embolism from the systemic venous system (e.g., a deep venous thrombosis) causing stroke (1) patent foramen ovale is not conclusively a risk factor for stroke, although it is a risk factor when it is associated with an atrial septal aneurysm (2) a patent foramen ovale is present in 20% of the general population

g.

aortic arch calcifications and atheroma, particularly if  4-mm thick or mobile

h.

cigarette smoking: stroke risk is proportionate to the amount of smoking; after cessation, the stroke risk reduces to nonsmoker’s level within 3 years i.

i.

in addition to promoting atherosclerosis, cigarette smoking increases fibrinogen levels leading to a hypercoagulable state

dyslipidemia i.

low-density lipoprotein (LDL)  100 mg/dL, although the benefit of treating an LDL between 100–130 mg/dL in patients without other risk factors is unknown

ii.

high-density lipoprotein (HDL)  40 mg/dL

iii. triglycerides  200 mg/dL j.

elevated homocysteine level: risk is proportionate to level, starting at  10 mol/L

k.

diabetes: a risk factor for all types of stroke, yet adequate glycemic control is known to reduce small vessel complications (e.g., retinopathy, nephropathy) but not large vessel complications

l.

alcohol use: heavy use ( 4 drinks/day) has an inconsistent association with stroke that may be race dependent; low-to-moderate use (1–2 drinks/day) may reduce the risk for stroke, likely by improving the lipid profile

m. estrogen use i.

contraceptives: high-dose estrogen ( 50 g) contraceptives increase stroke risk likely because they increase blood coagulability and blood pressure; lower dose estrogen contraceptives may also increase stroke risk (1) increased stroke risk is most marked in women  35 years old who smoke (2) oral or injectable progesterone-only contraceptives have no apparent effect on stroke risk on their own, but may increase stroke risk in women with hypertension

ii. n. 4.

life-style factors: obesity, physical inactivity, diet, and psychological stress all are likely covariates with other risk factors

Symptoms: Focal neurological deficits, by definition  24 hours in duration for stroke and  24 hours in duration for TIA, although most TIAs last  15 minutes; speed of onset is generally considered to be acute, however rarely may develop over hours or days a.

headache: occurs in 40% of strokes; often stroke is preceded by a sentinel headache i.

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hormone replacement therapy: estrogen plus progesterone replacement therapy increases stroke risk in postmenopausal women

headache is likely related to ischemia of the blood vessels or the meninges (Box 2.2)

Box 2.2 Only the proximal few centimeters of the named arteries are pain-sensitive.

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seizure occurring concurrently with the stroke (6%) i.

5.

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risk of developing epilepsy is greater if the first seizure occurs  2 weeks after the stroke

Diagnostic testing a.

infarction (Fig. 2–1) i.

computerized tomography: acute infarction may be identified by hypodensities at the interface of the gray and white matter (e.g., the insula and extreme capsule, the basal ganglia, and internal capsule) or by sulcal effacement (Fig. 2–2); however, a CT scan within the first 3 hours is often normal

ii.

magnetic resonance imaging (MRI): diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) mapping identify  90% of acute infarctions (Fig. 2–3)

Ischemic Stroke

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(1) DWI: a T2-like sequence that increases signal strength in areas where water molecules are not free to diffuse in the local environment (a) during infarction, the failure of membrane ion transports may prevent transmembrane water movement and cause cellular swelling (e.g., cytotoxic edema) that reduces the extracellular space, thereby limiting the diffusion of water (2) ADC: a calculated value that essentially accounts for any underlying increase in T2 signal (e.g., from vasogenic edema, as caused by tumors or inflammation) by subtracting the T2 signal from the DWI signal

Figure 2–1 Schematic of the arterial territories of the brain. (From Duus P. Topical Diagnosis in Neurology. Stuttgart, Germany: Georg Thieme; 1998:309, Fig. 8.39. Reprinted by permission.)

(3) an increase in T2 signal and a decrease in T1 signal indicate tissue loss, and are not considered accurate for identifying infarction within 8 hours of onset iii. hemorrhagic conversion of an ischemic infarction occurs in 20% by 3-weeks poststroke (1) typically develops in a gyral pattern (2) clinical deterioration tends to occur when the hemorrhage is  30% of the infarcted area or when it exhibits mass effect b. c.

TIA:  40% exhibit neuroanatomically relevant DWI and ADC changes despite symptomatic resolution carotid artery stenosis (Fig. 2–4) i.

for the purpose of identifying endarterectomy candidates, cerebral angiography should be used, although computed tomography angiography (CTA) provides essentially the same measures (1) when not using angiography, carotid Doppler ultrasound and magnetic resonance angiography (MRA) are usually used together because either alone can overestimate the degree of stenosis in comparison with angiography

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2 Vascular Diseases of the Nervous System

d.

e.

6.

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cardiac abnormalities: echocardiography may identify intracardiac thrombi and coagulated material (blood sludging, “spontaneous echo contrast,” “smoke”) i.

transesophageal echocardiography (TEE) is better than transthoracic echocardiography (TTE) specifically for left atrial appendage, septal abnormalities (e.g., patent foramen ovale), and aortic abnormalities; TEE also has a higher accuracy for overall detection of cardiac abnormalities when compared with TTE

ii.

paradoxical embolism: evaluation for right-left shunt requires intravenous bubble contrast or Doppler echocardiography or transcranial Doppler ultrasound study

serologies i.

for patients  45 years old: evaluation of risk factors; when suspecting temporal arteritis in patients  50 years old include sedimentation rate and C-reactive protein serologies

ii.

for patients  45 years old: evaluation of risk factors, as per older patients; consider evaluation for antiphospholipid antibodies, coagulation cascade disorders, and inherited stroke disorders

Treatment a.

acute setting i.

thrombolytic treatments

Figure 2–2 Early ischemic infarction demonstrating loss of gray-white differentiation in the right hemisphere, particularly around the basal ganglia. (From McKhann GM et al. Q&A Color Review of Clinical Neurology and Neurosurgery. Stuttgart, Germany: Georg Thieme; 2003:45, Fig. 36b. Reprinted by permission.)

(1) tissue plasminogen activator (tPA): if given by IV within 3 hours from the time the patient was last known to be normal; relative risk reduction for disability at 3 months  30% (a) exclusion criteria (i)

absolute 1.

occurrence of a seizure at the time of presentation

2.

history of any intracranial hemorrhage or of a known vascular malformation, evidence of intracranial hemorrhage on CT, or clinical suspicion of intracranial hemorrhage irrespective of CT findings

3.

active internal bleeding or arterial puncture at a noncompressible site within the preceding 7 days

4.

gastrointestinal or urinary tract hemorrhage within 3 weeks

5.

any neurosurgical procedure, major head trauma, or stroke within 3 months

6.

blood pressure consistently  185/110 mmHg or that requires aggressive management to reduce to that level

7.

blood glucose  50 or  400 mg/dL

8.

abnormal prothrombin time or partial thromboplastin time; platelet count  100,000

(ii) relative: age  18; possibility of endocarditis or pericarditis; recent lumbar puncture; rapidly improving condition; obtundation or coma (b) complications: 6% intracranial hemorrhage risk, proportionate to neurological impairment and infarct size but not to early CT findings of infarction

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Figure 2–3 Time course of the change in diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) mapping after cerebral infarction.

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Ischemic Stroke

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A

B

Figure 2–4 (A) Measurement of carotid stenosis (arrow in the angiogram image) according to the NASCET criteria. The minimal lumen diameter is divided by the diameter of the distal ICA where the walls become parallel to avoid any poststenosis dilatation (B). (From McKhann GM et al. Q&A Color Review of Clinical Neurology and Neurosurgery. Stuttgart, Germany: Georg Thieme; 2003:67, Fig. 59 and Loftus CM and Kresowik TF. Carotid Artery Surgery. Stuttgart, Germany: Georg Thieme; 2000:28, Fig. 2-18. Reprinted by permission.)

(2) intraarterial prourokinase: relative risk reduction for disability of 35% at 3 months in patients with MCA occlusion when administered within 6 hours of symptomatic onset; t-PA has been substituted for prourokinase (which is not FDA-approved) and intraarterial thrombolytics have been used for occlusion of other major arteries, but without proof of efficacy (a) 10% risk of intracranial hemorrhage ii.

carotid endarterectomy: may be performed on an urgent basis in patients with TIAs that are referable to a severe stenosis

iii. anticoagulation and antiplatelet drugs (Fig. 2–5) (1) aspirin: given acutely, relative risk reduction of recurrent stroke within 14 days  30%; also has small benefit in terms of mortality (a) do not give aspirin (or other antiplatelet or anticoagulant agents) within 24 hours of thrombolytic administration (2) heparin: reduces stroke recurrence but increases hemorrhage rate, therefore does not influence overall outcome when given in the acute setting (a) sometimes given in cases with suspected cardiac sources of embolization until Coumadin can achieve clinical effectiveness iv.

blood pressure management: elevated blood pressures following a stroke are associated with better outcomes, thus hypertension is usually left untreated 2–3 days poststroke unless systolic blood pressure (SBP)  220, diastolic blood pressure (DBP)  130, or mean arterial pressure (MAP)  130 mmHg (1) avoid using clonidine or diazoxide because they reduce cerebral blood flow (2) blood pressure typically begins to fall on its own after 3–4 days

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Figure 2–5 The coagulation cascade and sites of anticoagulant action.

v.

hyperglycemia management: elevated blood glucose is associated with worsened outcomes in stroke patients irrespective of the patient’s diabetic status

vi. seizure prophylaxis: no indication in the absence of a seizure (1) with a single seizure occurring less than 2 weeks from the time of stroke, treat with antiepileptics for 3–6 months before considering discontinuation (low risk of epilepsy) (2) for a single seizure  2 weeks from the time of stroke or for multiple seizures, treat for 2–3 years before considering discontinuation (high risk of epilepsy) b.

subacute to chronic setting, and preventative measures i.

deep vein thrombosis (DVT) prophylaxis, as stroke patients are at particularly high risk for DVTs

ii.

evaluation for cardiac ischemia, although large strokes cause transient ischemic-like EKG changes

iii. control of intracranial pressure: edema is maximal 3–5 days after large strokes, although it may be asymptomatic iv.

anticoagulation and antiplatelet drugs (1) aspirin: relative risk reduction for recurrent stroke  25% with 75–325 mg qd (once daily) (a) irreversibly inhibits cyclooxygenase production of thromboxane that causes platelet aggregation, but also inhibits vasodilatory prostacyclin production (b) low-dose (e.g., 81 mg qd) or enteric-coated aspirin will inhibit platelet aggregation in only 40% of patients, in comparison with 70% of patients taking higher doses or uncoated aspirin

60

(2) dipyridamole  aspirin (Aggrenox): modestly better than aspirin alone (relative risk reduction for stroke  30%); high side-effect rate, particularly headaches

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Table 2–1 Uses of Coumadin in Stroke Prevention

Established

Coumadin is better than aspirin

Aspirin can be sufficient

Intracardiac thrombus Artificial heart valve

Atrial fibrillation without other stroke risk factors {lone atrial fibrillation}

Atrial fibrillation with other stroke risk factors Limited evidence

Significant aortic plaque

Patients at risk for bleeding (e.g., fall risk)

Large areas of cardiac hypokinesis

(3) ticlopidine (Ticlid): relative risk reduction for stroke  25%; used in patients who cannot tolerate aspirin, but has a high side-effect rate (diarrhea, neutropenia [1%], thrombotic thrombocytopenic purpura) (a) reduces platelet aggregation through a poorly understood mechanism (4) clopidogrel (Plavix): equivalent efficacy against stroke in comparison with aspirin; benefit of clopidogrel over aspirin is its superior protection against myocardial infarction (a) reduces platelet aggregation by blocking ADP binding to adenosine receptors

Ischemic Stroke

(a) dipyridamole reduces platelet aggregation by inhibiting cAMP-phosphodiesterase and by blocking adenosine reuptake

(b) same side-effect profile as ticlopidine; fewer hemorrhagic side-effects in comparison with aspirin (5) Coumadin: 67% stroke risk reduction of stroke from atrial fibrillation when international normalized ratio (INR) is 2.0–3.0 (Table 2–1) (a) for mechanical heart valves, target INR 3.0–4.0; for bioprosthetic heart valve, target INR 2.0–3.0 (b) side effects (i)

hemorrhage (usually gastrointestinal)  7%/year with INR  3.0; hemorrhage risk increases with age  80 years old

(ii) skin necrosis, usually occurring at the initiation of Coumadin therapy (rare) (iii) blue toe syndrome: ischemia of the extremities caused by embolization of cardiac material (6) heparin: no proven benefit in stroke management; used commonly as a bridge to Coumadin therapy and for temporary management of unstable major artery stenosis prior to surgical or endovascular intervention (a) side effects: syndromes (i)

heparin-induced

thrombocytopenia

(HIT)

type I HIT: develops  5 days after starting treatment and is clinically benign; heparin causes platelet aggregation, thereby increasing blood viscosity

(ii) type II HIT: develops 1–2 weeks after starting treatment and is associated with arterial and venous thromboses; heparin-induced autoantibodies cause thrombocytopenia but also a paradoxical hypercoagulable state v.

blood pressure management: reduction to a blood pressure  140/90 mmHg or as low as is tolerated (1) dietary modification and salt restriction, exercise, and reduction in alcohol consumption should be attempted in conjunction with medication treatment

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(2) unclear benefit of any particular antihypertensive agent, although first-line recommendations remain angiotensin converting enzyme (ACE) inhibitors or diuretic agents; effectiveness of specific drugs may be related primarily to the degree of blood pressure reduction they achieve

2 Vascular Diseases of the Nervous System

(3) treat isolated systolic or diastolic hypertension vi. dyslipidemia management: as with hypertension treatment, the particular drug may not be as important as the degree of lipid lowering that it achieves (1) HMG-CoA reductase inhibitors/statin agents: relative-risk reduction for recurrent stroke  25% (a) have demonstrated ability to reduce arterial plaque size over time, and may have particular benefit in stroke prophylaxis in cases where aortic plaque is a suspected source of embolization (2) other agents (clofibrate, cholestyramine, gemfibrozil, niacin) and dietary modification generally do not lower lipid levels as much as statin agents vii. homocysteine reduction: reduction with vitamin therapy (i.e., vitamin B1  vitamin B12  folate) has an unclear effect on recurrent stroke prophylaxis, but reduction is certainly beneficial in inherited disorders of homocysteine metabolism (see p. 72) viii. control of hyperglycemia: no proven benefit in stroke prevention; considerable evidence exists that small-vessel disease in other organs (e.g., retinopathy, nephropathy) is reduced with strict glycemic control ix. carotid endarterectomy (Box 2.3) (1) in some studies, asymptomatic stenosis of 60–99% has a 55% relative risk reduction for stroke if operative mortality  3% and if the patient has a 5-year life expectancy; untreated stroke risk of asymptomatic stenosis is 1%/year (2) symptomatic stenosis of 70–99% has a 65% relative risk reduction for stroke if operative mortality  6% and if the patient has a 5-year life expectancy (a) untreated stroke risk of symptomatic stenosis is 13%/year (b) benefit of surgery persists for only less than 1 year after stroke or TIA, therefore surgery is best done as soon as possible after a stroke (usually within 4–6 weeks) (c) 50–70% symptomatic stenosis may also benefit from surgery in (i)

male patients

(ii) conjunction with plaque ulceration (iii) cases involving nonlacunar hemispheric stroke or TIA (d) endovascular stenting appears as effective as endarterectomy, with a greater restenosis rate but fewer procedural complications

II. Subarachnoid Hemorrhage 1.

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Causes a.

aneurysms: account for 80% of all nontraumatic subarachnoid hemorrhage (SAH)

b.

other vascular malformations: arteriovenous malformations (AVM); moyamoya disease

c.

head trauma: the most common cause of SAH

d.

venous or capillary bleeding into the prepontine; and/or ambient cisterns {perimesencephalic hemorrhage}; not associated with aneurysms

e.

venous thrombosis

Box 2.3 There is no proven treatment for completely occluded (i.e., 100%) carotid stenosis.

2.

3.

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Risk factors: as per aneurysms (see p. 77), but also a.

hypertension

b.

coagulopathy/anticoagulant use

c.

smoking

d.

drug use, particularly cocaine and amphetamines: suspecting drug abuse as the cause of SAH does not eliminate the need to search for a vascular malformation

e.

estrogen use: high-dose preparations (e.g., birth control pills) may increased SAH risk; no effect of hormone replacement therapy

Epidemiology: accounts for  10% of all strokes a.

4.

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exhibits a familial tendency that is likely related to an inherited predisposition to aneurysm formation

Symptoms: pronounced headache, nausea, and stupor  focal neurological deficits; severity of nonfocal symptoms in SAH is generally greater than in intracranial hemorrhage a.

seizure at the time of SAH (5%)

b.

vision loss may be due to intracranial focal injury or to simultaneous retinal hemorrhage {Terson’s hemorrhage}

c.

mild nonfocal symptoms often occur with small SAH {sentinel hemorrhage}

Diagnostic testing (Box 2.4) a.

neuroimaging: CT to determine Fisher grade of SAH and any hydrocephalus i.

thick blood layer or clot in subarachnoid space (Fisher grade III) is associated with vasospasm

ii.

intraventricular blood (Fisher grade IV) is associated with noncommunicating hydrocephalus (Box 2.5)

Box 2.4 Fisher Scale for SAH Using CT

Subarachnoid Hemorrhage

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1–No blood detected 2–Diffuse or thin blood 3–Clot or thick layer 4–Intraparenchymal or intraventricular blood  subarachnoid hemorrhage

iii. SAH can extend into the brain parenchyma (Fisher grade 4) iv.

CT identifies only  95% of SAH cases within the first 24 hours, therefore must evaluate for nonclearing hemorrhagic cerebrospinal fluid and xanthochromia if suspicion of SAH is high (see p. 35) (1) cerebrospinal fluid xanthochromia is present in 70% of SAH cases within 6 hours and in 90% within 12 hours of SAH, but is rarely present within 2 hours of SAH

b.

Box 2.5 Subarachnoid hemorrhage may also cause communicating hydrocephalus by direct obstruction of arachnoid granulations.

angiography, either conventional or CT angiography: MRA detects only  70% of aneurysms and has high false-positive rate in the MCA and ACA territories i.

angiography is negative for aneurysms in 20% of SAH cases, probably because the aneurysm is hidden by the blood clot; therefore, if the first angiogram is negative, repeat it after 2–3 weeks (1) 50% of angiography-negative SAH is perimesencephalic hemorrhage (a) if distribution of blood is typical of perimesencephalic hemorrhage and the first angiogram is negative, do not repeat the angiogram because there is low yield and good prognosis of the condition

ii. 6.

angiography demonstrates early venous drainage through AVMs, but associated aneurysms may be hidden in the AVM nidus

Treatment a.

acute treatment i.

blood pressure management: with an untreated aneurysm, reduce blood pressure to premorbid levels or to a MAP  130 mmHg while keeping cerebral perfusion pressure  70 mmHg (1) “controlled” (e.g., clipped or coiled) aneurysms allow for aggressive use of hypervolemic–hypertensive–hemodilution (“triple H”) therapy for vasospasm

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reverse coagulopathy (1) for patients on Coumadin, use (a) 2–3 units fresh-frozen plasma; titrate to normalization of coagulation measures, which may require up to 6 units

2 Vascular Diseases of the Nervous System

(b) vitamin K 10 mg intramuscularly: takes 12 hours to have any effect (2) for patients on heparin, use protamine 1 mg/100 units of heparin administered iii. control of intracranial pressure and acute hydrocephalus: place ventriculostomy to measure and control intracranial pressure so as to maintain cerebral perfusion pressure  70 mmHg; removal of bloody cerebrospinal fluid may also reduce the risk of vasospasm iv.

surgery (1) timing of surgery: after aneurysmal SAH, the rebleeding rate is 20% in first week without controlling the aneurysm; the rebleeding rate for AVMs is only 6%/year (a) early surgery (in  3 days) for aneurysmal SAH lowers the risk of rebleeding, but increases the risk of iatrogenic brain injury; generally reserved for patients exhibiting at most focal neurological deficits and lethargy (b) late surgery (in  10 days) for aneurysmal SAH allows for stabilization of the patient’s clinical condition and reduction of tissue swelling for better surgical access; generally chosen for stuporous or comatose patients

b.

preventative treatments i.

surgical treatment of unruptured aneurysms: the decision to surgically treat an unruptured aneurysm is made by comparing the cumulative rate of aneurysm rupture against the expected surgical morbidity and mortality (typically  15%) (1) rehemorrhage from  10-mm aneurysms: 0.05%/year unruptured; 0.5%/year ruptured (2) rehemorrhage from 10–25-mm aneurysms: 1%/year unruptured or ruptured (3) rehemorrhage from  25-mm aneurysms: 6%/year unruptured

ii.

surgical treatment of unruptured AVMs: rupture risk is only 3%; risk is higher in AVMs that are small (due to concentrated exposure of the nidus to the high pressure of the feeding artery), that are associated with aneurysms, and that have limited venous drainage (1) as with aneurysms, the risk of SAH must be balanced against the risk of surgical intervention, which is increased by the size of the AVM, its location in eloquent cortex, and its involvement of deep venous drainage (2) may use endovascular treatment and/or stereotactic radiosurgery when craniotomy is not feasible, or in combination with partial surgical resection (3) the treatment must completely destroy the AVM; residual AVM has a high risk of hemorrhage and can regrow

iii. reduction of hypertension, including isolated systolic or diastolic hypertension iv. 7.

Complications of SAH a.

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avoid use of anticoagulation but not necessarily antiplatelet agents

vasospasm: a focal arterial constriction possibly related to a loss of vasodilatory substances (e.g., nitric oxide, which is bound by hemoglobin), the release of vasoconstrictive compounds (e.g., endothelins, prostaglandins), and/or a proliferative vascular reaction i.

period of highest risk is 4–7 days post-SAH, but vasospasm may occur up to 3 weeks post-SAH

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symptomatic effects of vasospasm may be focal or diffuse (i.e., encephalopathy-like)

iii. diagnostic testing: screen patients for vasospasm with daily transcranial Doppler ultrasonography to detect increased flow velocities in major arteries (1) ultrasound flow velocities are artificially increased by a low pCO2 or hematocrit (2) confirm ultrasonographic findings as vasospasm with cerebral angiography iv.

treatment/prophylaxis

Intracranial Hemorrhage

(1) nimodipine 60 mg PO q4h for 21 days beginning immediately after SAH (a) may have direct protective effect on the brain because it does not have much effect on vascular caliber (2) hypervolemic–hypertensive–hemodilution (“triple H”) therapy has no proven benefit, but is standard-of-care (3) intraarterial papaverine or angioplasty of the vasospastic artery segments has no established benefit b.

hydrocephalus: treat with intraventricular shunt; intraventricular thrombolytics may be used with clipped aneurysms to clear the subarachnoid blood clot

c.

hyponatremia: caused by natriuresis from excessive sympathetic activity (i.e., cerebral salt wasting (see p. 16)), rarely by syndrome of inappropriate antidiuretic hormone (SIADH)

d.

cardiac arrhythmias and ischemic-like EKG changes due to increased sympathetic activity

e.

seizures: prophylaxis is commonly used in the acute setting, but there is no evidence that it prevents the development of epilepsy

III. Intracranial Hemorrhage 1.

Pathophysiology: hemorrhage within the brain parenchyma that separates tissue planes, forming a well-demarcated hematoma; intracranial hemorrhages (ICHs) are located more often in the putamen than in the cortex, thalamus, cerebellum, or pons a.

ICHs from large vessel disease are rare and generally are from rupture of an AVM or extension of SAH into the brain parenchyma (Fisher grade 4 SAH)

b.

ICH from small vessel disease is usually related to i.

hypertensive angiopathy—breakdown of the blood–brain barrier in arterioles of chronic hypertensive patients leads to deposition of plasma proteins in the tunica media, inflammatory degeneration of the smooth muscle, and endothelial hypertrophy {lipohyalinosis}; affected arterioles usually also exhibit atherosclerotic changes (1) many arteriolar microaneurysms {Charcot–Bouchard aneurysms} are likely coils of small arterioles, but aneurysmal dilation of severely hyalinized arterioles do occur; however, ICH does not necessarily occur by rupture of a microaneurysm

ii.

amyloid angiopathy—develops when fibrillary proteins form a -pleated sheet conformation that deposits in the walls of arterioles as amyloid, causing wall thickening and lumen narrowing; amyloid deposits can extend into the surrounding perivascular tissue, resembling senile plaques of Alzheimer’s disease (1) histology: similar to lipohyalinosis except that amyloid angiopathy is congophilic (i.e., exhibits apple green birefringence after Congo red staining) whereas lipohyalinosis is eosinophilic (i.e., stains with hematoxylin) (2) ICH from amyloid angiopathy often extends into a SAH because of the cortical location of the ICH (Box 2.6)

Box 2.6 Other Symptoms of Amyloidosis ✧ Dementia, either from multiple infarcts

or from coincident Alzheimer’s disease ✧ Peripheral neuropathy (e.g., carpel

tunnel syndrome) ✧ Renal failure, heart failure, purpura,

macroglossia

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(3) genetics: most cases are sporadic and involve the amyloid precursor protein (APP; i.e., the A1–42 protein) that is found in senile plaques of Alzheimer’s disease (a) rare hereditary forms of amyloid angiopathy (i)

(ii) Dutch-type amyloid angiopathy—mutations in APP that cause accumulation as amyloid; causes fatal ICH by 40 years of age (iii) mutations of transthyretin, the thyroxine (T4) carrier protein 2.

3.

4.

Other risk factors a.

coagulopathy/anticoagulant use: risk of ICH is particularly increased with INR  3

b.

drug use (amphetamines, cocaine): tend to cause ICH in cortex; administration by IV is more prone to cause ICH than other routes

c.

alcohol use, which is linearly related with the risk of ICH

d.

hyperperfusion states (e.g., after carotid endarterectomy)

e.

brain tumor, either primary (e.g., high-grade astrocytomas, pituitary adenoma) or metastatic (e.g., lymphoma, choriocarcinoma, melanoma)

f.

apolipoprotein E 2 and 4 alleles

a.

headache (30%)

b.

seizures: occur in 30% with lobar hemorrhage, but only 5% with subcortical hemorrhage

Diagnostic testing: neuroimaging may demonstrate some enlargement of the ICH within the first 12 hours; generally, the hemorrhage is a monophasic event MRI signal characteristics of ICH (Fig. 2–6) as an incidental finding i.

5.

Figure 2–6 Stages of blood aging on magnetic resonance image scans. (A) Acute:  48 hours. (B) Early subacute: 3–7 days. (C) Late subacute: 7–10 days. (D) Chronic:  14 days. (From Tsementis SA. Differential Diagnosis in Neurology and Neurosurgery. Stuttgart, Germany: Georg Thieme; 2000:42, Fig. 4. Reprinted by permission.)

Symptoms: focal neurological deficits, often resembling ischemic infarction; symptoms are always persistent, that is, never appearing as a TIA

a.

small spots (1–2 mm) of decreased T2 signal are suggestive of microhemorrhages, which are typically observed in amyloid angiopathy (Fig. 2–7)

Treatment a.

66

Icelandic-type amyloid angiopathy—mutations of cystatin C, a protease inhibitor that accumulates as amyloid when mutated; causes fatal ICH by 20–30 years of age

acute treatment i.

medical: reduce blood pressure to premorbid levels or keep the MAP  130 mmHg with cerebral perfusion pressure  70 mmHg if premorbid blood pressure is unknown; reverse coagulopathy

ii.

surgery: first-line treatment for cerebellar ICH  3 cm or in patients exhibiting clinical deterioration; otherwise surgery is only reasonable for expanding ICH in the nondominant hemisphere with simultaneous worsening of the patient’s clinical condition

Figure 2–7 Microhemorrhages demonstrated on T2 magnetic resonance image as multiple punctate areas of decreased signal.

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(1) more favorable locations for surgery are in the putamen, frontal cortex, and temporal cortex b.

chronic and preventative treatment: control of hypertension; avoidance of anticoagulants i.

patients with a history of ICH are more likely to have another ICH than an ischemic infarction

IV. Inherited Stroke Disorders CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) a.

pathophysiology: caused by autosomal dominant mutations of the Notch 3 gene on chromosome 19, the protein of which acts as a cell–cell adhesion molecule with nuclear transcription regulatory properties i.

transcription-regulatory properties require cleavage of the protein by -secretase and transport to the nucleus (Box 2.7)

ii.

Notch 3 protein binds the delta ligand on other cells

iii. Notch 3 gene is located very close to the CACNL1A4 gene, which is mutated in familial hemiplegic migraines b.

c.

histology: fibrosis of the tunica adventitia and granular deposits in the tunica media that develop in arteries of 100–400 m in diameter (i.e., penetrating arteries) i.

deposits are of an unknown composition that is not amyloid

ii.

deposits surround the smooth muscle cells, and also occur in muscle and skin arteries in some patients

Box 2.7 -secretase also cleaves amyloid precursor protein (APP) into A1–42 in Alzheimer’s disease.

Inherited Stroke Disorders

1.

symptoms: onset between 30–50 years of age i.

recurrent lacunar stroke and TIA, sparing the cortex

ii.

dementia (30%): usually develops more than 10 years after the first stroke from a combination of multiple strokes (i.e., a vascular dementia) and progressive leukoencephalopathy

iii. migraine with aura (25%): does not develop in childhood like other migraines, and typically involves fever and/or stupor {confusional migraine} iv. d.

mood disorders: develop early in the disease course

diagnostic testing i.

gene testing

ii.

MRI demonstrates (1) patchy and diffuse T2 signal increases in the white matter that spares subcortical U fibers (2) multiple small subcortical infarcts that are occasionally hemorrhagic

2.

MELAS (Mitochondrial Encephalomyopathy with Lactic Acidosis and Strokes) a.

pathophysiology: caused by point mutations in a tRNA encoded by the mitochondrial genome; exhibits maternal inheritance i.

b.

highly variable penetrance dependent on the number of affected mitochondria

symptoms: usually presents in childhood i.

stroke, particularly in the occipital region and frequently in a distribution that is not defined by a single artery

ii.

migraine, often occurring at the time of a stroke

iii. vision loss from retinopathy; sensorineural hearing loss iv.

diffuse weakness from myopathy

v.

seizures and dementia, which develop during adolescence

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A

B Figure 2–8 Ragged red muscle on biopsy. Some muscle fibers exhibit internal accumulations of dense material that represent mitochondria (A). Under EM, mitochondria in an area of proliferation exhibit paracrystalline inclusions (B). (From Sladky JT. Histopathological features of peripheral nerve and muscle in mitochondrial disease. Semin Neurol 2001:21, 296, Fig. 1; 298, Fig. 3. Reprinted by permission.)

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c.

diagnostic testing: lactic acidosis; ragged red fibers on muscle biopsy (Fig. 2–8)

d.

treatment: B-complex vitamins  niacin  coenzyme Q10; dichloroacetate

V. Special Stroke Conditions Endocarditis a.

b.

marantic endocarditis—caused by the hypercoagulable state associated with chronic disseminated intravascular coagulation, AIDS, mucinsecreting tumors, or lupus (i.e., Libman–Sacks endocarditis) i.

diagnostic testing: transesophageal echocardiography demonstrates multiple vegetations  3-mm diameter on the aortic and mitral valves

ii.

treatment: anticoagulation; treatment of the underlying causative condition

infectious endocarditis—causative organisms are Streptococcus viridans, Staphylococcus aureus, Enterococcus  HACEK organisms (Haemophilus, Acinteobacillus, Cardiobacterium, Eikenella, Kingella), fungi i.

risk factors include IV drug abuse (usually causes right-sided endocarditis) and cardiac abnormalities (e.g., artificial heart valves)

ii.

infectious endocarditis leads to an infectious arteritis that progresses to

Special Stroke Conditions

1.

(1) mycotic aneurysm formation on the distal superficial cerebral arteries (2) microabscess formation (3) meningoencephalitis iii. symptoms (1) stroke: occurs in 10% of infectious endocarditis cases; 75% of strokes are ischemic, 25% are hemorrhagic (2) cerebral abscess and empyema formation (3) bacteremia/fungemia (4) peripheral emboli: painless lesions of the palms and soles { Janeway lesions}, septic pulmonary infarcts; conjunctival hemorrhages; multiple retinal hemorrhages {Roth spots} (a) not a reliable finding in acute bacterial endocarditis (5) immunological reactions: glomerulonephritis; painful nodules in the fingers and toes {Osler’s nodes} (6) new cardiac murmur; valvular destruction that can progress to heart failure iv.

diagnostic testing (1) echocardiography: demonstrates intracardiac mass, abscess, or new valvular regurgitation (2) blood cultures: identification of the causative organism may require three sets of blood cultures prior to antibiotic administration (3) angiography: may use MRA and CT angiography to detect mycotic aneurysms, and cerebral angiography to confirm their location

v.

treatment: broad-spectrum antibiotics and antifungals initiated immediately after obtaining blood cultures, and adjusted to the sensitivities of isolated microorganisms as the blood cultures identify them (1) avoid anticoagulation, which increases the risk of embolization of infected cardiac material and of hemorrhage from mycotic aneurysms (2) surgical resection of enlarging or ruptured mycotic aneurysms (3) cardiac valve replacement

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vi. prognosis: 50% of endocarditis patients who have had a stroke (1) greater stroke risk and larger vegetation size in mitral valve disease; however, there is a lower 1-year survival rate in patients with aortic valve vegetations 2.

Fibromuscular dysplasia

2 Vascular Diseases of the Nervous System

a.

4.

i.

a noninflammatory condition that does not involve atherosclerosis or vascular calcification but that is associated with the development of cerebral aneurysms

ii.

involvement of the extracranial carotid and vertebral arteries is much more common than involvement of the intracranial vasculature

b.

epidemiology: usually occurs in middle-aged women

c.

symptoms: ischemic stroke (30%); hypertension from renal artery stenosis; limb claudication and bowel ischemia

d.

diagnostic testing: angiography demonstrates alternating segments of constriction and dilation {string of beads sign, tubular stenosis} (Fig. 2–9); arterial dissection rarely develops at sites of disease

e. 3.

pathophysiology: smooth muscle hyperplasia and fibrosis of small- and medium-sized arteries (renal  cervical  visceral  extremities); variants of the disease can involve hypertrophy of the tunica intima or adventitia

treatment: antiplatelet agents or anticoagulation; surgical relief of obstruction in high-grade lesions

Global hypoxia and watershed infarction a.

pathophysiology: infarction occurs in areas between vascular territories during periods of diffusely reduced blood flow (e.g., after surgery that involves unexpected decreases in blood pressure, cardiac arrest with resuscitation, atrioventricular conduction block leading to syncope {Stokes-Adams attacks}) (Fig. 2–10)

b.

treatment: hypothermic coma initiated acutely improves functional outcome in adults after cardiac arrest, and may improve outcome in neonates immediately after perinatal ischemia

Arterial dissection a.

pathophysiology: a tear in the tunic intima leads to blood collection underneath the tunica intima or inside the tunica media; blood collection in deeper layers, or absence of a connection between the dissection cavity and artery lumen (i.e., primary hemorrhage within the artery wall) are rare i.

caused by (1) trauma (50%): carotid injury occurs with compression against transverse process of vertebrae during neck extension and rotation; vertebral injury occurs with stretching between C1 and C2 vertebrae during neck rotation (2) connective tissue disorders: Ehlers-Danlos syndromes, Marfan’s syndrome, osteogenesis imperfecta (3) fibromuscular dysplasia (4) anomalous cerebral arteries (coils, kinks, etc.)

ii.

idiopathic cerebral artery dissections (1) careful evaluation of skin biopsies from such patients demonstrates a high frequency of abnormal elastin and collagen deposition (2) patients with spontaneous dissection will rarely also demonstrate a bicuspid aortic valve, suggesting developmental abnormalities of neural crest structures

iii. dissection location (1) carotid artery: usually within 2–3 cm of the bifurcation; rarely enters the petrous bone or extends intracranially

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(2) vertebral artery: generally starts around C1–2 vertebrae levels and often extends intracranially

Figure 2–9 Fibromuscular dysplasia typified by an irregular extracranial carotid artery. (From Fischbein NJ et al. Teaching Atlas of Brain Imaging. Stuttgart, Germany: Georg Thieme; 2000:299, Fig. D. Reprinted by permission.)

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epidemiology: increased risk in people with a family history of cerebral artery dissection

symptoms i.

unilateral head or facial pain

ii.

stroke or TIA: 45% with carotid dissection, 75% with vertebral dissection

iii. Horner’s syndrome, CN XII more than IX, X, XI palsies are caused by mass effect from an enlarged dissected carotid artery c.

d.

diagnostic testing: 25% of cases exhibit multiple vessel dissections i.

angiography (Fig. 2–11)

ii.

MRI: intramural hematoma is most visible on fat-saturation sequences (Fig. 2–12), which has a diagnostic accuracy comparable to cerebral angiography for carotid artery dissections

A

Special Stroke Conditions

(1) intracranial vertebral dissection may often present with subarachnoid hemorrhage, which is very rare for carotid or extracranial vertebral dissection

treatment i.

anticoagulation: immediate heparinization followed by conversion to Coumadin with a target INR 2–3; continue Coumadin for 3–6 months before reassessing the patency of dissected artery with neuroimaging (1) anticoagulation has not been proven superior to antiplatelet agents, and antiplatelet agents can be used if anticoagulation is contraindicated (e.g., because the dissection extends intracranially)

ii.

B

antiplatelet agents: used commonly for stroke prophylaxis after resolution of the dissection and completion of the anticoagulation treatment

iii. endovascular stenting iv.

e.

5.

surgery: carotid ligation with extracranial–intracranial bypass for patients with persistent ischemic symptoms while on anticoagulation

prognosis: 1% annual risk of another dissection, but it rarely occurs in the same location i.

1% stroke risk in the 30 months following initial dissection while on treatment

ii.

majority of dissections will recanalize within 2–3 months

C Figure 2–10 Patterns of infarction. (A) Thromboembolic/large artery infarction. (B) Watershed infarction. (C) Microangiopathic/small artery infarction. (From Hosten N, Liebig T. CT of the Head and Spine. Stuttgart, Germany: Georg Thieme; 2002:28, Fig. 1.24. Reprinted by permission.)

Inherited coagulation cascade disorders: all exhibit autosomal dominant inheritance and develop symptoms at  30 years of age a.

subtypes i.

antithrombin III deficiency

ii.

protein C or S deficiencies

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B

A

Figure 2–11 Carotid dissection. (A) Pouch sign. (B) Flame sign. (C) Double lumen sign. (From Martin JE, Armonda RA. Carotid dissection: a clinical review. Semin Neurosurg 2002:13, 267, Fig. 2A; and Stallmeyer

C MJB et al. Emergency evaluation and treatment of injury to the extracranial carotid and vertebral arteries. Semin Intervent Radiol 2003:20, 267, Fig. 2A; 128, Fig. 1C;135, Fig. 8A. Reprinted by permission.)

iii. activated protein C resistance/factor V Leiden mutation: cause a decreased ability of protein C to cleave coagulation factor V due to a point mutation in the factor V gene (1) activated protein C resistance is the biochemical measurement of factor V cleavage, whereas the factor V Leiden mutation is a genetic test iv.

6.

prothrombin G20210A gene mutation

b.

symptoms: usually limited to deep venous thrombosis; strokes are relatively rare and almost exclusively due to venous obstruction

c.

treatment: acute treatment with heparin, chronic treatment with Coumadin for venous thrombosis prophylaxis i.

heparin must be given concurrently when initiating Coumadin therapy in protein C or S deficiencies because of the risk for skin necrosis

ii.

standard antiplatelet agent therapy should be used in cases with ischemic stroke; anticoagulation is not proven to be superior

Homocystinuria/homocystinemia a.

general pathophysiology: accelerates atherosclerosis (in heterozygotes) and increases platelet aggregation (in homozygotes, which is often a lethal condition)

b.

subtypes (Fig. 2–13) i.

cystathionine -synthase deficiency: exhibits autosomal recessive inheritance (1) symptoms: onset  5 years of age in homozygotes; heterozygotes are asymptomatic (a) ischemic stroke, myocardial infarction (b) mental retardation (c) glaucoma and downward lens dislocation; marfanoid habitus; osteoporosis

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Figure 2–12 Intramural hematoma within a carotid dissection or fat-saturation MRI. (From Fischbein NJ et al. Teaching Atlas of Brain Imaging. Stuttgart, Germany: Georg Thieme; 2000:263, Fig. F. Reprinted by permission.)

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(2) diagnostic testing: elevated blood methionine and homocysteine levels (a) routine neonatal testing is performed for increased methionine levels (3) treatment: methionine-deficient, cysteinerich diet; vitamin B6 (pyridoxine) ii.

methylenetetrahydrofolate reductase (MHTFR) deficiency: exhibits autosomal recessive inheritance; homozygosity is very rare

(2) diagnostic testing: decreased blood methionine, increased blood homocysteine; decreased serum folate (a) genetic testing for MHTFR mutations in adults

Figure 2–13 The homocysteine metabolic pathway.

(3) treatment: folate  vitamin B6  vitamin B12 iii. deficiencies of vitamin B12 coenzyme synthesis and transport 7.

Antiphospholipid antibody syndrome a.

pathophysiology: includes anticardiolipin antibodies (immunoglobulin [Ig]G, IgM, IgA) or lupus anticoagulant (an antibody); antiphospholipid antibodies may increase stroke risk by i.

inducing platelet aggregation

ii.

inhibiting endothelial prostacyclin release

Special Stroke Conditions

(1) symptoms: similar to cystathionine -synthase deficiency, but more severe

iii. inhibiting protein C and/or antithrombin III activities iv. b.

epidemiology: occurs mostly in young women i.

c.

inhibiting of endothelial release of plasminogen activator frequently associated with lupus, other autoimmune diseases, cancer, or infection (including HIV infection)

symptoms (Box 2.8) i.

spontaneous abortions, intrauterine growth retardation, preeclampsia

ii.

venous thrombosis in extremities and abdomen (renal vein, hepatic vein) {Budd-Chiari syndrome}; rarely acute and disseminated

Box 2.8 Sneddon’s syndrome—lupus anticoagulant, livedo reticularis, and strokes (arterial or venous)

iii. cardiac vegetations may be an embolic source for strokes iv. d.

i. e.

8.

antiphospholipid antibodies may cause a false-positive VDRL, prolonged PTT, and/or thrombocytopenia

treatment: Coumadin with a target INR of 3–4, although this has not proven to be superior to antiplatelet therapy i.

f.

ischemic encephalopathy

diagnostic testing: RIA or ELISA of IgG, IgA, or IgM antibodies

acute disseminated thrombosis may also require glucocorticoids and/or immunosuppressants

prognosis: risk of recurrent stroke within 2 years is increased only in patients who have both the lupus anticoagulant and anticardiolipin antibodies

Sickle cell disease a.

pathophysiology: caused by autosomal dominant mutations in the adult  subunit of hemoglobin that causes irreversible polymerization of hemoglobin when it is deoxygenated (i.e., during relatively hypoxic states) i.

distortion of the erythrocytes’ shape leads to cell–cell and cell– endothelium adhesion, causing vascular occlusion

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(1) erythrocyte adhesion damages the endothelium, promoting thrombus formation and luminal narrowing or aneurysm formation b.

epidemiology: 8% of Blacks are sickle cell carriers, but only 0.2% are homozygotes with symptomatic disease

c.

symptoms i.

painful vaso-occlusive crises {sickle cell crisis}

ii.

frequent infections that can involve the brain

iii. stroke: 75% are ischemic, 25% are hemorrhagic; risk for hemorrhagic stroke increases with age (1) greater than 60% recurrence rate after first stroke if untreated (2) average age of initial stroke  8 years old; 10% of sickle cell patients have had a stroke by 14 years of age, and 22% have a recurrent stroke within 10 years iv. d.

e.

hearing loss

diagnostic testing i.

hemoglobin electrophoresis

ii.

transcranial Doppler ultrasonography should be used for regular screening to detect elevated flow velocities in the MCA ( 200 cm/s), which is associated with an increased risk of stroke and is an indication for transfusion

treatment i.

ischemic stroke (1) acute management: oxygen supplementation; transfusion and blood exchange; hydration; pain management (2) prophylactic management (a) transfusion and blood exchange to reduce sickle hemoglobin to  30% of total hemoglobin, keeping the total hematocrit  35 mg/dL to prevent hyperviscosity (i)

reduces risk of recurrent stroke by  80%

(b) hydroxyurea: increases the amount of fetal hemoglobin, which is resistant to aggregation (c) bone marrow transplantation: reduces risk of recurrent stroke by  80% ii.

9.

hemorrhagic strokes: sickle cell patients with hemorrhagic strokes must be evaluated for vascular malformations; transfusion and blood exchange do not have an established effect against hemorrhagic strokes

Venous infarction a.

pathophysiology: can involve either cortical draining veins or venous sinuses i.

conditions directly affecting venous system that promote venous infarctions (1) sarcoid; malignancy (2) infections: meningitis; mastoiditis; periorbital or sinus infection (typically causing cavernous sinus thrombosis)

ii.

conditions indirectly affecting the venous system that promote venous infarctions (1) inherited coagulation cascade disorders (2) oral contraceptive use, usually in conjunction with smoking (3) pregnancy: 90% of infarctions during pregnancy are arterial, but 80% of strokes immediately after birth are venous (a) pregnancy is a hypercoagulable state due to (i)

increased fibrinogen levels

(ii) decreased antithrombin III, protein S, and protein C levels

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(iii) increased platelet adhesiveness

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(4) polycythemia; paroxysmal nocturnal hemoglobinuria (5) cancer, causing a hypercoagulable state or leukemic leukostasis (6) drugs: asparaginase-induced antithrombin III deficiency symptoms: focal neurological injury from ischemic or hemorrhagic infarction, and from increased intracranial pressure (e.g., headache, papilledema); frequently exhibits a step-wise symptomatic course, but often has an acute onset i.

c.

cavernous sinus thrombosis also can cause proptosis from orbital vasocongestion, ophthalmoplegia, and vision loss from retinal hemorrhages

diagnostic testing: only 50% of cases have an identifiable cause for venous thrombosis i.

Special Stroke Conditions

b.

neuroimaging may reveal infarction with hemorrhagic conversion in a nonarterial pattern associated with a disproportionate amount of edema, or even the venous thrombus (Fig. 2–14) (1) venography (MRV, magnetic resonance venography; venousphase angiography) demonstrates a restricted venous outflow pattern in 30% of normal subjects

ii. d.

elevated intracranial pressure as measured by lumbar puncture

treatment i.

anticoagulation for acute treatment and for prophylaxis, although it has not been proven superior to antiplatelet therapy

ii.

local intravascular thrombolytics or endovascular clot removal; surgical thrombectomy

10. Vasculitis a.

general symptoms include flu-like illness, headache, weight loss, and skin rash

b.

subtypes i.

temporal arteritis/giant cell arteritis (1) pathophysiology: granulomatous inflammation with monocyte infiltration and giant cell formation in segments of large arteries that may be initiated by antibody deposition in the internal elastic lamina

A

B

Figure 2–14 Thrombosis of the right transverse sinus on noncontrast CT (A) and T1 MRI (B). (From Citow JS et al. Neuropathology and Neuroradiology. Stuttgart, Germany: Georg Thieme; 2001:151, Fig. 196. Reprinted by permission.)

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(2) epidemiology: incidence increases with age  50 years old (0.2% of cases are  50 years of age); threefold more common in women (a) associated with polymyalgia rheumatica in 60% (Box 2.9)

2 Vascular Diseases of the Nervous System

(3) specific symptoms: most diagnostic are palpable cranial artery abnormalities, jaw claudication, diplopia, and cranial tenderness (a) headache (70%): generally is bilateral, throbbing, and slowly increasing in severity over many days (i)

associated with scalp and cranial artery tenderness

(b) stroke: monocular vision loss (10%); nonocular strokes (7%), of which 50% are in posterior circulation (c) ischemia of soft tissues of the head, leading to use-dependent symptoms (e.g., jaw claudication [40%], tongue claudication [5%], sore throat [10%]) (d) ischemia of extremities, leading to claudication (10%) (4) diagnostic testing: useful in clinically suspected patients only (a) erythrocyte sedimentation rate (ESR): elevated in only 80%, and low sensitivity of high ESR thresholds makes it a poor screening test; typically is  100 in biopsy-confirmed cases (b) C-reactive protein (CRP): typically is  4 mg/dL; more sensitive than ESR, and is not affected by patient age or gender as is the ESR (c) temporal artery biopsy: 90% diagnostic accuracy with large, bilateral samples (i)

utility of biopsy is not reduced by glucocorticoid treatment even after several days of treatment

(5) treatment: high-dose IV or oral glucocorticoids for 3–5 days, tapered over a period of several months such that symptoms do not recur and the ESR and CRP levels stay within the normal ranges (6) prognosis: treatment protects the remaining vision, but does not restore vision (a) 1% 5-year risk of vision loss when treatment is begun before vision loss (b) 13% 5-year risk of further vision loss when treatment is begun after vision loss ii.

Takayasu’s arteritis—inflammation followed by progressive lumen occlusion in the aorta and large branches thereof including the carotid and vertebral arteries (1) specific symptoms: predominantly position dependent symptoms that may have a focal distribution

iii. polyarteritis nodosa—a necrotizing vasculitis of small- and mediumsized arteries associated with hepatitis B and C infection, rheumatoid arthritis, and collagen-vascular diseases (1) specific symptoms: mononeuritis multiplex, new-onset hypertension, renal failure (2) specific diagnostic testing: 30% exhibit a positive antinuclear antibodies (ANA) test; visceral angiography demonstrates microaneurysms iv.

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isolated CNS vasculitis—involves small to large intracranial or spinal cord vessels (most often small leptomeningeal vessels); associated with Hodgkin’s lymphoma (40%) and HIV infection

Box 2.9 Symptoms of Polymyalgia Rheumatica ✧ Muscle stiffness and pain, particularly in

the morning ✧ Fatigue, malaise ✧ Fevers ✧ Night sweats ✧ Unexplained weight loss

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Table 2–2 Infectious Vasculitis Type

Vessels

Notes

Bacterial or fungal meningitis

Arteries near the infection

Infarction in 10% of adults, 25% of children

Tuberculosis

Basal arteries

Infarction in 40%, develops during chronic meningitis Can produce aneurysms in small arteries

Tertiary syphilis

MCA branches

Strokes usually present after a subacute course of encephalitis and insomnia

Lyme disease

Small vessels

Can progress to subarachnoid hemorrhage

Herpes virus

ACA and MCA

Usually follows 2–3 weeks after ophthalmic infection

Varicella zoster virus

Unilateral ACA and MCA

Large vessel disease usually follows 2–3 weeks after ophthalmic infection

HIV

Large and/or small arteries

Vasculitis develops in 30% of HIV patients

Whipple’s disease

Small arteries

Causes a pendular convergence–divergence eye movement and contraction of the mastication muscles {oculomasticatory myorhythmia} that persists in sleep Also causes dementia, myoclonus, panhypopituitarism, supranuclear ophthalmoplegia Isolated brain involvement in 30% of patients

Abbreviations: ACA, anterior cerebral artery; HIV, human immunodeficiency virus; MCA, middle cerebral artery.

Cerebrovascular Malformations

Focal neurological injury develops progressively

(1) specific symptoms: encephalopathy (from small vessel disease) and/or focal neurological injury (from large vessel disease) (a) cases with focal neurological injury will eventually progress to diffuse small vessel involvement and encephalopathy v.

drug-induced vasculitis: most strongly associated with use of heroin or amphetamines; cocaine appears to cause a vasospasm-like reaction, not vasculitis

vi. infectious vasculitis (Table 2–2)

VI. Cerebrovascular Malformations 1.

Aneurysms a.

pathophysiology: sporadic aneurysms do not exhibit tunica media or internal elastic lamina {a true aneurysm}, and often endothelial surface is irregular, inflamed, and atherosclerotic i.

development of aneurysms is associated with polycystic kidney disease, aortic coarctation, collagen-vascular diseases (Marfan’s disease, Ehlers-Danlos, pseudoxanthoma elasticum), fibromuscular dysplasia, and vasculitis (including lupus)

ii.

aneurysms are usually located at arterial bifurcations, probably because of a relative weakness of the tunica media at those sites (1) anterior circulation (90% of all aneurysms): anterior communicating artery  posterior communicating artery  MCA (2) posterior circulation (10% of all aneurysms): basilar tip  vertebral-PICA junction

iii.  25% of SAH patients have multiple aneurysms b.

size:  25-mm diameter is considered giant, and giant aneurysms have a greater risk of hemorrhage and generally are located in the carotidophthalmic artery region

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A

B

Figure 2–15 AVM on T1 MRI demonstrating multiple flow voids on T1 MRI (A) and enlarged arterial channels supplying the nidus as well as early venous drainage on anteroposterior angiogram (B). (From

c.

Fischbein NJ et al. Teaching Atlas of Brain Imaging. Stuttgart, Germany: Georg Thieme; 2000:277, Fig. C; 278, Fig. F. Reprinted by permission.)

shape i.

saccular/berry: exhibit a well-formed neck; develop more commonly in the carotid circulation

ii.

fusiform: longitudinal dilatation of an artery that has no neck; develop at sites of atherosclerotic vessel injury or a winding arterial course {dolichoectasia} (1) more commonly in the vertebrobasilar circulation

iii. serpentine: a fusiform aneurysm with an irregular lumen that develops after thrombosis and recanalization 2.

Arteriovenous malformations (Fig. 2–15) a.

pathophysiology: formed by anastomoses between superficial feeding arteries and draining veins that form a nidus of dysplastic vessels; 90% are supratentorial i.

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vein of Galen malformations are direct arterial–venous connections that may present in adulthood with SAH and/or ICH

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b.

sizes: large AVMs are usually wedge-shaped with a broad base on cortex surface; small AVMs are usually spherical

c.

histology: AVMs are developmental malformations; therefore, no brain parenchyma exists within the AVM i.

3.

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the surrounding brain parenchyma is often stained with hemosiderin suggesting previous small hemorrhages, and exhibits gliosis with Rosenthal fibers

Cavernous angioma/cavernoma/cavernous hemangioma—a cluster of vascular channels with thick, hyalinized walls with thrombosis of large vascular lumens and the absence of intervening brain parenchyma (Fig. 2–16) a.

entirely venous structures, unlike AVMs

b.

genetics: most are sporadic, but some are related to autosomal dominant mutations of the Krit1 gene (a tumor suppressor gene)

4.

Venous angioma—a cluster of normal venous channels of varying sizes separated by normal brain parenchyma

5.

Moyamoya disease—idiopathic development of abnormal small arteries from the circle of Willis associated with a narrowing of an intracranial basal artery (typically the MCA, and often bilateral); abnormal small arteries have thickening of all layers and are prone to occlusion or rupture a.

epidemiology: peak incidences in children  10 years old and in adults 20–30 years old; more common in Asians

b.

specific diagnostic testing: angiography demonstrates the tangle of small arteries {puff of smoke} (Fig. 2–17)

Figure 2–16 Cavernoma of the pons (arrow). Cavernomas generally exhibit high T2 MRI signal but often involve areas of low signal from calcifications or hemorrhage (as on the rim of this cavernoma). (From Antunovic V et al. Magnetic Resonance in the Diagnosis of C.N.S. Disorders. Stuttgart, Germany: Georg Thieme; 2001:61, Fig. 60. Reprinted by permission.)

Figure 2–17 Lateral carotid view of moyamoya disease in the lenticulostriate region (arrowheads) with a prominent posterior communicating artery (double arrow) and ophthalmic artery (single arrow). Pruning of MCA and ACA branches helps differentiate this condition from an AVM. (From Fischbein NJ et al. Teaching Atlas of Brain Imaging. Stuttgart, Germany: Georg Thieme; 2000:316, Fig. E. Reprinted by permission.)

Cerebrovascular Malformations

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3 3 Seizures and Epilepsy

Seizures and Epilepsy

Note: Significant diseases are indicated in bold and syndromes in italics.

I. Diagnostic Testing 1.

Scalp electroencephalogram (EEG): scalp recordings cannot detect electrical synchronization of  6 cm2 of cortex, and have poor resolution of mesial and orbital frontal cortex, mesial parietal cortex, and mesial temporal cortex (Box 3.1) a.

special electrodes i.

sphenoid electrodes: inserted through temporal and masseter muscles underneath the zygomatic arch and positioned next to the foramen ovale; assesses the mesial temporal cortex

ii.

nasopharyngeal electrodes: inserted into the posterior nasopharynx; assesses the mesial temporal cortex (1) can also be advanced into the ethmoid sinuses to record the orbitofrontal cortex

b.

effects of hyperventilation: induce a clinical seizure in  0.1% of generalized epilepsy and 0.5% of partial epilepsy, but increase interictal epileptiform discharges in 12% of generalized epilepsy and 3% of partial epilepsies; may induce  50% of absence seizures

c.

effects of sleep, waking, and sleep deprivation: all can provoke epileptiform activity i.

d.

particularly good at inducing epileptiform activity in cases of infantile spasms and juvenile myoclonic epilepsy

effects of photic stimulation: strobe light stimulation may produce i.

photic driving responses: composed of rhythmic activity elicited over the posterior regions; occurs in 80% of epilepsies, but it also can be a normal physiological response

ii.

photoparoxysmal response: spike-and-waves or polyspike-and-waves triggered by photic stimulation in 50% of generalized seizures but only 3% of focal seizures

iii. photomyoclonic response: brief repetitive spikes generated by contraction of muscles of the face or scalp that are driven by photic stimulation; seen in normal and epileptic patients e.

abnormalities consistent with seizure foci (Fig. 3–1) i.

sharp waves (also known as sharp-wave complexes, spikes, and spikewave complexes) (1) occipital sharp waves are commonly seen in children and are not predictive of seizure foci (2) absence of sharp waves does not rule out seizure foci

ii.

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amplitude asymmetries: alpha rhythm asymmetries occur normally, but generally one side is augmented rather than decreased; increased amplitudes also occur in the context of removal of portions of the skull {breech rhythm}

Box 3.1 EEG frequencies – delta ( 4 Hz); theta (4–7 Hz); alpha (8–13 Hz); beta ( 13 Hz)

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Diagnostic Testing

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A

B Figure 3–1 Abnormalities consistent with a seizure focus. (A) Spike-and-wave discharge; (B) periodic lateralizing epileptiform discharges (PLEDS).

(1) reduced amplitudes may occur because of cortex injury or tissue collection between the cortex surface and the electrodes (e.g., subdural hemorrhage) iii. frequency asymmetries: hemispheric background frequencies should be within 1 Hz of each other; asymmetry is a very nonspecific finding iv.

polymorphic delta activity: delta activity that is variable in morphology and frequency; when present focally, it usually indicates a lesion of the white matter, but it localizes the lesion quite poorly

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3 Seizures and Epilepsy

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C Figure 3–1 (Continued) (C) frontal intermittent rhythmic delta activity (FIRDA). (From Drazkowski J. Use of EEG in a consultative role. Semin Neurol 2000, 23: 296, Fig. 1; 300, Fig. 6; 302, Fig. 8. Reprinted by permission.)

v.

rhythmic delta activities: typically are associated with subcortical or even brainstem lesions when the background rhythm is otherwise normal (1) frontal intermittent rhythmic delta activity (FIRDA): occurs in adults, particularly with renal or hepatic encephalopathies or hydrocephalus (2) occipital intermittent rhythmic delta activity (OIRDA): occurs in children, particularly in the context of absence epilepsies

vi. periodic lateralizing epileptiform discharges (PLEDS): focal bursts epileptiform discharges that occur repetitively every 1–5 seconds; indicates acute or subacute focal cortical injury, or occasionally a metabolic disorder (particularly nonketotic hyperglycemia) superimposed on a chronic, focal cortical injury (1) bilateral PLEDS is suggestive of diffuse cortical injury or encephalopathy 2.

Prolactin level: Useful only if collected within 15–20 minutes of the seizure a.

prolactin levels are increased over baseline level in 80% of generalized seizures and 70% of complex-partial seizures

b.

prolactin levels are rarely increased after pseudoseizures, after prefrontal seizures that symptomatically resemble the bizarre behaviors of pseudoseizures {pseudo-pseudoseizures}, or after status epilepticus

c.

seizures also increase CRH and LH secretion (Box 3.2)

II. Partial Seizures 1.

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Simple partial seizures (Fig. 3–2): do not involve impairment or loss of consciousness irrespective of the complexity or distribution of convulsive activity; form the aura of complex partial seizures a.

simple partial motor seizures

Box 3.2 Recurrence of Seizures: Overall risk of seizure recurrence is 40% after two years. ✧ Low-recurrence risk with idiopathic or

cryptogenic seizures and a normal EEG (25%) ✧ Medium-recurrence risk with an abnormal neurological exam, neuroimaging, or EEG (50%) ✧ High-recurrence risk with an abnormal neurological exam, neuroimaging, and EEG (65%) ✧ The likelihood of developing epilepsy is increased by having antecedent conditions associated with an increased risk of epilepsy, seizures occurring during sleep, a family history of seizures, an abnormal EEG, particularly one with epileptiform abnormalities, or partial seizures

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Partial Seizures

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Figure 3–2 Symptomatic manifestations of focal seizures according to the seizure focus. (From Mumenthaler M. Neurological Differential Diagnosis. 2nd ed. Stuttgart, Germany: Georg Thieme; 1992:56, Fig. 20. Reprinted by permission.)

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primary motor cortex focus (Brodmann area 4): causes clonic or tonic-clonic movements according to the motor homunculus; rarely causes weakness without movements (1) Jacksonian march—progression of convulsive movements as the epileptiform activity migrates along the motor homunculus

ii.

supplementary motor area focus (Brodmann area 6): frequent, brief seizures occurring in clusters with a rapid onset and offset; posturing usually involves the contralateral upper extremity and contraversive head and eye deviation {fencer’s position}

3 Seizures and Epilepsy

iii. premotor cortex focus (Brodmann area 6) and frontal eye field focus (Brodmann area 8): cause unilateral forced gaze and head deviation {version seizures}, which are reliably contralateral only when the focus is in the frontal eye field (1) may involve a decrease in the level of consciousness, which would be better classified as a complex-partial seizure iv.

v.

insula cortex focus: typical symptomatic progression involves abnormal laryngeal sensation, followed by dysarthria with perioral and/or contralateral body paresthesias, and finally contralateral convulsions in the face and/or arm (Box 3.3) frontal operculum focus: causes bilateral facial movements accompanied by mastication, salivation, and swallowing after an aura consisting of epigastric sensations, fear, and/or autonomic phenomena; may cause speech arrest or vocalizations with foci in either hemisphere, or a Broca’s-type aphasia with a focus in the dominant hemisphere

vi. dorsolateral prefrontal cortex focus: causes contralateral forced head and gaze deviation b.

simple partial sensory seizures i.

parietal lobe focus: most seizure foci are in the primary somatosensory cortex (Brodmann areas 3-1–2), which causes contralateral tingling and/or numbness according to the sensory homunculus that frequently progresses to frank motor seizure activity after a period of general tremulousness (1) sensory symptoms can have a Jacksonian march equivalent (2) negative seizure phenomena with parietal seizures (a) loss of awareness of a body part {asomatognosia} can occur with nondominant hemisphere seizures (b) receptive- or conductive-like aphasias can occur with dominant hemisphere seizures (3) pain or temperature sensations, or bilateral sensations suggest involvement of the secondary somatosensory cortex (Brodmann area 40) (4) the sensation of vertigo (10%), sinking, choking, or nausea indicates inferior parietal lobe involvement (5) changes in affect may also be associated with parietal lobe seizures

ii.

primary visual cortex focus (Brodmann area 17): causes elementary visual sensations (flashes, scotoma, hemianopia, amaurosis) (1) seizures often involve tonic eye contraversion, oculoclonic, or nystagmoid eye movements, forced eye closure, eyelid fluttering, sensory hallucinations of eye movements, or even the sensation of eye pain

iii. occipito-parieto-temporal junction focus: causes complex imagery or hallucinations; frequently visualized objects are recognizable but are distorted in size {micropsia, macropsia} and/or shape {metamorphopsia} iv.

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temporal lobe focus: two thirds of seizure foci are mesial; one third are lateral (i.e., neocortical)

Box 3.3 Gelastic Seizures ✧ Related to hypothalamic hamartomas

but EEG identifies epileptiform activity in frontal or temporal lobes ✧ Laughter begins in childhood; later involves drop attacks, generalized seizures, cognitive impairment, precocious puberty, and behavioral disorders ✧ Treatment: lamictal or clonazepam; surgery, particularly stereotaxic

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Table 3–1 Complex Partial Versus Absence Seizures Feature

Complex Partial

Absence

Aura

Yes

No

Hyperventilation-inducible

No

Yes

Photic stimulation-inducible

No

Maybe

EEG

Temporal spike & wave

Diffuse 3 Hz spike & wave

Postictal confusion

Yes

No

Duration

Minutes

Seconds

Automatisms

Present

Only if prolonged

Partial Seizures

(1) causes auditory or olfactory hallucinations, emotional, or psychic symptoms (e.g., flashbacks, déjà vu, jamais vu), sensations of vertigo, and autonomic changes (e.g., epigastric rising sensation, GI upset with nausea and hypermotility, respiratory arrest) (a) olfactory hallucinations are usually unpleasant, indicating medial temporal lobe involvement {uncinate fits} (b) gustatory sensations suggest involvement of the temporal opercular cortex (2) rare manifestations include forced thinking (a rapid recollection of past life experiences), depersonalization, extremes in affect, or rage 2.

Complex partial seizures: involves some impairment of consciousness without tonic-clonic activity; does not have to involve a complete loss of consciousness (Table 3–1) a.

general pathophysiology: 40% of cases have seizures that are initiated by a temporal lobe focus, either mesial or neocortical

b.

general symptoms: can begin with a simple partial seizure that serves as an aura, or with outright impairment of consciousness i.

complex partial seizures often involve coordinated involuntary movements (1) reactive automatism: a reaction to the environment (i.e., drinking from a cup that is placed in the hands) (2) perseverative automatism: the persistence during a seizure of a complex action that was being performed before the seizure onset

c.

mesial temporal cortex seizure foci: typically begins with auras consisting of epigastric sensations, fear, and/or oro-alimentary automatisms i.

mesial temporal/hippocampal sclerosis (1) subtypes: do not correlate with seizure severity or responsiveness to treatment (a) classic mesial temporal sclerosis: cell loss in the hilum of the dentate gyrus, the tip of the CA4 region, and the CA1subiculum interface; the CA2 region is relatively preserved (Box 3.4) (b) minimal mesial temporal sclerosis: cell loss in the hilum of the dentate gyrus

Box 3.4 The CA2 region is particularly susceptible to damage from status epilepticus.

(c) total mesial temporal sclerosis: cell loss in the dentate gyrus and CA1–4 regions (2) histology: sclerosis implies neuron loss and gliosis in the affected regions (a) 50% of cases exhibit bilateral sclerosis but usually it is asymmetric (b) 20% of cases coexist with another pathological process (e.g., cortical dysplasia, tumor)

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(3) pathophysiology: unknown cause but often disease onset is preceded by febrile seizures (a) atrophy of the mesial temporal lobes exists at the time of seizure onset, and can be observed even in neonates (b) mesial temporal sclerosis exhibits familial segregation, so it likely has a genetic predisposition (4) specific diagnostic testing: EEG demonstrates spike-and-wave complexes in the inferior temporal leads or low-voltage beta activity at seizure onset that remains local for several seconds before spreading; best observed with subdural/depth electrodes

3 Seizures and Epilepsy

d.

neocortical temporal foci: seizures often begin with auditory hallucinations, vertigo, or visual misperceptions; language disturbance can occur with foci in the dominant hemisphere i.

musicogenic seizures: a type of reflex seizure (Box 3.5) that is triggered by music (e.g., a particular composition, the sound from a certain instrument, or discussing or thinking about music) (1) not the same as a seizure involving the perception of sound or musical notes {musical partial seizure}, wherein the perceived sound tends to be relative unformed (e.g., ringing, whistling)

e.

frontal lobe seizure foci: cause complex and bizarre motor automatisms (e.g., eyelid fluttering, repetitive bilateral movements) that occur in clusters, often with minimal post-ictal confusion; frequently are confused with pseudoseizures i.

frontal operculum focus: causes auditory or visceral auras and visceral motor phenomena (salivation, spitting, vomiting)

ii.

cingulate cortex or supplementary motor area (Brodmann area 6) focus: cause asymmetric bilateral posturing movements with automatisms; cingulate foci may cause gesturing, simple sexual behavior, or ictal laughter

iii. frontopolar cortex focus: causes forced thinking, aversive head movements, and/or axial clonic jerks

3.

iv.

orbitofrontal cortex focus: causes complex motor automatisms and olfactory hallucinations due to involvement of the cortex overlying the septal nuclei that receives the medial olfactory stria; may involve formed vocalizations (e.g., cursing)

v.

dorsolateral frontal cortex focus: causes tonic posturing and speech arrest

Diagnostic testing: Scalp EEG gives adequate localization in only 50% of cases with temporal foci, and is even worse with frontal lobe foci; a single EEG demonstrates abnormalities in 40% of possible seizure cases, which is increased to 75% with prolonged EEG monitoring a.

ictal EEG patterns of complex partial seizures i.

rhythmic spike and wave activity, which are bilateral in 30% of cases

ii.

rhythmic 5–7 Hz activity without spikes

iii. focal attenuation of background activity

III. Nonsyndromal Generalized Seizures 1.

Tonic-clonic seizures a.

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symptoms: convulsive activity typically lasts  1 minute; five phrases include i.

premonition phase: involves mood changes (e.g., irritability) and headaches that may last for days prior to the seizure

ii.

immediately pre-tonic-clonic phase: involves a few myoclonic jerks or brief clonic seizure activity; occasionally begins with forced eye and head deviation {aversive movements}

Box 3.5 Reflex Seizure Triggers ✧ Visual patterns (as in 3% of all epilepsies) ✧ Tactile stimuli: hot water, body postures ✧ Problem-solving ✧ Reading, writing, or speaking ✧ Specific movements ✧ Startle involving any kind of stimulus

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Figure 3–3 Generalized tonic-clonic seizure. (From Mumenthaler M. Neurological Differential Diagnosis. 2nd ed. Stuttgart, Germany: Georg Thieme; 1992, Fig. 1, p. 1. Reprinted by permission.)

iii. tonic phase: contracture of the axial musculature with upward eye deviation, pupillary dilation, and forced expiration of air {epileptic cry}; usually involves some decerebrate posturing

Nonsyndromal Generalized Seizures

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(1) tongue and jaw muscle tonus causes perioral injury, typically lateral tongue biting (2) frequently patient becomes cyanotic, tachycardic, and hypertensive iv.

clonic phase: starts as low-amplitude, high-frequency ( 8 Hz) convulsive movements of the extremities  thorax and abdomen that progresses to high-amplitude, low-frequency ( 4 Hz) movements (1) development of atonia breaks the seizure and causes incontinence (2) bilaterally asynchronous movements may be caused by separate unilateral seizure foci, but this is rare

v.

post-ictal phase: patient is poorly responsive and hypotonic; confusion and memory impairment may last a few minutes to hours, occasionally followed by psychiatric changes (depression, psychosis, anxiety, irritability) that can persist for a day (1) post-ictal phase involves generalized fatigue, soreness, and migraine headaches (2) laboratory testing during the post-ictal phase demonstrates respiratory-metabolic acidosis, hyperglycemia, and mild cerebrospinal fluid pleocytosis

b. c.

epidemiology: unlike most other seizure types, occurs with similar incidences across all ages diagnostic testing (Fig. 3–3) i.

ictal EEG: bilateral hemispheric involvement from the seizure onset that is bilaterally synchronous; refined computer analysis may identify asynchronous ictal onset, but this is not necessarily exclusive of a primarily generalized seizure (1) immediate pre-tonic-clonic phase: any myoclonic or clonic activity is represented as a generalized burst of spike or polyspike activity (2) tonic phase: identified by an abrupt decrease in voltage with diffuse 20–40 Hz activity {desynchronization pattern}; 8–10 Hz sharp waves build in amplitude during the tonic phase (3) clonic phase: 8–10 Hz sharp waves of the late tonic phase are replaced by polyspike-and-wave pattern that slows to 4 Hz (4) post-ictal phase: diffuse suppression of EEG activity with a lowvoltage delta frequency predominance

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interictal EEG: 50% show epileptiform activity with 5 days of a seizure, and the yield is higher closer to the time of the seizure (1) subtypes of interictal abnormalities: often multiple subtypes occur in the same patient (a) multifocal spike complexes (b) 3–5 Hz spike-and-wave complexes (usually are bilateral with frontocentral predominance) (c) irregular spike-and-wave complexes

3 Seizures and Epilepsy

(2) anticonvulsants tend to slow the background rhythm, except for barbiturates and benzodiazepines, which characteristically increase the beta activity in the 14–20 Hz range iii. cerebrospinal fluid: any post-ictal pleocytosis should be assumed to be caused by an inflammatory process until proven otherwise 2.

Tonic seizures a.

symptoms: diffuse contraction of the axial musculature, sometimes involving the proximal limbs or proximal and distal limbs; paralysis of respiration causes apnea i.

often results in the patient falling {drop attack}, so tonic seizures are frequently confused with atonic seizures

ii.

startle seizures—a type of reflex seizure that is usually tonic in nature, triggered by the sudden or unexpected presentation of a stimulus (Box 3.6) (1) specific symptoms: the seizure follows a startle response (i.e., eye closure with facial grimacing and flexion of the limbs and trunk) induced by a sudden stimulus of any type (2) often occurs in children with diffuse cerebral abnormalities (e.g., Down’s syndrome, anoxic encephalopathy)

Box 3.6 Hyperekplexia ✧ A hyperactive startle response followed

by rigidity leading to falls (no impairment of consciousness) ✧ Caused by glycine receptor mutations; treat with clonazepam

(3) treatment: benzodiazepines, carbamazepine, lamotrigine b.

diagnostic testing: subtypes of ictal EEG patterns i.

sudden reduction of response} (Fig. 3–4)

background

activity

{electrodecremental

ii.

bilaterally synchronous 15–25 Hz activity with increasing voltage

iii. diffuse high-voltage 10 Hz activity iv.

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diffuse theta or delta activity

Figure 3–4 Electrodecremental response of an infantile spasm. (From Markand ON. Pearls, perils, and pitfalls in the use of the electroencephalogram. Semin Neurol 2003, 23: 29, Fig. 23. Reprinted by permission.)

3.

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Atonic seizures a.

b.

4.

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symptoms: sudden loss of consciousness and postural muscle tone that can be limited to the head but generally involves the whole body {drop attack} or only the head, usually occurring after a brief myoclonic seizure; lasts several seconds i.

loss of consciousness with preservation of muscle tone {akinetic seizures} can also occur

ii.

overall, drop attacks are more likely to be caused by tonic than atonic seizures

diagnostic testing: ictal EEG demonstrates polyspike-and-wave discharges followed by diffuse slowing that is maximal over central regions during the atonia

Myoclonic seizures a.

symptoms: shock-like ( 50 ms), irregular, and asynchronous contraction of one or a few muscle groups that may be singular or repetitive; affects predominantly the eyelids, facial muscles, and upper more than lower extremities

b.

diagnostic testing: ictal EEG demonstrates diffuse polyspike and wave discharges

Status Epilepticus

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IV. Status Epilepticus 1.

Definition: any type of seizure  30-minute duration or that recurs without the patient fully regaining consciousness; in practice, seizures  5 minutes are treated as status epilepticus

2.

Causes (Box 3.7)

3.

Box 3.7

a.

acute brain injury from infarction, mass lesions, or head trauma

b.

metabolic abnormality (particularly non-ketotic hyperglycemia)

c.

drug intoxication/withdrawal

d.

abrupt reduction or discontinuation of antiepileptic medication

e.

idiopathic (30%)

Epilepsia partialis continua—spontaneous, regular or irregular clonic epileptic movements that last for long periods of time

Treatment (Table 3–2)

Table 3–2 Treatment of Status Epilepticus Drug (in order of use)

Dose

Time to effect

Duration of action

#1: Benzodiazepines Lorazepam (Ativan)

Adult: 4–8 mg IV

6 min

24 h

2 min

30 min

15 min

2h

10 min

24 h

20 min

 48 h

Pediatric: 1–4 mg IV Diazepam (Valium, Diastat)

Adult: 10 mg IV

Midazolam (Versed)

Adult: 0.2 mg/kg IM

Pediatric: 5–10 mg IV or PR Pediatric : 0.1 mg/kg IM

#2: Phenytoin (Dilantin) Phosphenytoin (Cerebyx) #3: Phenobarbital #4: Anesthetic coma Propofol drip Pentobarbital drip

20 mg/kg IV, or same of phenytoin equivalents for phosphenytoin Supplement 10 mg/kg if first dose fails 20 mg/kg IV Load 2 mg/kg IV, then 2–10 mg/kg/h titrated Load 10 mg/kg IV, then 0.5–3 mg/kg/h titrated

Abbreviations: IV, intravenously; IM, intramuscularly; PR , per rectum.

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a.

thiamine 100 mg IM  50 mL of D50 IV (adult) or 2 mL/kg D25 IV (pediatric) should be routinely administered to all status epilepticus patients considering the possibility of Wernicke’s encephalopathy

b.

continuous EEG monitoring is indicated when the patient becomes overly sedated and is not overtly seizing to evaluate for subclinical status epilepticus

Prognosis: 3–30% mortality, depending upon the cause, duration, and patient age a.

outcome is worse with prolonged seizures because of the development of hypoglycemia, hypotension, and/or acidosis

b.

cognitive dysfunction is often the residual of status epilepticus

3 Seizures and Epilepsy

V. Inherited and Pediatric Seizures A. Neonatal Seizures 1.

Subtypes: generalized seizures do not exist in neonates because myelination is incomplete, thereby preventing spread of epileptiform activity a.

focal clonic seizures: usually caused by focal cerebral injury; Jacksonian march does not occur in neonates because of the lack of myelination

b.

multifocal clonic seizures: involve random migration of seizure activity across several muscle groups; usually occurs after diffuse cerebral injury, particularly severe hypoxic encephalopathy

c.

tonic seizures: extension and stiffening of the body with apnea and upward eye deviation i.

2.

usually caused by focal cerebral injury or by intraventricular hemorrhage in premature infants; very poorly localized with EEG, may involve a brainstem release mechanism that accounts for the majority of symptoms

d.

myoclonic seizures: rare in neonates; can be misinterpreted as a generalized seizure; usually are caused by diffuse cerebral injury in the children of drug-addicted mothers

e.

“subtle” seizures: involves tonic eye deviations (most diagnostic symptom for this condition), sucking behavior, and/or cycling movements of the extremities

Causes (Table 3–3) a.

severe hypoxic encephalopathy: symptoms also include stupor or coma, hypotonia, multiple cranial nerve palsies; EEG demonstrates slow-wave, flat-line, or burst-suppression EEG i.

usually occurs in fetuses with irregular heart rates or meconium aspiration

Table 3–3 Causes of Neonatal Seizures Seizure onset

Cause (in order)

 1 d from birth

cerebral ischemia meningitis, sepsis intracranial hemorrhage (intraventricular, subependymal, or subarachnoid)

1–3 d from birth

intracranial hemorrhage (intraventricular, subependymal, or subarachnoid) meningitis, sepsis hypercalcemia

3d–1wk from birth

metabolic diseases (e.g., aminoacidurias, urea cycle disorders)

1–4wk from birth

cerebral malformations

herpetic encephalitis

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seizures from severe hypoxic encephalopathy are difficult to control because of elevated intracranial pressure but become manageable with a lowering of the pressure

mild hypoxic encephalopathy: symptoms also include lethargy, jitteriness, and sympathetic hyperactivity (tachycardia, dilated pupils); unlike severe hypoxic encephalopathy, the EEG is relatively normal i.

mild hypoxic encephalopathy does not cause seizures except when provoked by hypoglycemia or an electrolyte disturbance

c.

trauma: usually occurs in large-for-gestational-age neonates after complicated deliveries; often associated with intracranial hemorrhage

d.

intracranial hemorrhage i.

subarachnoid hemorrhage in neonates is more likely caused by ruptured superficial veins than arteries

ii.

subdural hemorrhage in neonates is caused by disruption of the veins on the tentorium near the falx due to excessive vertical head molding

e.

hypoglycemia: defined as blood glucose  20 mg/dL in premature infants or  30 mg/dL in fullterm infants; occurs in 10% of all neonates

i.

symptoms also include apnea, vomiting, hypotonia, seizures; progression to coma during hypoglycemia is associated with long-term neurological impairment

f.

hypocalcemia: may exacerbate seizures but is not likely their underlying cause

Inherited and Pediatric Seizures

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B. Pediatric Seizures 1.

Febrile seizures a.

pathophysiology: convulsions that are not necessarily associated with a rising or peak body temperature; exhibits an autosomal dominant inheritance with incomplete penetrance i.

subtypes (1) simple febrile seizures (70%): a generalized tonic-clonic seizure that lasts  1 minute; no further seizures occur in the next 24hour period (2) complex febrile seizures (30%): a seizure with focal or multifocal features that lasts  15 minutes, or that recurs within 24 hours

ii.

epidemiology: occur in 3% of children (1) 3% of febrile seizure children will ultimately develop epilepsy (2) 40% of children with a single febrile seizure will have a second febrile seizure, and 50% of children with two febrile seizures will have a third febrile seizure (a) the risk of further febrile seizures is increased by having (i)

the first seizure at age  1 year

(ii) a seizure with a body temperature  40°C (iii) an abnormal neurological exam or developmental delays (iv) prolonged, focal-onset, or multiple episodes of febrile seizures (v) a family history of seizures iii. febrile seizures are triggered by the measles–mumps–rubella (MMR) vaccine (that induces a fever), but this does not increase the risk of developing epilepsy over that of febrile seizures not caused by a vaccination b.

diagnostic testing i.

cerebrospinal fluid analysis to rule-out meningitis or encephalitis, particularly in children  6 months old; however, 90% of children with meningitis or encephalitis are obtunded after a seizure, which is rare with simple febrile seizures (1) lumbar puncture is not necessary if child recovers rapidly and completely after the seizure, and if the fever is readily explained by an extracranial source of infection

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EEG and neuroimaging are indicated only if child has an abnormal neurological exam or atypical febrile seizures

treatment: no treatment is indicated after simple febrile seizures; antiepileptic medications are indicated for complex febrile seizures, febrile seizures in patients  1 year of age, and patients with an abnormal neurological exam

Generalized myoclonic seizures a.

infantile spasms/West’s syndrome (Box 3.8) i.

3 Seizures and Epilepsy

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ii.

pathophysiology: 75% of cases have an underlying structural lesion (e.g., a phakomatosis), acquired cerebral injury (e.g., intracranial hemorrhage or infection), or genetic abnormality (e.g., non-ketotic hyperglycinemia, Down’s syndrome) symptoms: onset between 4–6 months of age

Box 3.8 Aicardi’s Syndrome ✧ Infantile spasms  agenesis of the cor-

pus callosum  retinal malformations

✧ Exhibits X-linked dominant inheritance

(a hemizygous lethal phenotype in males)

(1) seizures: classically manifests as clusters of symmetric extensor and/or flexor movements, followed by tonic contractions lasting  10 seconds; seizures most commonly occur after waking (a) abdominal flexions are often mistaken for colic (2) autism (3) progressive mental retardation (usually in patients with an underlying malformation) (4) microcephaly (5) focal neurological injury (60%): can be cortical or subcortical (e.g., athetosis) in nature iii. diagnostic testing (1) interictal EEG demonstrates a chaotic background with randomlydispersed high-voltage slow waves and spike discharges across all leads {hypsarrhythmia} (Fig. 3–5) (a) the multifocality of hypsarrhythmia is replaced within a few months by generalized synchronous discharges, which eventually degrade into a slow spike-and-wave discharge similar to Lennox-Gastaut syndrome by 2 years of age (2) ictal EEG demonstrates background suppression during the convulsive movements {electrodecremental response} (Fig. 3–4), high-voltage generalized slow waves, and/or paroxysmal lowvoltage fast activity (3) in the absence of an underlying structural lesion on neuroimaging, combined positron emission tomography (PET) scanning and video EEG monitoring may identify an area of cortical abnormality

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Figure 3–5 Infantile spasms demonstrating hypsarrhythmia. (From Mumenthaler M. Neurological Differential Diagnosis. 2nd ed. Stuttgart, Germany: Georg Thieme; 1992:266, Fig. 6.2. Reprinted by permission.)

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treatment (1) vigabatrin: highly effective, particularly in tuberous sclerosis patients; however, vigabatrin is not approved for use in the United States (2) adrenocorticotropic hormone (ACTH) (3) high-dose pyridoxine, presumptively assuming the infantile spasms are due to vitamin deficiency (4) surgery to remove seizure foci

v.

prognosis: 5% mortality (1) in 65% of survivors, the infantile spasms are replaced by another seizure type such as Lennox-Gastaut or complex partial seizures (2) only 10% of patients have normal mental and motor development, although the likelihood of normal development is higher in patients with idiopathic/cryptogenic infantile spasms

b.

Lennox-Gastaut syndrome i.

pathophysiology: 60% of cases are related to structural brain abnormalities; 20% of cases develop from infantile spasms

ii.

symptoms: onset between 3–5 years of age (1) multiple coexisting seizures (a) tonic seizures (90%)

Box 3.9

(b) atypical absence seizures (65%) that involve repetitive facial motions followed by loss of tone in head and face

Epileptic Pseudoataxia

(c) myoclonic seizures (20%)

gait produced by repeated myoclonus and/or brief periods of akinesis; exhibits confusion but no nystagmus with episodes ✧ Exhibits 2–2.5 Hz spike-and-wave complexes, like Lennox-Gastaut syndrome ✧ Treat with clonazepam or valproate

(2) mental retardation iii. diagnostic testing (Fig. 3–6) (1) interictal EEG: exhibit 2–2.5 Hz slow spike-and-wave complexes with frontotemporal predominance; paroxysmal fast activity  10 Hz is apparent while sleeping (Box 3.9)

Inherited and Pediatric Seizures

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✧ Episodic ataxic limb movements and

(2) ictal EEG: atypical absence seizures exhibit 2–2.5 Hz spike-and-wave similar to interictal pattern; tonic seizures exhibit synchronous 15–25 Hz activity that is dominant in the frontal and vertex EEG leads iv.

treatment (1) numerous medications can be used, although they nearly always fail to completely control the seizures (a) vigabatrin is effective but not approved for use in the United States (2) ketogenic diet (3) vagal nerve stimulator; corpus callosotomy

c.

benign myoclonic epilepsy  benign myoclonus of infancy i.

symptoms: onset between 6 months–2 years of age, with remission within 5 years from onset; involves brief myoclonic jerking without a loss of consciousness that in 15% of cases develops into generalized tonic-clonic seizures by adolescence

Figure 3–6 Lennox-Gastaut syndrome while awake (A) and during sleep (B) during which it demonstrates generalized paroxysmal fast activity. (From Markand ON. Pearls, perils, and pitfalls in the use of the electroencephalogram. Semin Neurol 2000, 23: 31, Fig. 26. Reprinted by permission.)

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(1) does not involve mental retardation ii.

diagnostic testing: interictal EEG is normal; ictal EEG identifies generalized polyspike or spike-and-wave discharges during myoclonic jerks (1) EEG during sleep exhibits exaggerated discharges that occur with or without myoclonic jerks

iii. treatment: valproate

3 Seizures and Epilepsy

d.

severe myoclonic epilepsy (Box 3.10) i.

pathophysiology: unknown, but appears to have a familial predilection

ii.

symptoms: develops by 1 year of age; typically begins as a febrile seizure that then exhibits nonfebrile clonic seizures, with the eventual development of myoclonus within several years (1) interictal neurological deficits (e.g., gait ataxia, dystonia, weakness) also develop (2) associated with mental retardation

iii. diagnostic testing: EEG eventually demonstrates spontaneous and photic stimulation-induced bursts of generalized spike-and-wave activity with a reduction in background activity iv. e.

treatment: resistant to therapy

juvenile myoclonic epilepsy i.

pathophysiology: autosomal dominant inheritance of unknown genetic factors

ii.

symptoms: seizures involve bilateral but asymmetric flexor movements of the upper extremities or rarely of the lower extremities that develop most commonly after awakening; no loss of consciousness occurs with seizures

iii. diagnostic testing: interictal EEG demonstrates bilateral, symmetric 3.5–6 Hz spike-and-wave and polyspike discharges; ictal EEG exhibits diffuse polyspike activity followed by 1–3 Hz slow waves (Fig. 3–7) (1) photic stimulation provokes discharges iv.

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treatment: valproate

Figure 3–7 Juvenile myoclonic epilepsy. (From Markand ON. Pearls, perils, and pitfalls in the use of the electroencephalogram. Semin Neurol 2000, 23: 27, Fig. 21. Reprinted by permission.)

Box 3.10 O h t a h a ra’s S y n d r o m e / I n f a n t i l e Epileptic Encephalopathy Symptoms: onset shortly after birth, up to 3 months of age, rarely begins in utero; involves tonic spasms, erratic motor clonic movements, and/or hemiconvulsions Diagnostic testing: clusters of burstsuppression Treatment: seizures are poorly responsive; may attempt ACTH, vigabatrin, valproate, or benzodiazepines; avoid carbamazepine, which increases seizure frequency

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Syndrome

Mutated gene/protein

Age of onset

Specific clinical sign

Notes

Neuronal ceroid lipofuscinosis (infant form)

Tripeptidyl peptidase

9

Macular degeneration, dementia, dystonia

Neuronal curvilinear bodies (infant form) enlarged axons & dendrites

UnverrichtLundborg disease

EPM1/cystatin B (see Box 3.11)

6–15

Cerebellar signs, startle myoclonus

Diffuse atrophy, particularly of cerebellar Purkinje cells

Lafora disease

EPM2A/laforin

6–20

Occipital seizures causing visual hallucinations, blindness, scotomata

Perinuclear polyglucosan inclusion bodies

Sialidosis type 1

NEU1/neuraminidase

6–15

Retinal cherry-red spot

Urine oligosaccharides

Myoclonic epilepsy with ragged red fibers (MERRF)

Mitochondrial tRNA

3–65

Short stature, muscle weakness

Ragged red muscle fibers; lactic acidosis

Box 3.11 f. 3.

myoclonic seizure syndromes: all exhibit a progressive course (Table 3–4)

Cystatin C mutated in Icelandic-type hereditary cerebral amyloidosis

Absence seizures (Box 3.12) a.

childhood and juvenile absence seizures i.

ii.

pathophysiology: autosomal dominant inheritance; slow wave discharges on EEG may relate to cyclic activity of T-type calcium channels and repolarizing potassium currents in reticular thalamic nucleus

Box 3.12

(1) childhood-onset form is self-limited, whereas the juvenile-onset form is more likely to persist into adulthood

✧ Rapid blinking of the eyelids with up-

Eyelid Myoclonus with Absence Seizures (Jeavon’s Syndrome)

(a) occur on a daily basis in the childhood-onset form, more infrequent in the juvenile-onset form

ward eye deviation, typically occurring immediately after eye closure; does not occur in the dark ✧ Associated with brief bilateral spikeand-wave activity ✧ Unclear if this is a type of seizure or a means by which the patient induces seizures

(b) 50% also have generalized tonic-clonic seizures, more commonly in the juvenile-onset form; these are infrequent and well controlled with medication

Box 3.13

symptoms (1) 5–10 second long unresponsive staring spells (Box 3.13)  rhythmic facial movements or picking behaviors; does not have an aura or post-ictal state

(2) mental retardation, focal neurological dysfunction (in 15% of cases)

Inherited and Pediatric Seizures

Table 3–4 Myoclonic Seizure Syndromes

Staring spells are most likely to be due to complex-partial seizures at this age.

iii. diagnostic testing: EEG demonstrates bilateral spike-and-wave complexes at 3 Hz that are reliably activated by hyperventilation (Fig. 3–8) (1) interictal EEG is usually normal; abnormal interictal EEGs are associated with mental retardation iv.

treatment: ethosuximide, valproate, acetazolamide (1) avoid carbamazepine, which increases seizure frequency (as in severe myoclonic epilepsy) and may induce absence status epilepticus

4.

Partial seizures a.

simple partial seizures i.

acquired epileptiform aphasia/Landau-Kleffner syndrome (1) pathophysiology: an idiopathic disorder involving simultaneous hypoperfusion and epileptiform activity in one or both temporal lobes (2) symptoms: onset between 2–11 years of age (a) receptive aphasia progressing to global aphasia over a period of several days (i)

the patient must have normal language and cognitive development prior to seizure onset to rule out autism

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(ii) progression of aphasia not related to frequency of seizures, and is fluctuant (iii) auditory agnosia may occur with involvement of the nondominant hemisphere (b) focal or generalized seizures, usually atonic (70%) (c) behavioral changes: hyperactivity, aggression (3) diagnostic testing: EEG demonstrates multifocal cortical spike discharges predominantly in the temporal and parietal lobes that are bilateral in 90%; these EEG abnormalities are minimal or even absent during waking, but become so severe during sleep (particularly at sleep onset) as to be nearly continuous

3 Seizures and Epilepsy

(4) treatment (a) glucocorticoids often improve seizures and aphasia (b) antiepileptic drugs control seizures but has an unclear effect on aphasia (c) subpial transection to isolate seizure focus, or have surgical resection of seizure focus improve seizures and aphasia (5) prognosis: seizure always remit by age 15; aphasia may persist into early adulthood before improving ii.

acquired epileptiform opercula syndrome (1) pathophysiology: exhibits autosomal dominant inheritance with anticipation (2) symptoms: oral dysphasia and an inability to perform complex facial movements {facial apraxia} associated with focal or generalized seizures (3) diagnostic testing: ictal EEG demonstrates centrotemporal discharges (4) treatment: completely unresponsive to treatment

iii. autosomal dominant nocturnal frontal lobe epilepsy (1) pathophysiology: mutation of the presynaptic nicotinic acetylcholine receptor 4 subunit causing a decreased calcium conductance of the channel; exhibits autosomal dominant inheritance with 70% penetrance (2) symptoms: seizures begin with vocalization or a psychic prodrome that wakes the patient from sleep, followed by tonic-clonic movements without loss of consciousness; occur only during sleep, often in clusters (a) previously was considered a movement disorder (“nocturnal paroxysmal dystonia”) (3) diagnostic testing: normal interictal EEG in 85%; requires continuous video monitoring to distinguish from REM sleep behavior disorder (4) treatment: carbamazepine iv.

benign occipital epilepsy (1) pathophysiology: unknown; frequently occurs in patients with migraine; not associated with structural lesions (2) symptoms: seizures involve unformed visual hallucinations, visual illusions (micropsia, macropsia, metamorphopsia), vision loss (either complete or hemianopic), vomiting and drooling, and/or forced blinking and forced gaze deviation; some patients will have seizures followed by a loss of consciousness lasting several hours (a) seizures usually develop after a migraine headache, and after the patient will typically have a migraine headache

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(b) seizures usually occur at sleep onset

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(3) diagnostic testing: interictal EEG demonstrates unilateral or bilateral high-amplitude occipital spike-and-wave discharges at 1.5–2.5 Hz that are inhibited by eye opening; ictal EEG is similar except that the spike-and-wave discharges are at higher frequencies (a) epileptiform activity is reliably induced by photic stimulation v.

Rolandic epilepsy/centrotemporal epilepsy (1) pathophysiology: two subtypes based on inheritance patterns (a) autosomal dominant inheritance: 10% of cases with this subtype have only a single seizure, and the rest have very infrequent seizures; 70% of seizures occur during sleep (b) autosomal recessive inheritance: linked to chromosome 15 (2) symptoms: perioral paresthesias followed by twitching of face and mouth with speech arrest and drooling but without impairment of consciousness; convulsions may develop in an upper extremity or generalize, usually in patients  5 years of age (a) in the autosomal recessive subtype, seizures occur in conjunction with paroxysmal dystonias (e.g., writer’s cramp) (3) diagnostic testing: EEG demonstrates unilateral or bilateral high-voltage spike discharges in central or centrotemporal region (Fig. 3–8) that are increased during sleep

Inherited and Pediatric Seizures

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(a) frequency of spike discharges does not correlate with seizures (b) neuroimaging is warranted only in patients with atypical features or treatment-refractory seizures (4) treatment: phenobarbital or trileptal only if the seizures are frequent (5) prognosis: spontaneous resolution of seizures by age 14; withdrawal of antiepileptic medication after 2 years leaves 80% seizurefree

Figure 3–8 Rolandic epilepsy. Note that sharp waves occur independently in the central regions. (From Panteliadis CP, Darras BT. Encyclopaedia of Paediatric Neurology: Theory and Practice, 2nd ed. Stuttgart, Germany: Georg Thieme;1999:415, Fig. 6. Reprinted by permission.)

vi. Rasmussen’s syndrome/hemiconvulsion-hemiplegia-epilepsy syndrome (1) pathophysiology: inflammatory degeneration of the cortex and supratentorial subcortical structures involving lymphocyte and macrophage invasion, microglial nodule formation, and neuronophagia that is initially limited to a single hemisphere or part thereof; inflammatory degeneration does not involve the contralateral hemisphere or posterior fossa structures (a) resembles the histological changes of a rare Russian tick-born encephalitis; however, there is no reproducible evidence of an infectious agent causing Rasmussen’s syndrome (b) autoantibodies against GluR3 subunit of glutamate receptors are infrequent and do not clearly mediate the inflammatory degeneration, although their levels may indicate disease activity (2) symptoms: focal motor seizures that spread to contiguous muscle groups; 60% develop focal status epilepticus {epilepsia partialis continua} before the disease burns out in 2–10 years

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(3) diagnostic testing (a) EEG demonstrates continuous focal spike discharges that spread to contiguous areas of cortex, and eventually mirror foci on the contralateral hemisphere (b) neuroimaging: may be normal initially, but hemispheric atrophy and ipsilateral hydrocephalus ex vacuo develop within 6 months (c) PET and single photon emission computed tomography (SPECT) scanning demonstrate hypometabolism and decreased cerebral blood flow over large areas of the affected hemisphere

3 Seizures and Epilepsy

(d) cerebrospinal fluid analysis is usually normal (4) treatment: refractory to antiepileptic medications, immunosuppressive agents, and antiviral therapy; early hemispherectomy can be curative b.

complex partial seizures: epileptogenic focus is usually in the temporal  frontal or parietal lobes i.

general symptoms: staring spells, automatic behaviors (e.g., facial grimacing, hand wringing), posturing, or loss of body tone lasting 1–2 minutes (1) post-ictal confusion and lethargy can occur with or without secondary generalization (2) 30% of patients exhibit an aura consisting of a nondescript unpleasant feeling, auditory hallucination, or abdominal discomfort; auras are particularly common with mesial temporal foci

ii.

subtypes (1) autosomal dominant partial epilepsy with auditory features (a) genetics: caused by mutations of leucine-rich gliomainactivated-1 gene (LGI-1), which has an unknown function (Box 3.14) (b) specific symptoms: seizures involve unformed sounds (e.g., clicks, buzzing), changes in sound perception (e.g., deafness, muffling, increase in volume), or complex sounds, then usually progresses to a psychic symptom (e.g., déjà vu) (i)

30% of patients have unilateral symptoms

(ii) some patients with familial seizures exhibit a Wernicke’stype aphasia at the seizure onset (iii) seizures may be triggered by sounds (2) benign familial neonatal convulsions (a) genetics: caused by mutations in the voltage-gated potassium channel KCNQ-2 gene (chromosome 20) and KCNQ-3 gene (chromosome 8); abnormal channels reduce the repolarizing potassium current, allowing prolonged neuronal depolarization (b) specific symptoms: clonic or apneic seizures that occur in clusters within the first few postnatal days (c) prognosis: seizures resolve by a few months of age (3) benign familial infantile convulsions (a) genetics: most cases are linked to poorly defined abnormalities on chromosome 16; cases associated with familial hemiplegic migraine are caused by mutations of ATP1A2 sodium-potassium ATPase gene on chromosome 1 (b) specific symptoms: seizure onset between 3–12 months of age; otherwise normal development, and seizures remit by adulthood (i)

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can be associated with familial hemiplegic migraine

(4) benign familial neonatal-infantile convulsions

Box 3.14 LGI-1 is located in the loss of heterogeneity region on chromosome 10 in glioblastoma multiforme (see p. 120)

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(a) genetics: caused by mutations in the SCN2A gene for voltagegated sodium channel (b) specific symptoms: clonic seizures developing within first few postnatal weeks, which is later than benign familial neonatal convulsions but earlier than benign familial infantile convulsions

Pseudoseizures/Nonepileptiform Seizures

iii. treatment: carbamazepine, phenytoin, primidone, valproate; surgical removal of medically refractory seizure foci

C. Nonseizure Paroxysmal Disorders of Children 1.

Pediatric apnea syndromes a.

periodic breathing—irregular respiratory pattern with intermittent pauses of 3–6 seconds duration, followed by 10–15 seconds of hyperventilation without associated autonomic changes; seen mostly in premature infants due to immaturity of the brainstem respiratory centers

b.

true apnea—cessation of breathing  15 seconds, or  15 seconds if associated with bradycardia i.

can be considered normal if the patient is  3 months of age and if the apnea is not associated with tonic eye deviation, limb stiffening, or clonic movements (1) seizure-induced apnea rarely is associated with bradycardia

2.

3.

Jitteriness—an excessive response to stimulation characterized by a lowfrequency, high-amplitude shaking of the limbs and jaw; can be confused with myoclonic seizures but jitteriness is more rhythmic a.

jitteriness occurs in the newborns of drug-abusing mothers (particularly those using cocaine and methadone) or mothers using phenothiazines or propoxyphene, in newborns with perinatal hypoxia, or in newborns with metabolic disorders, therefore it has a high coincidence with seizures

b.

identify episodes of jitteriness by a normal EEG, the absence of eye movements, and the lack of change in respiration; jittery neonates also have a hyperactive Moro reflex

c.

treatment: paregoric; phenobarbital

Breath-holding spells a.

pathophysiology: a type of syncope thought to be related to immaturity of the brainstem respiratory centers; exhibits autosomal dominant inheritance with incomplete penetrance i.

b.

breathing stops after expiration (not after inspiration) in response to an adverse stimuli

subtypes i.

pallid breath-holding spells—breathing stops in response to a painful stimulus; the child often falls asleep after the breath-holding spell but is otherwise normal

ii.

cyanotic breath-holding spells—breathing stops during a crying episode; long episodes can exhibit tonic posturing, extremity trembling, and upward eye deviation; recovery is rapid without any post-ictal confusion

Box 3.15

(1) EEG during the breath-holding spell is low-voltage and nonepileptiform

✧ Short duration ( 30 seconds) repeti-

VI. Pseudoseizures/Nonepileptiform Seizures (Box 3.15) 1.

Pathophysiology a.

subtypes i.

posttraumatic pseudoseizures: develop in response to physical, psychological, or sexual abuse

Pseudo-Pseudoseizures tive episodes with bizarre behavior (e.g., complex automatisms) and large movements (e.g., abduction of upper extremities) ✧ Involve the epileptiform activity developing out of mesial frontal lobes or mesial parietal lobes ✧ Epileptiform activity is EEG inaccessible; may require high-frequency filters to demonstrate theta activity in parasagittal leads

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b.

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developmental pseudoseizures: develop in response to poor coping with increasingly complex developmental challenges or failure to achieve developmental milestones

other risk factors i.

comorbid psychiatric disorders: anxiety; depression; histrionic or borderline personality disorders (1) pseudoseizures may represent the presentation of a conversion disorder

ii.

family history of pseudoseizures

3 Seizures and Epilepsy

iii. head trauma iv.

pending disability claims

v.

abrupt elimination of epileptiform seizures, as after seizure surgery

vi. epileptiform seizures 2.

3.

Epidemiology: more common in late adolescence and early adulthood as well as in women; rare at  5 years of age and  55 years of age a.

present in upwards of 30% of patients in specialty seizure clinics and 20% of adolescents with new-onset seizures

b.

30% coincidence with epileptiform seizures

Symptoms: Seizure-like episodes without electroencephalographic epileptiform activity a.

symptoms differentiating pseudoseizures from epileptiform seizures: none are sufficiently accurate to ensure the diagnosis i.

clonic activity in which the limbs are out-of-phase with each other

ii.

events occurring while the patient appears to be asleep but has EEG activity indicating wakefulness {preictal pseudosleep}

iii. pelvic thrusting iv.

eye movements or fluttering eyelids during the event

v.

preserved recall of the event

vi. complex, well-formed vocalizations at the beginning of the event (1) vocalizations are simple (e.g., grunting) and occur more commonly during the convulsive movements in epileptiform seizures vii. incontinence: incontinence early in the course of pseudoseizures is rare, it often develops later after the patient is repeatedly questioned about it viii. lip biting or biting the tip of the tongue is suggestive of pseudoseizures (1) biting the side of the tongue is suggestive of epileptiform seizures ix. typical events are inducible by suggestion (e.g., saline injection) b.

4.

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symptoms that are unable to differentiate pseudoseizures from epileptiform seizures: the presence of an aura, the duration of event, post-ictal confusion, physical trauma from events, prolonged course of events (i.e., there is a “pseudo-status epilepticus”

Diagnostic testing a.

continuous video EEG monitoring, which must capture some of the suspect events

b.

prolactin level: generally does not increase from baseline after a pseudoseizure

c.

neuropsychiatric testing: generally is not helpful in distinguishing pseudoseizures from epileptiform seizures

5.

Treatment: no proven treatment; divulging diagnosis in a supportive manner may improve pseudoseizure frequency in 80% of cases that developed as an acute or situation-dependent reaction

6.

Prognosis: with multidisciplinary treatment, one third completely resolve and one third have a reduction in the frequency of the events; as with epilepsy, quality of life improves only with complete resolution of pseudoseizures

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Figure 3–9 Treatments for primary generalized seizures.

1.

General Treatment of Seizures

VII. General Treatment of Seizures Medical treatment: Quality of life improves only with complete seizure control (Fig. 3–9; Fig. 3–10) a.

prophylactic antiepileptic medication use in patients with neurological disorder but without seizures i.

severe head trauma (prolonged loss of consciousness, amnesia, depressed skull fracture, contusion, or hematoma): prophylaxis does not reduce seizure rate

ii.

brain tumor: prophylaxis does not seem to reduce development of seizures in patients with primary or metastatic tumors

iii. stroke: no indication, although it is routinely used short-term in subarachnoid hemorrhage patients because of the fear of increased intracranial pressure that accompanies seizures b.

discontinuing medication therapy i.

predictive factors for successful seizure remission (Box 3.16) (1) the patient will most likely be seizure free if he or she has (a) a single type of seizure

Box 3.16 All four factors achieve 70% remission in children, and 60% remission in adults.

(b) had no seizures for  3.5 years (c) a normalized EEG on antiepileptic treatment (d) a normal neurological exam and intelligence quota (IQ) i.

general rules (1) hepatic-inducing medications (e.g., lower other drug levels): phenytoin, carbamazepine, phenobarbital, primidone (2) hepatic-suppressing medications (e.g., raise other drug levels): valproate (3) albumin-binding medications (e.g., raise other drug levels): phenytoin, valproate

d.

management of medication failures i.

if maximal doses of an antiepileptic medication fail to control the seizures, there is only a 10% likelihood of developing control over seizures by adding a second antiepileptic medication

ii.

there is  5% likelihood of developing control over seizures by adding a third antiepileptic medication or by using multiple antiepileptic drugs after failing a second antiepileptic medication

Figure 3–10 Treatments for partial seizures.

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Surgical treatment a.

preoperative evaluation involves i.

video-EEG monitoring

ii.

neuroimaging: CT, MRI; ictal studies with SPECT or PET scanning

iii. invasive continuous monitoring with subdural electrodes iv.

3 Seizures and Epilepsy

b.

Wada test evaluation of hemispheric dominance for language function and verbal memory

procedures i.

multiple subpial transections: vertical incisions that interrupt intracortical connections; can be used to isolate a seizure focus in eloquent cortex, leaving minimal neurological deficits (as in Landau-Kleffner syndrome where it is effective in 55% of cases)

ii.

focal cortical resection: removal of a small block of epileptogenic cortex; 80% effective with temporal lobe foci,  50% effective with extratemporal foci

iii. temporal lobectomy: eliminates seizures in 70% of mesial temporal sclerosis cases

c.

iv.

hemispherectomy: for large blocks of epileptogenic cortex, as in Rasmussen’s syndrome where it is effective in 90%

v.

corpus callosotomy: for multifocal seizures or unidentified epileptogenic foci that cause seizures with a high risk of physical injury (e.g., the drop attacks of tonic or atonic seizures)

vagal nerve stimulation: reduces frequency by 30% of either generalized or partial seizures; chief side effect is hoarseness during activation i.

likely acts by desynchronization of brain activity and/or by inhibition of epileptogenic foci by monoaminergic modulation

Appendix 3–1 Antiepileptic Drugs Drug

Mechanism of action

Specific side effects

Notes

carbamazepine (Tegretol, Carbatrol)

Slows recovery of voltagegated Na channels

Hyponatremia, transient diplopia or visual blurring after dosing, asymptomatic leukopenia

Also used for trigeminal neuralgia, bipolar disorder; avoid in absence, myotonic, atonic seizures Target range  8–12 g/mL

clonazepam, clorazepate

Increases GABAA receptor currents

Respiratory depression, somnolence

Other benzodiazepines are not approved for longterm seizure treatment; generally tolerance develops within 6 months

ethosuximide (Zarontin)

Inhibits T-type voltagegated Ca channels in thalamus

Nausea, exacerbation of behavioral disorders

Useful only in absence seizures; no effect on other generalized seizures

gabapentin (Neurontin)

Unknown

None in particular

As effective as carbamazepine for partial seizures Used for neuropathic pain

lamotrigine (Lamictal)

May decrease glutamate release

Ataxia, diplopia, rash (1%)

Effective in Lennox-Gastaut syndrome and juvenile myoclonic epilepsy Synergistic effect when used with valproate but also increases its toxicity Lowest teratogenic risk of the antiepileptic drugs Nonsedating

levetiracetam (Keppra)

Unknown

Psychosis

oxcarbazepine (Trileptal)

Unknown

Hyponatremia

Equivalent dose is 1.5 that of carbamazepine Converted to bioactive monohydroxy-derivative Does not affect levels of other medications

phenobarbital

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Activates GABAA receptor; inhibits voltage-gated Ca channels

Respiratory depression, somnolence, cognitive slowing with chronic use

Target range 0  15–40 g/mL

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(Continued)

Drug

Mechanism of action

Specific side effects

Notes

phenytoin (Dilantin)

Slows recovery of voltagegated Na channels

Gum hyperplasia, hirsutism, coarse facies, pseudolymphoma, skin rash (5%), purple glove syndrome (IV route); osteoporosis

Half-life depends upon dose

fosphenytoin (Cerebyx)

Dilantin by IV precipitates in glucose solution Dilantin brand is sustained release qd dose when given PO fosphenytoin loaded 3 faster not useful in absence seizures Target range  1–2 g/mL free level

As per phenobarbital

As per phenobarbital

Converted to phenobarbital and PEMA Not useful in absence seizures Used for essential tremor

tiagabine (Gabitril)

Inhibits GABA reuptake

Nonconvulsive status epilepticus (contraindicated in generalized seizures)

topiramate (Topamax)

Inhibits voltage-gated Na channels; inhibits AMPA receptors; activates GABAA receptors

Transient aphasia/anomia, nephrolithiasis, acute angle closure glaucoma

Useful in infantile spasms, Lennox-Gastaut syndrome, atonic and myoclonic seizures Inhibits oral contraceptives Causes weight loss

valproate (Depakote, Depacon)

Slows recovery of voltagegated Na channels; inhibits T-type voltage-gated Ca channels in thalamus; increases GABA synthesis

Weight gain, hair loss, tremor; thrombocytopenia; hyperammonemia; carnitine depletion, which can be fatal in the malnourished

Depakote ER can be divided bid

zonisamide (Zonegran)

Inhibits T-type voltagegated Ca channels slows recovery of voltagegated Na channels

Nephrolithiasis; weight loss

Also used for migraine

felbamate*

Antagonizes the glycine site on NMDA receptors

Rarely used due to high incidence of aplastic anemia

vigabatrin*

Inhibits GABA metabolism

Effective against infantile spasms, particularly those caused by tuberous sclerosis; not approved for use in US because of high rates of peripheral visual field loss

Also used for migraine, bipolar disorders

Last Head General Treatment 1 of Seizures

primidone (Mysoline)

Can cause status when given with clonazepam Target range  30–100 g/mL

*Not available in the United States. Abbreviations: bid, twice a day; IV, intravenously.

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4 4 Disorders of Myelination

Disorders of Myelination

Note: Significant diseases are indicated in bold and syndromes in italics.

I. Multiple Sclerosis (MS) 1.

Pathophysiology a.

etiological hypotheses i.

the autoimmune hypothesis: peripheral leukocytes become sensitized to central nervous system myelin antigens by (1) direct exposure of leukocytes to antigens after breakdown of the blood–brain barrier during a local infection (2) sensitizing leukocytes to viral antigens that are similar to myelin antigens {molecular mimicry}

ii.

the infectious hypothesis: stems from epidemiological studies linking geographical location with disease susceptibility, although no definitive links have been made; it is thought that demyelination is a reaction to chronic viral infection, such as that from (1) herpes 6 virus infection: evidence of viral infection is present more commonly in patients with MS, although a causative association is not established (2) Epstein-Barr virus (EBV) infection: pediatric MS patients have twice the rate of EBV exposure than do controls, suggesting an early exposure to the virus; MS patients exhibit higher antibody levels against EBV (3) other viruses: herpes simplex 1, simian cytomegalovirus, MSassociated retrovirus (HERV-W) (a) patients with MS have a later mean age of infection with measles, rubella, and mumps, but not a greater overall incidence of infection (4) Chlamydia pneumoniae—MS patients exhibit greater reactivity to Chlamydia, but equal rates of infection

b.

genetics i.

associated with human leukocyte antigen (HLA) A3, -B7, -Dw2, -DQ, and -DR2 subtypes

ii.

familial aggregation occurs in 15% of cases; dizygotic twin risk is 5%, similar to the risk of non-twin siblings; monozygotic twin risk is 35%

iii. risk of MS  3% with one affected parent, 30% with two affected parents c.

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epidemiology i.

geography: common in northern North America, Europe, Scandinavia, New Zealand, and southern Australia (i.e., maximal distances from the equator)

ii.

age: clinical onset occurs almost invariably in patients  60 years of age (1) risk of developing MS related to geography is acquired by 12 years of age

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B

A Figure 4–1 Typical multiple “sclerosis” lesions. (A) T1 non-contrast MRI showing black holes (arrows) within a chronic, inactive lesion. (B) T1 with contrast MRI demonstrating enhancement of active lesions (arrows).

(From Balassy C et al. Long-term MRI observations of childhood-onset relapsing-remitting multiple sclerosis. Neuropediat 2000;32: 33, Fig. 2a,b. Reprinted by permission.)

Multiple Sclerosis (MS)

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iii. sex: for women, relative risk of the relapsing-remitting subtype  3; equal risk for men and women for the primary-progressive subtype iv. 2.

race: relative risk  8% for Whites

Histology (Fig. 4–1) a.

plaques: areas of demyelination typically occurring around venules in the white matter i.

acute/active plaques: characterized by T lymphocyte and macrophage infiltration (1) macrophages are predominant in the core of the plaque and phagocytize myelin debris; reactive astrocytes are also present in the plaque core (2) T lymphocytes are sensitized to multiple antigens in myelin (i.e., myelin basic protein, proteolipid protein, “P-0” protein, myelinassociated glycoprotein), but the molecule that initiates the inflammatory response is unknown

ii.

chronic plaques: hypercellular areas that contain mostly astrocytes, sometimes with a periphery of lipid-containing macrophages (1) axons are demyelinated but otherwise relatively normal in appearance; loss of axons may approach 50% within the plaque (a) axon loss is likely a reaction to demyelination and to direct injury from the inflammatory process (2) most chronic plaques do not contain inflammatory cells, but some have ongoing myelin phagocytosis by macrophages {chronic active plaque}

iii. shadow plaques: areas of demyelination with partial remyelination (1) oligodendroglia are reduced in the core of plaque but are increased at periphery, which accounts for the limited remyelination that occurs in chronic plaques; most of the oligodendroglia surrounding the plaque are not of a myelinating phenotype iv.

normal appearing white matter (NAWM) that does not contain plaques may show evidence of gliosis

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Symptoms (Box 4.1) a.

acute symptoms i.

sensory abnormalities: the most common deficit of MS (1) subjective sensory complaints include numbness, paresthesias, band-like sensations around the chest or abdomen, saddle anesthesia, itching, and (rarely) radicular pain (a) Lhermitte’s sign: an electric shock sensation that radiates down the spine and into the limbs upon flexion of the neck; a nonspecific finding that can be seen with many types of cervical spine lesions that involve the dorsal columns (e.g., subacute combined degeneration, tabes dorsalis)

4 Disorders of Myelination

(b) loss of proprioceptive sensation in a limb may produce significant discoordination {useless hand sign of Oppenheim} (2) objective findings on sensory testing (in order of occurrence) (a) loss of vibration and position sense (b) loss of pain and light touch (c) saddle anesthesia/associated with bowel and bladder hypotonia ii.

vision loss from optic neuritis: most commonly is a centrocecal scotoma (see p. 38), which reduces acuity; commonly is caused by lesions behind optic chiasm {retrobulbar optic neuritis} (1) vision loss is usually gradual and associated with retroorbital or periorbital pain (2) vision loss is often associated with a direct afferent pupillary defect {Marcus-Gunn pupil} (3) papillitis occurs only when the head of the optic nerve is involved

iii. diplopia from ocular motor dysfunction: internuclear ophthalmoplegia  impairment of CN VI  CN III  CN IV function iv.

weakness: acute focal weakness is fairly uncommon except in the primary progressive subtype; slow-developing, progressive weakness is more common

v.

cerebellar dysfunction involving ataxia of both the trunk and extremities

vi. syndromes of spinal cord injury (see transverse myelitis below) vii. bladder and bowel dysfunction: typically includes urinary frequency and urgency with retention, and constipation; sexual dysfunction is also common viii. epilepsy ( 5%): any type of seizure may occur

4.

b.

chronic symptoms: spasticity, appendicular tremor; fatigue; sexual dysfunction; psychiatric disturbance, particularly depression (65%); dementia (5%)

c.

paroxysmal symptoms: trigeminal neuralgia; hemifacial spasm; tonic spasms; hemiataxia; paresthesias; dysarthria i.

symptoms last only a few seconds but may recur repeatedly or occur in clusters

ii.

paroxysmal symptoms are likely caused by ephaptic neural transmission between demyelinated neural systems that are in direct contact (i.e., a short circuit)

Subtypes based on symptomatic progression a.

relapsing-remitting MS (55% of all cases; 85% of cases at the time of presentation)—involves multiple discrete episodes of neurological injury followed by partial recovery

b.

secondary progressive MS (30% of all cases)—a progressive course of neurological injury developing after several years of an apparent relapsingremitting course; likelihood of transforming into secondary progressive subtype from relapsing-remitting subtype increases with disease duration ( 90% likelihood after 25 years of disease) i.

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some patients develop progressive neurological dysfunction after a single episode of acute neurological injury (“single progressive MS”)

Box 4.1 MS symptoms are exacerbated or induced by heat, {Uthoff’s phenomenon} menses, and the post-partum period. MS symptoms are reduced by pregnancy, particularly in the third trimester (due to reduced Th2 leukocytes).

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primary progressive MS (10% of all cases)—neurological injury that progresses from the onset of the disease and never remits i.

d.

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progressive relapsing MS—after a minimum of 1 year of apparent primary progressive MS, the patient develops relapses in addition to the progressive course

clinically isolated MS i.

optic/retrobulbar neuritis—as a clinically isolated event, most patients recover to 20/40 acuity but only a third will recover completely and most will have persistent deficits in color vision and/or contrast sensitivity

(2) associated with a 60% 10-year risk of developing MS if the brain magnetic resonance image scan (MRI) is abnormal; only a 10% 10-year risk if the brain MRI is normal ii.

transverse myelitis—symptoms include lower extremity weakness and sensory loss, bowel/bladder dysfunction, back pain, and occasionally spinal shock (1) does not exhibit a familial pattern (2) likely due to MS in cases with (a) asymmetric symptoms (e.g., an incomplete lesion) (b) involvement of less than two spinal segments

Multiple Sclerosis (MS)

(1) recurrence occurs in 30%, and often causes a greater impairment of the visual acuity than did the original episode

(c) oligoclonal bands in the cerebrospinal fluid (d) evidence of plaque-like brain lesions on neuroimaging iii. monophasic brainstem or cerebellar syndromes 5.

Diagnostic testing: the Poser criteria for MS and the International Panel on Multiple Sclerosis diagnostic criteria (the McDonald criteria) (Table 4–1) a.

neuroimaging: cognitive and behavioral impairment correlates better with general atrophy than with lesion load

Table 4–1 Diagnostic Criteria for Multiple Sclerosis (MS) Poser criteria for multiple sclerosis

Category Definite MS Probable MS

# attacks by history

# exam findings

Supportive laboratory evidence*

2

2

None required

2

1

1 Type

2

1

None

1

2

None

1

1

1 Type

McDonald criteria for definite multiple sclerosis # attacks by history

# of physical findings

Abnormal laboratory test

2

2

None are required for diagnosis, although abnormalities should be found if the various tests are performed

2

1

Barkhof MRI criteria*

1

2

New gad-enhancing lesion within 3 months

1

1

Barkhof MRI criteria*

2 MRI lesions  abnormal CSF

2 MRI lesions  abnormal CSF *Supportive laboratory evidence = typical MRI lesions, asymmetric evoked potentials, abnormal urodynamic testing. Abbreviations: CSF, cerebrospinal fluid; gad, gadolinium.

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i.

plaques are commonly located radiating outward from the ventricle surface {Dawson’s fingers} or in the corpus callosum; plaques can occur anywhere with oligodendrocyte myelination including the cortical white matter

ii.

Barkhof MRI criteria: require at least three of the following four conditions. (1) one gadolinium-enhancing lesion, or at least nine T2-hyperintense lesions (2) three periventricular lesions (3) one infratentorial lesion

4 Disorders of Myelination

(4) one juxtacortical lesion b.

electrophysiological testing i.

visual-evoked responses: 85% abnormal in Poserdefinite MS (see p. 42)

ii.

brainstem auditory-evoked responses: abnormal in Poser-definite MS (see p. 50)

65%

iii. somatosensory-evoked responses: 80% abnormal in Poser-definite MS (1) transcutaneous electrical stimulation of a distal sensory nerve produces electrical potentials that can be measured over the spinal cord and the centroparietal and frontopolar cranial regions

Figure 4–2 Electrodes are placed on the base of the lateral neck inferior to the sternocleidomastoid muscle {Erb’s point} measure the potential generated by the brachial plexus. Somatosensory evoked potential from median nerve stimulation. Potentials are labeled according to positive (P) or negative (N) deflections and their expected delay (in milliseconds). Typically, N11  dorsal columns, N13 potential  cervical spinal cord (? cuneate nucleus), N14 and P15  medial lemniscus, N16 and 17  upper brainstem/thalamus, and N20  parietal cortex (for tibial nerve stimulation in a normal person: N34  upper brainstem/thalamus; P37  parietal cortex).

(a) potentials are labeled according to their latencies (in milliseconds) from the stimulus and the polarity of the response (i) c.

median nerve stimulation in a normal person (Fig. 4–2)

cerebrospinal fluid: typical abnormalities include i.

normal or mildly elevated protein (1) myelin basic protein: very nonspecific; it is no longer used for diagnosis (2) elevated IgG, usually measured as a fraction of the serum albumin (  0.27 in 65% of patients with Poser-definite MS versus 3% of controls) or as a fraction of serum IgG {IgG index} ( 0.7 in 80% of patients with Poser-definite MS versus 3% of controls) (3) oligoclonal bands: detectable in 95% of definite MS but also in 10% of controls (4) albumin level: a very insensitive measure for MS

ii. d.

6.

leukocytosis  50 in 60% of patients

serology: serum anti-myelin antibodies (anti-myelin oligodendroglial glycoprotein and anti-myelin basic protein) may predict second demyelinating events in patients after an initial demyelinating event, although this has not been confirmed

Treatment a.

therapy for the relapsing-remitting subtype of MS i.

acute attack treatment: generally reserved for significant neurological impairment (1) methylprednisolone 1 g IV once q.d. for 3–5 days, or prednisone 1250 mg PO q.d. for 3–5 days; tapering is not required (a) glucocorticoids increase the rate of recovery, but do not improve overall level of recovered function

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(b) after an initial demyelinating event, glucocorticoids decrease the likelihood of developing MS over the following 2 years, but they do not reduce the long-term likelihood of developing MS (c) high-dose oral glucocorticoids are likely to be as efficacious as IV glucocorticoids, although this has not been directly tested (2) plasmapheresis, although it has no supportive evidence (a) intravenous immunoglobulin (Ig) has failed to demonstrate any benefit as an adjuvant therapy for glucocorticoids (3) methotrexate, cladribine, mitoxantrone (4) combinations of the above therapies ii.

preventative therapy for acute attacks: all are contraindicated during pregnancy, and all have a modest effect on disability in the available short-term follow-up from clinical trials (1) interferon 1a 30 g IM weekly (qwk.) (Avonex): reduces relapse rate by 18% (2) interferon 1a 22–44 mg IM q.o.d (Rebif): reduces relapse rate by 30% (3) interferon 1b 22–44 mg subcutaneously (SQ) 3 times a week (t.i.w.) (Betaseron): reduces relapse rate by 30% (4) glatiramer acetate (Copaxone) 20 g SQ q.d., if interferons are not tolerated or antibodies against interferons develop; decreases relapse rate by 30% but inconsistent effectiveness against long-term disability

Multiple Sclerosis (MS)

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(5) mitoxantrone: used to stabilize patients with rapidly progressive disability or frequent relapses; it exhibits significant cardiotoxicity and is typically given only for a few months iii. therapy for paroxysmal symptoms: full-dose anticonvulsants, benzodiazepines b.

therapy for progressive subtypes of MS: no therapy has yet proven effective for primary progressive MS; for second progressive MS, or for rapidly developing progressive symptoms, consider i.

interferons, as above

ii.

monthly bolus of methylprednisolone

iii. monthly cyclophosphamide treatment iv. c.

methotrexate, cladribine, mitoxantrone

treatment for chronic symptoms i.

spasticity: baclofen, tizanidine, dantrolene, benzodiazepines, botulinum toxin

ii.

tremor: anticonvulsants, clonazepam, propranolol, ondansetron, gabapentin; stereotactic thalamotomy in refractory cases

iii. fatigue: amantadine, pemoline, SSRIs, modafinil, 4-aminopyridine, acetylcarnitine iv.

spastic bladder: oxybutynin (Ditropan), propantheline, imipramine (1) hypotonic bladder is rare

v.

psychiatric impairment (1) depression: SSRIs, amitriptyline, second-generation antidepressants (e.g., venlafaxine, bupropion) (2) dementia: donepezil may be beneficial

d.

treatment for paroxysmal symptoms: full-dose antiepileptics; benzodiazepines; glucocorticoids when resistant to other therapies

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II. Pediatric Multiple Sclerosis/Early-Onset Multiple Sclerosis 1.

2.

Pathophysiology a.

pediatric multiple sclerosis has a stronger association with HLA-DR than adult multiple sclerosis but has no gender preference

b.

pediatric- and adult-onset multiple sclerosis exhibit similar familial patterns

Symptoms: as per relapsing-remitting multiple sclerosis; onset  16 years of age but usually continues into adulthood as multiple sclerosis

4 Disorders of Myelination

a.

episodes of optic neuritis are typically simultaneous or sequentially bilateral, not isolated unilateral episodes as in adult multiple sclerosis i.

b.

cases with unilateral optic neuritis are more likely to develop into typical multiple sclerosis

Devic’s disease-like presentation is extremely rare in children

3.

Diagnostic testing: neuroimaging can differentiate the disorder from acute disseminated encephalomyelitis (ADEM). However, neuroimaging and cerebrospinal fluid studies are of uncertain utility in children, therefore establishing the diagnosis of pediatric multiple sclerosis is generally made according to the Poser criteria

4.

Treatment a.

b.

acute attack treatment i.

methylprednisolone 20–30 mg/kg/d for 3–5 days, followed by PO prednisone with tapering

ii.

IVIg in cases unresponsive to glucocorticoids

preventative therapy for acute attacks i.

interferons, adjusting the dose for weight and age

ii.

cyclophosphamide

III. Multiple Sclerosis Variants 1.

Devic’s disease/neuromyelitis optica a.

b.

histology: inflammatory demyelinating lesions with complete loss of oligodendrocytes and significant leukocyte infiltration that may progress to frank necrosis and cavitation in severe cases (spinal cord  optic nerves); inflammation involves gray and white matter of the spinal cord  optic nerves, and does not involve much gliosis as does multiple sclerosis i.

lesions exhibit perivascular immunoglobulin and complement deposits

ii.

necrotic demyelinating lesions that exhibit near complete axon loss typically occur in the optic nerves and cervical spinal cord

symptoms: rapid-onset of bilateral painful vision loss, and symptoms of complete spinal cord injury associated with back pain (back pain is rare for spinal multiple sclerosis); may exhibit a relapsing course, but more commonly is fulminant i.

c.

d.

110

the optic neuritis may be bilaterally simultaneous or sequential

diagnostic testing: different than opticospinal multiple sclerosis in that i.

neuroimaging demonstrates a normal brain in 90% of cases, and a spinal cord lesion  two spinal segments in length

ii.

cerebrospinal fluid analysis demonstrates oligoclonal bands only in 30% of cases and then only transiently; elevated protein and a neutrophil pleocytosis are observed

treatment i.

acutely treat with glucocorticoids, plasmapheresis, or IVg

ii.

treat relapsing-remitting cases chronically with interferon therapy, prednisone  azathioprine, or cyclophosphamide

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prognosis: 90% 5-year survival in fulminant disease; 70% 5-year survival in relapsing-remitting disease

Marburg’s variant of multiple sclerosis a.

pathophysiology: the pathophysiology is generally considered to be the same as that for multiple sclerosis, although there is evidence that Marburg’s variant is related to expression of an immature or modified form of myelin basic protein i.

3.

10:12 AM

histology: a large, acute demyelinating lesion of a single hemisphere (60% of cases) that rapidly increases in size and is associated with mass effect due to edema

b.

symptoms: predominantly relate to rapidly increased in intracranial pressure

c.

diagnostic testing i.

cerebrospinal fluid is usually normal except for a minimal pleocytosis

ii.

neuroimaging: lesions are often mistaken for tumor or cerebritis because the lesion contrast enhances and shrinks after steroid treatment

d.

treatment: glucocorticoids, IVg, plasmapheresis, mitoxantrone, cyclophosphamide

e.

prognosis: mortality is usually due to mass effect and herniation, or to involvement of the brainstem in the demyelinating process

Box 4.2

Balo’s concentric sclerosis (Box 4.2) a.

histology: demyelinating lesions that are centered around a perivascular collection of inflammatory leukocytes, wherein demyelination and inflammation occur in concentric rings that alternate with areas of preserved myelin that are of decreasing severity with increasing distance from the center i.

areas of preserved myelin exhibit small amounts of demyelination and remyelination, suggesting active suppression of the disease process or else a lesion involving acute and chronic demyelination

b.

symptoms: headache, impaired cognitive and behavioral function, seizures

c.

diagnostic testing i.

neuroimaging demonstrates multiple concentric ring-enhancing lesions that may have mass effect (Fig. 4–3); typical multiple sclerosis lesions are also observable

ii.

cerebrospinal fluid usually exhibits monocyte pleocytosis and occasionally oligoclonal bands

d.

treatment: as per multiple sclerosis

e.

prognosis: usually has a fatal outcome within a few weeks, although spontaneous remission is possible; survivors do not reliably develop multiple sclerosis

Schilder’s Disease

Acute Disseminated Encephalomyelitis (ADEM)

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✧ This unclear disease entity typically is

thought to have a monophasic course of focal neurological injury and elevated intracranial pressure. ✧ Neuroimaging often demonstrates large enhancing lesions with mass effect.

IV. Acute Disseminated Encephalomyelitis (ADEM) 1.

Pathophysiology: typically develops during or within 2 weeks of a preceding infection with measles, rubella, smallpox, or chickenpox, or after a vaccination (rabies or smallpox vaccines), although a preceding infection or vaccination is not necessary to establish the diagnosis a.

mumps, influenza, and Mycoplasma pneumoniae upper respiratory tract infection are rare associations

2.

Histology: diffuse and extensive demyelination with axonal sparing involving perivascular cuffing with lymphocytes and reactive astrocyte hyperplasia; demyelination often involves the cortical–subcortical junction

3.

Epidemiology: common in children

4.

Symptoms: acute-onset multifocal neurological abnormalities that increase in severity over a few days and that may involve any part of the brain and spinal cord; ADEM typically has encephalopathy, fever, meningismus, and (possibly) seizures

Figure 4–3 Balo’s concentric sclerosis demonstrating the hallmark alternating layers of demyelination and preserved myelin (straight arrow), as well as a confluent area of demyelination (curved arrow). (From Gharagozloo AM, Poe LB, Collins GH. Antemortem diagnosis of Balo concentric sclerosis. Radiology 1994; 191:818, Fig. 2A. Reprinted by permission.)

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Diagnostic testing a.

b.

4 Disorders of Myelination

10:12 AM

cerebrospinal fluid exhibits mild lymphocytosis and increased protein but a normal opening pressure i.

differentiate ADEM from Reye syndrome, which has normal cerebrospinal fluid and elevated serum ammonia levels; oligoclonal bands are likely to be present in postinfectious ADEM

ii.

serology also for measles, mumps, varicella zoster, and herpes simplex virus (HSV)

neuroimaging: unlike the MRI lesions of multiple sclerosis, ADEM may involve the basal ganglia and thalamus, and have large confluent lesions with mass effect (Fig. 4–4)

6.

Treatment: High-dose glucocorticoids; IVg, cyclophosphamide, or plasmapheresis in refractory cases

7.

Prognosis: 20% mortality and at least 35% eventually will develop multiple sclerosis a.

Figure 4–4 Acute disseminated encephalomyelitis. (From McKhann GM et al. Q&A Color Review of Clinical Neurology and Neurosurgery. Stuttgart, Germany: Georg Thieme; 2003:145, Fig. 146a. Reprinted by permission.)

focal neurological deficits generally improve but 95% survivors with infectious ADEM and 30% with postvaccine ADEM have residual psychiatric disorders, dementia, or epilepsy

V. Acute Necrotizing Hemorrhagic Encephalomyelitis 1.

Pathophysiology: essentially a hyperacute form of ADEM that may be associated with Mycoplasma pneumoniae upper respiratory tract infection a.

histology: intense lymphocytic perivascular inflammation with necrosis and hemorrhage from small blood vessels, causing petechiae; progresses to liquefactive destruction of the white matter of both hemispheres, brainstem, and cerebellar peduncles

2.

Symptoms: initially meningitis-like symptoms but rapidly develops seizures and focal neurological injury; progresses to coma that rapidly is fatal

3.

Diagnostic testing a.

systemic evidence of infection (e.g., increased WBC count)

b.

cerebrospinal fluid exhibits increased opening pressure, monocytosis, increased protein, and normal glucose

c.

neuroimaging: large areas of increased T2 signal intensity with small areas of reduced T2 signal representing hemorrhage; lesions have significant edema and mass effect

4.

Treatment: as per multiple sclerosis

5.

Prognosis: usually fatal within several days

VI. Nutrition- and Electrolyte-Related Demyelinating Disorders 1.

Central pontine myelinosis a.

112

pathophysiology: usually occurs as a reaction to the rapid correction of severe, long-standing (i.e.,  2-day duration) hyponatremia i.

prolonged systemic hyponatremia causes loss of sodium and potassium from the brain interstitial fluid into the cerebrospinal fluid, and the loss of intracellular organic molecules (e.g., myoinositol, taurine, glutamate) that maintain cellular tonicity; rapid increases in the extracellular tonicity do not permit water equilibration with the intracellular environment, thereby causing cell death

ii.

particularly at risk are alcoholics (e.g., 10% occurrence after Wernicke’s encephalopathy), burn victims, patients with liver failure or transplantation, anorexics, malnourished patients, and patients on prolonged diuretic therapy

Figure 4–5 Central pontine myelinosis. (From McKhann GM et al. Q&A Color Review of Clinical Neurology and Neurosurgery. Stuttgart, Germany: Georg Thieme; 2003: 11, Fig. 2. Reprinted by permission.)

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iii. histology: symmetric areas of myelin sheath splitting with some axon swelling that does not lead to axon loss; inflammation develops several days after injury (1) involves a large demyelinating lesion in the center of the pons that spares a rim of the tegmentum and does not involving the tectum (Fig. 4–5); 10% also have demyelinating lesions elsewhere in the brain symptoms: usually has a biphasic course that progresses over several days i.

encephalopathy and seizures caused by hyponatremia, which remit with correction to normonatremia

ii.

dysarthria and dysphagia developing several days after correction to normonatremia, progressing to flaccid quadriparesis {locked-in syndrome} (1) involvement of the tegmentum may result in pupillary and ocular motor abnormalities

c.

d. 2.

treatment: prevention with gradual correction of hyponatremia, for example, no more than 8 mmol/L in 24 hours using 3% saline required sodium in mmol  ([Na]target  [Na]actual) • (30 L) (Box 4.3)

Box 4.3

wherein 1 mL of 3% saline has 0.5 mmol Na

30 L is estimated body volume

prognosis: unpredictable recovery

Marchiafava-Bignami disease a.

pathophysiology: classically described in chronic alcoholics who drink red wine but may occur in any alcoholic or malnourished patient; no known relation to nutritional deficiency, although associated with niacin deficiency (i.e., pellagra; see Chapter 13) i.

histology: symmetric areas of demyelination develop in the corpus callosum with histological changes similar to central pontine myelinosis but more frequently involving necrosis; demyelination may occur in any other region of white matter including the optic nerves

b.

symptoms: most commonly resembles a rapid-onset frontal lobe dementia but its clinical course is highly variable and dependant upon the location of demyelination

c.

treatment: vitamin supplementation

d.

prognosis: often remits but may be acutely fatal

VII. Dysmyelinating Disorder (Box 4.4)

Box 4.4

1.

“Dysmyelinating disease” is a misnomer— these diseases are not always characterized by abnormal myelin.

Pelizaeus-Merzbacher disease a.

pathophysiology: caused by abnormalities of the proteolipid protein (PLP) gene (Box 4.5); alternative splicing of this gene produces PLP (which accounts for 50% of myelin protein) and DM-20 protein (a minor myelin protein), which are necessary for myelin compaction i.

Dysmyelinating Disorder

b.

abnormalities in the PLP gene (1) segmental aberrations: cause PLP overproduction; phenotype is of variable severity, depending upon involvement of surrounding genes

Box 4.5 PLP is also mutated in a hereditary spastic paraplegia (SPG-2)

(2) point mutations that prevent PLP translation: causes dysmyelination; phenotype is mild (3) point mutations that cause incorrect PLP folding: causes oligodendrocyte apoptosis; phenotype is severe (4) complete gene deletion: prevents PLP production; causes dysmyelination; phenotype is mild ii.

X-linked inheritance; mosaic inactivation of the X chromosome in heterozygous females leads to (1) no symptoms if the abnormal PLP gene causes oligodendrocyte apoptosis because the few dead oligodendrocytes are replaced by healthy oligodendrocytes

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(2) minimal, transient symptoms during childhood if abnormal PLP gene only causes abnormal myelin compaction iii. histology (1) with oligodendrocyte apoptosis: patchy, tiger skin-like (“tigroid”) myelination with a reduced number of oligodendrocytes (Fig. 4–6); severity may be such that no myelin or oligodendrocytes are present in affected areas

4 Disorders of Myelination

(2) with abnormal oligodendrocyte myelination: diffusely reduced myelin staining of the white matter with a normal number of oligodendrocytes b.

symptoms (Table 4–2)

c.

diagnostic testing: genetic testing for PLP duplications i.

2.

neuroimaging: large, symmetric areas of increased T2 signal in the white matter with diffuse atrophy

d.

treatment: none specific

e.

prognosis: severe disease with stridor causes death by 10 years of age

Alexander’s disease a.

b.

pathophysiology: caused by mutations in i.

glial fibrillary acidic protein (GFAP) (in 90% cases): mutations cause a toxic gain-of-function that disrupts the normal ability of astrocytes to maintain oligodendrocyte viability

ii.

nicotinamide adenine dinucleotide (NADH) ubiquinone oxidoreductase flavoprotein-1: an uncommon association that has yet to be substantiated by autopsy confirmation

Figure 4–6 T2-weighted MRI scans through the centrum semiovale demonstrate inhomogeneous signals corresponding to areas of myelination in otherwise widely unmyelinated white matter {tigroid myelination}. (From Plecko B et al. Degree of hypomyelination and magnetic resonance spectroscopy findings in patients with Pelizaeus Merzbacher phenotype. Neuropediat 2003; 34:132, Fig. 4A. Reprinted by permission.)

histology i.

infants: a failure of normal central nervous system myelination followed by demyelination that is associated with eosinophilic inclusion bodies in swollen astrocyte processes {Rosenthal fibers}; areas with these abnormalities develop in a perivascular and subependymal distribution

ii.

adult form: central nervous system demyelination is minimal; the key histological feature is a predominance of Rosenthal fibers that contain GFAP, heat-shock proteins, and --crystallin (1) difficult to distinguish from multiple sclerosis or conditions with reactive gliosis, which also have Rosenthal fibers

c.

Box 4.6

symptoms (Box 4.6) i.

infantile form: onset of symptoms  2 years of age (1) developmental regression; megalencephaly with progressive head enlargement that can be (but is not always) due to underlying hydrocephalus (2) spasticity (3) seizures

Table 4–2 Symptoms of Diseases with Proteolipid Protein (PLP) Abnormalities Neonatal PMD

Classic PMD

Spastic paraplegic type 2

Intellectual impairment

Severe

Mild

Mild

Motor impairment

Severe

Mild

Mild

Speech acquisition

None

Normal

Motor aphasia

Ataxia

Severe

Mild

Mild

Nystagmus

Present

Present

Absent

Other features

Stridor, seizures

Dystonias

Vision loss

Abbreviations: PMD, Pelizaeus-Merzbacher disease.

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Symptomatically, Alexander’s disease is indistinguishable from Canavan’s disease

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juvenile form: onset at 3–6 years of age; symptoms are a mix between infantile and adult forms, with more signs of brainstem dysfunction but a slower progressive dementia

iii. adult form (rare): exhibits relapsing-remitting course like multiple sclerosis; symptoms include spastic paraparesis, ataxia, and palatal myoclonus d.

diagnostic testing i.

neuroimaging: decreased white matter density initially in the frontal lobes that progresses to all areas of white matter throughout the brain, often contrast enhancing in areas of active demyelination

(2) late in the disease, generalized brain atrophy with cystic white matter degeneration develops, often with hydrocephalus ii.

3.

brain biopsy demonstrates demyelination and Rosenthal fibers; electron microscopy demonstrates increased number of cytoplasmic projections on astrocytes

e.

treatment: none specific

f.

prognosis: usually death within 10 years of symptomatic onset

Canavan’s disease/spongy degeneration of infancy a.

pathophysiology: caused by an autosomal recessive deficiency of aspartoacylase causes accumulation of N-acetylaspartate (NAA), which acts as an osmolite producing cellular edema that leads to spongiform degeneration of white matter

b.

symptoms: develop by 1 years of age i.

neonatal hypotonia that develops into spasticity

ii.

progressive macrocephaly

Dysmyelinating Disorder

(1) initially the subcortical white matter, diencephalon, and brainstem are spared

iii. dysphagia iv.

vision loss from optic nerve atrophy

v.

stimulation-induced posturing that involves extension of the lower extremity, flexion of the upper extremity, and head extension

vi. seizures c.

diagnostic testing i.

NAA levels in the urine  50-fold normal levels

ii.

reduced aspartoacylase activity in fibroblasts

iii. magnetic resonance spectroscopy demonstrates an increased NAA peak d. 4.

treatment: none specific; reduce intracranial pressure with acetazolamide

Vanishing white matter disease/childhood ataxia with central nervous system hypomyelination/myelopathia centralis diffusa a.

pathophysiology: caused by mutations in the gene for the EIF2B translation regulating protein on chromosome 3, which acts to downregulate protein synthesis in response to cell stressors i.

b.

symptoms: progressive ataxia and spasticity with relative preservation of cognition; optic atrophy and seizures develop late in the disease i.

c.

histology: leukoencephalopathy with cavitation but no evidence of myelin products in the form of inclusion bodies

fever or other metabolic stress can produce clinical deterioration

diagnostic testing i.

cerebrospinal fluid exhibits elevated glycine levels, although this is nonspecific for leukoencephalopathies or other diseases of the white matter

ii.

neuroimaging

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(1) MRI demonstrates diffuse increases in T2 signal in the subcortical white matter with evidence of cystic degeneration that leaves intervening strands of relatively normal tissue (2) magnetic resonance spectroscopy demonstrates reduced NAA, choline, and creatinine levels, and an increase in glucose and lactate levels; such changes are consistent with a replacement of tissue with cerebrospinal fluid d. 5.

Megaloencephalic leukoencephalopathy with subcortical cysts/vacuolating leukoencephalopathy a.

4 Disorders of Myelination

treatment: none specific

pathophysiology: caused by autosomal recessive-inherited mutations of the MLC1 gene on chromosome 22, which has an unknown function i.

histology: oligodendrocytes exhibit abnormal compaction of the outermost layers of the myelin sheath

b.

symptoms: macrocephaly with developmental delay particularly in motor function; mild mental retardation; seizures

c.

diagnostic testing i.

neuroimaging: MRI demonstrates diffusely increased T2 signal in the subcortical white matter associated with cystic degeneration that is particularly pronounced in the temporal lobes (1) cystic degeneration progresses with time; white matter signal changes are static

d. 6.

treatment: none specific

Aicardi-Goutieres syndrome a.

pathophysiology: caused by autosomal recessive-inheritance of the ASG1 locus, which causes an increased expression of interferon- thereby causing demyelination and diffuse atrophy; appears to be associated with corticallybased infarctions as well i.

histology: areas of inflammatory demyelination involve cavitation and infiltration with gemistocytic macrophages that contain neutral fats; dystrophic calcifications in the white matter, basal ganglia, thalamus, cerebellar nuclei, and cerebral arteries also occur (1) such abnormalities are commonly found after in utero infection with the toxoplasma, other viruses, rubella, cytomegalovirus, herpes simplex (TORCH) organisms

b.

symptoms: acquired microcephaly with mental retardation and loss of developmental milestones; skin lesions (erythema, acrocyanosis)

c.

diagnostic testing

d. 7.

i.

cerebrospinal fluid demonstrates a chronic lymphocytosis and increased levels of interferon-

ii.

neuroimaging demonstrates dystrophic calcifications, infarctions, and white matter loss

treatment: none specific

Adrenoleukodystrophy a.

pathophysiology: X-linked inherited mutation in the ALD gene, which encodes peroxisomal acyl-CoA synthetase that is involved in very long chain fatty acid (VLCFA) oxidization in the peroxisome; causes accumulation of VLCFA in blood and tissues i.

b.

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histology: perivascular lymphocyte infiltration and demyelination that spares only arcuate fibers; typically begins in the parietal and occipital lobes

symptoms i.

general symptoms: adrenal failure; testicular atrophy

ii.

neurological symptoms, according to subtype (1) childhood adrenoleukodystrophy: onset around 4 years of age but may develop in adolescence

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(a) hyperactivity, initially appearing as attention deficit hyperactivity disorder (b) dementia progressing to vegetative state within 2–3 years (c) gait ataxia (d) vision and hearing loss (e) seizures (2) adult-onset adrenoleukodystrophy (rare): symptoms include slowly progressive dementia, and psychosis or mood disorders (3) adrenomyeloneuropathy: onset around 30 years of age (a) progressive spastic paraparesis with bowel and bladder incontinence, and sexual dysfunction

Dysmyelinating Disorder

(b) sensorimotor neuropathy (c) mild dementia, mood disorders c.

diagnostic testing i.

increased VLCFA levels in blood or amniotic fluid

ii.

reduced urine androgens and glucocorticoids

iii. genetic testing to confirm carriers, 10% of whom have normal VLCFA levels iv. d.

neuroimaging: increased white matter T2 signal, particularly in posterior regions

treatment i.

glucocorticoid supplementation for adrenal failure

ii.

dietary fatty acid supplements (“Lorenzo’s oil”) does not reduce disease progression, but it may be beneficial if initiated in the presymptomatic state

iii. bone marrow transplantation only when neurological symptoms are mild and there is enhancement of brain lesions on the MRI 8.

Metachromatic leukodystrophy a.

pathophysiology: autosomal recessive inherited mutation of arylsulfatase A (Box 4.7), which converts sulfatide to galactocerebroside in the sphingolipid metabolic pathway; alternatively, may be caused by loss of the saposin B cofactor for arylsulfatase A i.

b.

histology: diffuse demyelination of the brain sparing U-fibers and the peripheral nerves; accumulation of sulfated lipids in neurons of the central and peripheral nervous system causes a change from blue to brown or red {metachromasia} when stained with toluidine blue or cresyl violet, respectively

Box 4.7 Benign deficiency of arylsulfatase A occurs in 1% of the population {aminosalicylic acid (ASA) pseudodeficiency}.

symptoms according to subtype i.

infantile metachromatic leukodystrophy: vision loss from optic atrophy; spastic ataxia with minimal extrapyramidal features; dementia; seizures

ii.

juvenile metachromatic leukodystrophy: behavioral change and mental retardation; spastic ataxia with extrapyramidal features

iii. adult metachromatic leukodystrophy: behavioral change, psychosis, and dementia

9.

c.

diagnostic testing: increased urine sulfatides, confirmed by reduced arylsulfatase activity or saposin B levels

d.

treatment: bone marrow transplantation, performed before the onset of significant neurological disease

Krabbe’s disease/globoid cell leukodystrophy a.

pathophysiology: autosomal recessive inherited deficiency of galactosylceramidase, which converts galactosylceramide into ceramide in the sphingolipid metabolic pathway; affects both central and peripheral nervous systems

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4 Disorders of Myelination

b.

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histology: galactosylceramide attracts and is phagocytized by macrophages that store the indigestible PAS-positive material {globoid cells}; advanced disease exhibits extensive fibrillary astrocytosis in areas of demyelination

symptoms according to subtype i.

infantile Krabbe’s disease: begins with an exaggerated startle reflex, fevers, and behavioral regression, but progresses to involve atrophy and spastic weakness

ii.

juvenile Krabbe’s disease: symptoms include vision loss, ataxia, behavioral regression, and spastic paraparesis

c.

diagnostic testing: enzymatic assay to evaluate for deficiency of galactosylceramidase

d.

treatment: bone marrow transplantation, performed before the onset of significant neurological disease

10. Giant cell neuropathy (see p. 221); phenylketonuria (see p. 279)

Appendix 4–1 Glucocorticoids* Steroid

Anti-inflammatory potency (vs. prednisone)

Prednisone dose equivalents

Mineralocorticoid potency (vs. prednisone)

Notes

Prednisone

–

–

–

PO form only

Prednisolone

1.25

1

1

PO and IV forms

Methylprednisolone

1.25

0.8

0

Triamcinolone

1.25

0.8

0

Dexamethasone

7.5

0.15

0

Fludrocortisone

2.5

0.4

830

Can be administered by IM injection; high rate of steroid myopathy Useful in orthostatic hypotension and dysautonomia

*Complications of glucocorticoid use: Psychosis, headache, from intracranial hypertension; peptic ulcers; hypertension from fluid retention (when using steroids with high mineralocorticoid potency); glucose intolerance and iatrogenic diabetes; opportunistic infections and poor wound healing (long-term use); cataracts, osteoporosis (long-term use); adrenal suppression: truncal obesity with muscle atrophy, hypertension, depression, hirsutism, amenorrhea, cutaneous striae. Complications of glucocorticoid withdrawal: Nausea, weight loss; diffuse myalgias and arthralgias; fatigue; orthostatic hypotension. Abbreviations: IM, intramuscularly.

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5 Central Nervous System Tumors

Tumors of the Nervous System

Note: Significant diseases are indicated in bold and syndromes in italics.

I. Central Nervous System Tumors A. Astrocytic Tumors 1.

Fibrillary astrocytomas a.

b.

tumor grades (Table 5–1) (Fig. 5–1): all exhibit nuclear atypia; can be cytologically defined as malignant according to MIB-1 antibody labeling of the Ki-67 nuclear antigen, which is a protein of unknown function that is expressed only during mitosis (Box 5.1)

Box 5.1 MIB-1-labeled Ki-67 ratio  The number of labeled cells divided by the number of unlabeled cells ✧ Histologically benign tumors with a good prognosis have a low MIB-1-labeled Ki-67 ratio, if not undetectable MIB-1 labeling ✧ Histologically benign tumors with a poor prognosis have a high MIB-1-labeled Ki-67 ratio

genetics (Fig. 5–2) i.

mutations of the p53 gene, which encodes a cell-cycle regulator that inhibits progression through G1 phase of mitosis; uncommon in primary glioblastoma

ii.

mutations of the MDM2 gene, which encodes a protein that binds p53 protein (1) mutations may cause overexpression of MDM2 protein, which leads to tumor formation by reducing levels of p53 (2) MDM2 protein also binds mutant p53, thus functional loss of MDM2 may allow abnormally active p53 to cause tumor formation

iii. mutations of the epidermal growth factor (EGF) receptor gene, which encodes the receptor for EGF and tumor growth factor (TGF)- (1) mutations may cause overexpression of mutant EGF receptor that are constitutively active (i.e., do not require ligand binding) (2) even without mutations, wild-type EGF receptor and related receptors (i.e., fibroblast growth factor receptor, vascular endothelial growth factor receptor) are commonly overexpressed in low-grade astrocytomas iv.

platelet-derived growth factor- (PDGF), which is involved in cell proliferation

Table 5–1 Grades of Astrocytomas Grade*

Mitosis

Pleomorphic cells

Vascular proliferation

Necrosis

Other features

II: Diffuse

No

No

No

No

–

III: Anaplastic

Yes

No

No

No

–

IV: Glioblastoma multiforme

Yes

Yes

Yes

Yes

Microvascular, glomeruli, drape-like cellularity {festoons}; “pseudopalisading”

*WHO grade I tumor (pilocytic astrocytoma) is an uncommon astrocytic tumor (see p. 121).

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Figure 5–1 Glioblastoma multiforme. Arrows identify pseudopalisading and festoons.

v.

mutations in the retinoblastoma (RB) factor gene (Box 5.2), which encodes an inhibitory binding protein for transcription factor E2F that promotes proliferation; mutations of RB factor allows inappropriate release of active E2F and progression through G1 phase of mitosis

Box 5.3 CDKN2A also mutated in oligodendrogliomas.

vii. loss of heterozygosity (LOH) on chromosomes 19 and 10: deletion of an unknown gene or genes on one pair of the chromosomes

Box 5.4

(a) the leucine-rich glioma-inactivated (LGI-1) protein (Box 5.4) (b) PTEN, a tumor suppressor gene tumor location: supratentorial  infratentorial, rarely cerebellum or spinal cord; may be multifocal i.

d.

Retinoblastma factor gene is also mutated in cases of retinoblastoma

vi. mutations of the CDKN2A (Box 5.3), which encode protein kinases that inhibit progression through the cell cycle by affecting the function of RB and p53

(1) LOH 10 region includes

c.

Box 5.2

tumors grow along white matter tracts and vasculature, occasionally disseminating into the CSF {seeding}, particularly with tumors in the cerebellum, corpus callosum, or along the ventricles (Box 5.5)

epidemiology: accounts for 60% of primary brain tumors in adults; only known risk factor is brain irradiation

LGI-1 is mutated in autosomal dominant partial epilepsy with auditory features

Box 5.5 Tumors with High “Seeding” Potential ✧ Glioblastoma ✧ Medulloblastoma ✧ Primitive neuroepidermal tumors ✧ Ependymoma ✧ Pineoblastoma ✧ Germinoma ✧ Choroid plexus papilloma

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Figure 5–2 Genetic abnormalities of astrocytomas. (EGFR, epidermal growth factor receptor; LOH, loss of heterozygosity; RB, retinoblastoma.)

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treatment i.

grade II/diffuse astrocytoma: observation, or treatment with irradiation or chemotherapy

ii.

grade III/anaplastic astrocytoma: surgery  irradiation  chemotherapy

iii. grade IV/glioblastoma multiforme: surgery  chemotherapy (temozolomide)  irradiation prognosis i.

grade II/diffuse astrocytoma: 5-year survival

ii.

grade III/anaplastic astrocytoma: 2.5-year survival

iii. grade IV/glioblastoma multiforme:  1-year survival 2.

Uncommon types of astrocytomas a.

juvenile pilocytic astrocytoma—grade I astrocytoma of the WHO classification i.

histology: tumor exhibits a dense cellular areas filled with long bipolar astrocytes and numerous Rosenthal fibers, which are interspersed with relatively cell-free regions (Fig. 5–3); also exhibits eosinophilic granular bodies

Figure 5–3 Juvenile pilocytic astrocytoma exhibits alternating compact and spongy areas that give a “floating” appearance to some of the cells. Multinucleated giant cells are also seen. (From Keating R et al. Tumors of the Pediatric Central Nervous System. Stuttgart, Germany: Georg Thieme; 2001:53, Fig. 5–6c. Reprinted by permission.)

(1) forms a large cystic mass when located in the cerebellum but a solid tumors when located elsewhere

Central Nervous System Tumors

f.

(2) strongly associated with neurofibromatosis I ii.

tumor location: cerebellum  hypothalamus, optic nerve

iii. epidemiology: common only in children iv. b.

treatment: surgery is usually curative; tumors in the optic-hypothalamic area respond to chemotherapy with carboplatin and vincristine

subependymal giant cell astrocytoma i.

histology: tumor typically consists of giant astrocytes mixed with differentiated neuron-like cells in a heavily calcified stroma (Fig. 5–4) (1) no anaplastic potential although exhibits locally invasive growth (2) typically grow along ependymal surface of lateral ventricles, may block cerebrospinal fluid flow causing hydrocephalus (3) associated with (a) soft-tissue sarcomas and breast cancer {Li-Fraumeni syndrome} (b) multiple intestinal polyps {Turcot syndrome} (c) phakomatoses: tuberous (see Chapter 12)

ii. c.

sclerosis,

neurofibromatosis-1

treatment: observation; surgery if the tumor grows or causes hydrocephalus

pleomorphic xanthoastrocytoma i.

histology: tumor exhibits pleomorphic astrocytes (therefore is glial fibrillary acidic protein- [GFAP] positive) filled with lipid vacuoles like adipocytes, but that are rarely mitotic; exhibits a dense reticulin network and a lymphocytic infiltrate, and can be cystic (1) very benign growth (rarely degenerate into malignant tumors), and only are symptomatic when they cause seizures

ii.

epidemiology: common in children

iii. tumor location: cortex (particularly temporal lobe), often extending into the subarachnoid space iv.

treatment: surgery is usually curative

Figure 5–4 Subependymal giant cell astrocytoma. (From Keating R et al. Tumors of the Pediatric Central Nervous System. Stuttgart, Germany: Georg Thieme; 2001:330, Fig. 23–3. Reprinted by permission.)

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B. Oligodendrogliomas

5 Tumors of the Nervous System

1.

122

Histology: composed of small, round cells that are GFAP-negative and that develop from oligodendrocytes a.

cells exhibit “fried egg” artifact and “chicken wire” vasculature after formalin fixation (Fig. 5–5), resembling the non-artifactual appearance of clear cell ependymomas or central neurocytomas

b.

50% of oligodendrogliomas have a mixed histology with pronounced astrocytoma features {oligoastrocytoma} that may ultimately degenerate into a malignant astrocytoma i.

both oligodendrocyte and astrocyte components show evidence of malignancy in oligoastrocytomas, that is, astrocytes are not simply trapped in an oligodendroglioma

c.

frequently are calcified, or have hemorrhagic or cystic components

d.

tumor location: often developing at the gray–white junction and growing toward the cortex, particularly in the frontal lobe

Figure 5–5 Oligodendroglioma histology. (Courtesy of Dr. C. Yamada)

2.

Tumor grades: histologically defined as low grade or anaplastic by the presence of mitosis, pleomorphism, vascular proliferation, and necrosis, as per astrocytomas; cytologically defined as malignant according to MIB-1 antibody labeling, as per astrocytomas

3.

Genetics a.

p53 gene mutations

b.

epidermal growth factor, platelet-derived growth factor, and vascular endothelial growth factor overexpression occurs without gene amplification

c.

loss of heterogeneity (LOH): low-grade oligodendrogliomas have LOH on chromosomes 1 or 19; high-grade oligodendrogliomas also have LOH on chromosomes 9 or 10 (Box 5.6)

d.

mutations in the CDKN2A gene, which encode the p16 protein cycle regulator (Box 5.7)

4.

Tumor location: frontal  temporal, parietal  occipital cortex; location is proportionate to the amount of white matter in these areas

5.

Epidemiology: bimodal peak incidences in children 8 years of age and adults 40 years of age

6.

Diagnostic testing: Exhibits heterogeneous densities on neuroimaging, most of which are calcified (“chunky” or “popcorn-like” calcification) (Fig. 5–6)

7.

Treatment a.

surgery  irradiation (may only observe low-grade oligodendrogliomas after surgery)

b.

chemotherapy: highly sensitive to PCV treatment (procarbazine, lomustine [CCNU], vincristine) or temozolomide (Temodar), particularly rapidly enlarging tumors with ring enhancement i.

response to chemotherapy is not related to MIB-1-labeled Ki-67 ratio but it is proportionate to the amount of oligodendroglial-like cells in the tumor

ii.

tumors with LOH 1 or 119 have greater chemotherapy responsiveness

Box 5.6 LOHs and CDKN2A mutations define two major subtypes of oligodendrogliomas

Box 5.7 CDK 4/6 genes are mutated in astrocytomas

8.

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Prognosis: Tumors with LOH 1 or 119 are associated with longer survival times; tumors with CDKN2A gene deletions are associated with shorter survival times a.

histologically defined benign oligodendroglioma i.

MIB-1-labeled Ki-67 ratio  5%  80% 5-year survival

ii.

MIB-1-labeled Ki-67 ratio  5%  25% 5-year survival

b.

histologically defined anaplastic oligodendroglioma: 20% 5-year-survival overall

c.

oligoastrocytoma: 60% 5-year survival

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C. Gliomatosis Cerebri 1.

Histology: a diffuse infiltration of brain parenchyma by neoplastic glial cells, generally occurring in multiple cerebral lobes but occasionally infratentorial a.

can develop from glial tumors (20%), but usually develops without preexisting tumor

b.

exhibits oligodendroglial, astrocytic, or mixed subtypes

2.

Symptoms: generally presents with seizures; may have a focal deficit (30%), dementia (30%), or headache (10%)

3.

Diagnostic testing: often is nonenhancing on neuroimaging

4.

Treatment: depends upon histology but typically treated with irradiation  chemotherapy

5.

Prognosis: 12-month-survival untreated, 2.5-year-survival treated a.

Figure 5–6 Oligodendroglioma calcifications. (From Fischbein NJ et al. Teaching Atlas of Brain Imaging. Stuttgart, Germany: Georg Thieme; 2000:10, Fig. A. Reprinted by permission.)

patients with oligodendroglial subtype have a significantly longer survival

D. Meningiomas 1.

Histology (Fig. 5–7): the MIB-1 antibody labeling of the Ki-67 antigen can provide a cytological definition of malignancy, as with astrocytomas and oligodendrogliomas a.

WHO grade I subtypes i.

meningothelial meningioma—exhibits groups of tumor cells surrounded by thin collagenous septa that are difficult to visualize, giving the impression of a syncytium

ii.

fibrous meningioma—appears similar to dense connective tissue

iii. transitional meningioma—exhibits clumps of cells surrounded by whorls of more cells {onion bulbs}; has elements of meningothelial and fibrous subtypes iv.

psammomatous meningioma—exhibits numerous laminated calcifications at the center of onion bulbs {psammoma bodies} that may become confluent and calcified

v.

angiomatous meningioma—appears similar to the meningothelial subtype but has a pronounced vascular component

vi. secretory meningioma—focal epithelial differentiation forms a lumen containing accumulation of glucose polymers (i.e., periodic acid Schiffpositive) vii. lymphocyte-rich meningioma—exhibits chronic inflammatory infiltrates

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A

B

C

D

Figure 5–7 Types of meningiomas: meningothelial (A); fibrous (B); transitional, demonstrating onion bulbs (C); psammomatous, demonstrating psammoma bodies (D). (Courtesy of Dr. C. Yamada)

b.

WHO grade II subtypes i.

clear cell meningioma—meningothelial-like but cells have clear, glycogen-rich cytoplasm

ii.

chordoid meningioma—exhibits cartilagelike myxoid extracellular matrix

iii. atypical meningioma—exhibits increased mitotic activity, hypercellularity, and necrosis c.

WHO grade III subtype i.

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anaplastic/malignant meningioma—exhibits high mitotic index ( 20 mitoses per highpowered field)

2.

Tumor location: falx cerebri  olfactory groove, sphenoid ridges, parasellar region

3.

Genetics: risk of meningioma formation is increased by prior irradiation; exhibits direct or progressive development of aggressive tumors, as with astrocytomas

4.

a.

mutations in the neurofibromatosis 2 (NF-2) gene on chromosome 22, which encodes the merlin/ schwannomin protein that acts as a tumor suppressor: promotes development of low-grade meningiomas as part of neurofibromatosis type 2

b.

numerous loss of chromosomal heterogeneities promote development of malignant meningiomas

Diagnostic testing: neuroimaging demonstrates duralbased masses with tails (Fig. 5–8)

Figure 5–8 Meningioma with dural tails. (From Fischbein NJ et al. Teaching Atlas of Brain Imaging. Stuttgart, Germany: Georg Thieme; 2000:205, Fig. D. Reprinted by permission.)

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a.

growth may occur entirely along meningeal surface without forming a tumor mass {en plaque meningioma}

b.

edema is prominent only with the secretory, atypical, or anaplastic/ malignant subtypes

5.

Treatment: surgery; may add irradiation for atypical and anaplastic/malignant subtypes

6.

Prognosis: 20% 20-year-recurrence rate following complete resection, considering all subtypes; however, up to 80% recurrence rate with anaplastic meningiomas

Box 5.8

E. Pineal Tumors (Box 5.8) 1.

General histology: All subtypes develop from pinealocytes that have neuroendocrine potential a.

2.

pinealocyte-derived cells express the synaptic marker protein synaptophysin, neuron-specific enolase, tau protein, and serotonin

Pineocytoma a.

specific histology: tumors show lobular aggregates of well-differentiated pinealocytes arranged as rosettes (Fig. 5–9) i.

3.

Pediatric Pineal Region Tumors (In Order of Occurrence) ✧ Germinoma ✧ Astrocytoma ✧ Pineocytoma ✧ Teratoma ✧ Dermoid ✧ Pineoblastoma

under electron microscopy, pinealocytes may exhibit annulate lamellae-like photoreceptor cells of the retina

b.

treatment: surgery

c.

prognosis: 85% 5-year survival

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Pineoblastoma—a primitive neuroepidermal tumors (PNET; see below)

F. Primitive Neuroepidermal Tumors 1.

General histology: A group of densely cellular tumors similar in appearance to Ewing’s sarcoma, rhabdomyosarcoma, and lymphoma {small blue-cell tumors}

2.

Pineoblastoma a.

specific histology: similar to pineocytoma, except rosettes do not have a true lumen i.

associated with familial bilateral retinoblastoma {trilateral retinoblastoma syndrome}

Figure 5–9 Pineocytoma rosettes. (From Keating R et al. Tumors of the Pediatric Central Nervous System. Stuttgart, Germany: Georg Thieme; 2001:315, Fig. 22–8. Reprinted by permission.)

(1) frequently is metastatic via cerebrospinal fluid b.

genetics: mutations of the RB gene are common in cases of trilateral retinoblastoma (Box 5.9)

Box 5.9

c.

epidemiology: occurs in all ages, but mostly before 20 years of age

d.

treatment: surgery  irradiation, with prophylactic irradiation of the entire neuraxis for possible metastases

RB factor gene is also mutated in some astrocytomas

e.

prognosis: without metastasis, 60% 5-year survival i.

3.

presence of RB mutations is associated with lower survival

Neuroblastoma a.

specific histology: tumor exhibits numerous mitotic figures and focal necrosis; cells form Homer-Wright rosettes and may secrete bioactive substances (e.g., vasoactive intestinal polypeptides [VIP], catecholamines) i.

tumor location: peripheral tumors in mediastinum, paravertebral sympathetic chain ganglia, and adrenal glands; tends to occur around the olfactory nerves when they develop inside the cranium, otherwise it is a metastasis to the brain (Box 5.10)

Box 5.10 Neuroblastoma is the most common brain metastasis in children

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diffuse peripheral metastases associated with a small primary tumor in children  1 year of age often spontaneously resolve; rarely neuroblastoma differentiates into a ganglioneuroma

genetics i.

segmental rearrangements of chromosomes 17  1  3, 11

ii.

amplification of the MYCN gene, which encodes a nuclear transcription factor (1) particularly common in metastatic neuroblastomas

c.

specific symptoms (each occurs in  5% of cases) i.

paraparesis due to intraspinal extension

ii.

diarrhea from VIP secretion

Figure 5–10 Medulloblastoma demonstrating Homer-Wright rosettes (e.g., arrowhead at center). (From Bernstein M, Berger M. Neurooncology: The Essentials. Stuttgart, Germany: Georg Thieme; 2000:367, Fig. 364A. Reprinted by permission.)

iii. diaphoresis, palpitations, and flushing from sudden catecholamine release

d.

iv.

paraneoplastic syndromes: cerebellar degeneration, encephalomyelitis, and/or peripheral neuropathy related to anti-Hu antibodies; opsoclonusmyoclonus syndrome related to anti-Ri antibodies

v.

Horner’s syndrome with involvement of lower cervical ganglia

prognosis i.

expression of nerve growth factor/trk receptors, polyploidy (versus diploidy), and tumor calcifications are good prognostic signs (1) nerve growth factor receptors are normally expressed by neural crest cells that are developing into monoamine secreting cells (e.g., adrenal medulla); normal loss of trophic stimulation during development may cause apoptosis and spontaneous tumor regression

ii. 4.

Medulloblastoma—The most common PNET a.

126

presence of MYCN amplification is a poor prognostic sign in all tumor grades

specific histology: cells are GFAP-negative, hyperchromatic, and highly mitotic; tumors exhibit Homer-Wright rosettes with no lumen (Fig. 5–10), and necrosis with pseudopalisading similar to glioblastoma multiforme i.

develops from embryologic cells of the external germinal layer of the cerebellum

ii.

adult tumors associated with Turcot’s syndrome and Li-Fraumeni syndrome (see p. 121)

b.

tumor location: roof of 4th ventricle; 75% are midline, and 25% extend into the cerebellar parenchyma; frequently metastasize by direct extension through the subarachnoid space

c.

epidemiology: mostly occur in children and adolescents; smaller adult peak incidence in adults 30 to 40 years of age

d.

diagnostic testing: requires neuroimaging of the spine and cerebrospinal fluid analysis

e.

treatment: surgery  chemotherapy (CCNU  vincristine)  irradiation

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Figure 5–11 Ependymoma pseudorosettes. (From Hirano A. Color Atlas of Pathology of the Nervous System, 2nd Ed. Tokyo/New York: Igaku-Shoin Press; 1988:110, Fig. 265. Reprinted by permission.)

G. Ependymoma 1.

2.

General histology: all subtypes of ependymomas develop from the ependyma and have thin layers of well-differentiated cuboidal or columnar GFAPpositive epithelium (Box 5.11) and spherical or rod-shaped intracytoplasmic inclusions {blepharoplasts}; epithelium forms perivascular pseudorosettes (Fig. 5–11)

GFAP-Positive Tumors ✧ Astrocytomas

a.

blepharoplasts are analogous to the basal bodies of cilia and are located at apical portion of cells in ependymal rosettes

✧ Oligodendrogliomas

b.

may be low grade or anaplastic

✧ Primitive neuroepidermal tumors (PNETs)

Subtypes a.

classic ependymoma—exhibits perivascular pseudorosettes  ependymal rosettes

b.

clear cell ependymoma—cells exhibit prominent perinuclear halos resembling “fried egg” artifact of the oligodendroglioma and the central neurocytoma

c.

papillary ependymoma—resembles choroid plexus papilloma

d.

myxopapillary ependymoma—exhibits microcysts, mucin cuffs around blood vessels, and a highly spindled pilocytic glial background i.

3.

Box 5.11

✧ Ependymoma ✧ Gangliocytomas ✧ Hemangioblastomas

always located in the filum terminale; growth is benign

Tumor location: 60% are infratentorial, 90% of which are located in the 4th ventricle growing from the dorsal brainstem surface a.

infratentorial ependymoma is largely intraventricular, but in the 4th ventricle (Box 5.12) they often grow through the foramen of Luschka and Magendie into the subarachnoid space; supratentorial ependymomas can grow into the brain parenchyma

4.

Epidemiology: bimodal distribution in children (1 to 5 years of age) and adults (20 to 30 years of age)

5.

Diagnostic testing: requires spinal imaging and cerebrospinal fluid analysis to rule out drop metastases a.

CT: hypo-/isodense mass with heterogenous enhancement; 50% have “chunky” or “popcorn” calcifications like oligodendrogliomas

Box 5.12 The growth pattern for the infratentorial ependymoma is the same as in choroid plexus papilloma.

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Table 5–2 Choroid Plexus Papilloma versus Papillary Ependymoma

5 Tumors of the Nervous System

Choroid plexus papilloma

Papillary ependymoma

Organized cells

Scattered cells

Transthyretin-positive

Transthyretin-negative

GFAP-negative

GFAP-positive

Homogeneous enhancement

Heterogenous enhancement

Little stroma

Abundant stroma

Abbreviations: GFAP, glial fibrillary acidic protein.

b.

MRI: hypo-/isointense on T1 with heterogenous enhancement; hyperintense on T2 (Box 5.13)

6.

Treatment: surgery  irradiation

7.

Prognosis: 45% 5-year survival

Box 5.13 In comparison with the ependymoma, choroid plexus papilloma homogeneously enhances and medulloblastoma is denser and rarely calcified.

H. Choroid Plexus Papilloma 1.

2.

Histology: Tumors arise from the epithelium of the choroid plexus and exhibit a modified ependymal covering with a heavily vascularized stromal core that contains nests of transthyretin/prealbumin-positive cells a.

15% undergo malignant degeneration, but even then they do not invade brain parenchyma

b.

disorganization and crowding of the columnar cells in the fibrovascular stroma distinguishes choroid plexus papillomas from papillary ependymomas (Table 5–2)

Tumor location: in children, the atria of lateral ventricle; in adults, the 4th ventricle a.

metastasize via cerebrospinal fluid; may grow through the foramen of Luschka and Magendie into the subarachnoid space like ependymomas

3.

Epidemiology: most common in children  2 years old

4.

Diagnostic testing a.

CT: hyperdense, homogenous enhancement, frond-like morphology i.

b. 5.

25% are calcified; internal hemorrhage is common

MRI: homogenous enhancement with flow voids; often associated with hydrocephalus

Treatment: surgical, possibly with irradiation and chemotherapy if it proves carcinomatous

I. Colloid Cyst 1.

Histology: a cystic cavity lined by cuboidal or columnar epithelial cells that rests on a thin capsule composed of collagen and fibroblasts; epithelial cells are uniformly benign a.

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tumor enlarges by accumulation of epithelial secretions that form a gelatinous material ( “crank case oil” of craniopharyngioma or Rathke’s pouch cyst) rd

2.

Tumor location: anterior portion of the 3 ventricle between the columns of the fornix, and attached to the ventricular roof and choroid plexus (Box 5.14)

3.

Symptoms: often causes transient neurological symptoms; may even be fatal from acute hydrocephalus

4.

Diagnostic testing a.

CT: cyst usually is hyperdense, not hypodense

b.

MRI: cyst usually is low on T2 signal, not high; may exhibit hydrocephalus

Box 5.14 Tumors in the ventricles Lateral ventricle—Subependymoma (frontal); choroid plexus papilloma (atrium) Third ventricle—Colloid cyst, central neurocytoma Fourth ventricle—Ependymoma; ependymoblastoma (brainstem side); medulloblastoma (cerebellum side)

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Treatment: surgery; stereotactic aspiration or cerebrospinal fluid shunting is also sufficient

1.

Histology: tumors exhibit densely packed clear cells, similar to oligodendroglioma and clear cell ependymoma; has immunohistochemical and ultrastructural features suggesting neuronal differentiation (e.g., cells are synaptophysin-positive, GFAP-negative)

2.

Tumor location: arise from the septum pellucidum and 3rd ventricle, often filling lateral ventricles and obstructing cerebrospinal fluid outflow through foramen of Monroe; rarely involves periventricular brain parenchyma, and symptoms are usually due to hydrocephalus a.

despite its name, tumor is not always located along midline

3.

Diagnostic testing: neuroimaging demonstrates solid intraventricular tumor; cysts and calcification are common

4.

Treatment: surgery

K. Mixed Neuronal-Glial Tumors 1.

General symptoms: a common cause of medically refractory complex partial seizures in children and young adults

2.

Dysembryoplastic neuroepithelial tumor

3.

a.

histology: tumors are composed of neuronal elements with bundled axons that project into the subcortical white matter, and glial elements that resemble low-grade oligodendrogliomas; may actually be a type of hamartoma

b.

tumor location: mesial temporal lobe  other cortical areas

c.

treatment: surgery is curative

Central Nervous System Tumors

J. Central Neurocytoma

Gangliocytoma/ganglioglioma a.

histology: tumors contain both neural and glial elements; commonly has cyst formation and calcifications i.

neuronal component is large, mature multipolar neurons arranged in groups (1) neuronal component always has dysplastic features but is nonproliferative (2) neurons are synaptophysin-positive

ii.

glial component is astrocytic in nature (1) if glial components are neoplastic, the tumor is a ganglioglioma; otherwise it is a gangliocytoma

b.

tumor location: temporal, occipital, and frontal lobes

c.

epidemiology: common in children and young adults

d.

treatment: surgery; irradiation is necessary for nonresectable tumors or for malignant tumors

e.

prognosis: determined by neoplastic activity of the glial component

L. Germinoma 1.

Pathophysiology: a type of germ cell tumor that is similar to testicular seminomas and ovarian dysgerminomas; likely develops from germ cells that abnormally migrate from the yolk sack of the embryo and survive in certain regions of the brain a.

genetics: 90% of cases are associated with abnormalities on chromosome 12; also associated with polyploidy of chromosome X or 21 i.

increased risk of germ cell tumors occurs in Down’s and Klinefelter’s syndromes

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2.

Histology: composed of large regularly shaped cells often with interspersed lymphocytes; exhibits reactivity for alkaline phosphatase

3.

Tumor location: midline structures (e.g., pineal gland or suprasellar region); metastatic in 15%

4.

Diagnostic testing: cerebrospinal fluid often exhibits increased alkaline phosphatase levels; diagnosis must be established with tissue biopsy

5.

Treatment: irradiation  surgery

6.

Prognosis: 95% 5-year survival

M. Hemangioblastoma 1.

Histology: Cystic, noninfiltrative masses with sharp demarcation, formed from capillary overgrowth a.

occasionally express erythropoietin-like hormone from mast cells, causing a pure erythrocytosis (i.e., a secondary polycythemia)

b.

tumor location: cerebellar vermis  hemisphere i.

c.

2.

occurrence in spinal cord is associated with syringomyelia

20% of cases have autosomal dominant-inherited hemangioblastomas of the brain and retina, and visceral mesoderm tumors {von Hippel-Lindau disease}

Treatment: surgery

N. Chordoma 1.

Histology: composed of groups of epithelial cells embedded in a mucinous or cartilaginous matrix that develops from notochord remnants that did not appropriately form bone a.

becomes symptomatic in adulthood, usually with pain from local bone destruction

2.

Tumor location: sacrum  sphenoid bone, clivus  vertebrae

3.

Treatment: surgery  irradiation, particularly focused/stereotactic irradiation

4.

Prognosis: high recurrence rate

O. Metastasis 1.

2.

3.

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Epidemiology: 25% risk of developing brain metastasis given all patients with a peripheral primary tumor a.

20% are asymptomatic at time of diagnosis; 75% involve multiple metastases

b.

primary tumors below the diaphragm often present as posterior fossa metastases

Pathophysiology: metastasis most commonly occurs by hematogenous spread (conversely, brain abscesses can develop by either hematogenous spread or direct extension) a.

location of metastases is proportionate to blood flow, so 80% locate in the cortex in watershed areas that have multiple vascular supplies and relatively slow blood flow, or at the gray–white matter junction

b.

development of dedicated tumor vasculature is necessary for growth  1 mm

Subtypes a.

brain: lung (50%); breast (15%); skin/melanoma (10%); unknown (10%)

b.

epidural spine: breast (20%); lung (15%); prostate (10%); lymphoma (10%)

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Treatment a.

medical i.

glucocorticoids for relief of edema; antiepileptics only in patients with seizures

ii.

chemotherapy: effective if the primary tumor is sensitive

iii. whole-brain irradiation: 30 Gray irradiation divided over 10 sessions improves survival, regardless of the tumor type

iv.

stereotactic radiosurgery: fewer radiation-related complications than whole-brain irradiation but effective only for metastases  3 cm; can be used for  three metastases

b.

surgical: excision of single metastases reduces the likelihood of death from a neurological cause but does not improve overall survival i.

anecdotal evidence suggests that resection of two to three metastases may be beneficial

P. Primary Spinal Cord Tumors 1.

Figure 5–12 Intraparenchymal spinal cord tumor. Note ballooning of the spinal cord parenchyma and the lapering of the CSF space around it. (From McKhann GM et al. Q&A Color Review of Clinical Neurology and Neurosurgery. Stuttgart, Germany: Georg Thieme; 2003:139, Fig. 2. Reprinted by permission.)

Tumor location: distinguishing intraparenchymal, extraparenchymal–intradural, and extradural tumors a.

Central Nervous System Tumors

(1) no evidence of benefit of high-dose or highly fractionated irradiation schedules

imaging characteristics by location i.

intraparenchymal tumor causes widening of the cord (must be demonstrated in multiple views) with T2 signal abnormalities in the cord (Fig. 5–12); may or may not contrast enhance, depending upon the tumor type

ii.

extraparenchymal–intradural tumor causes widening of the ipsilateral subarachnoid gutter with cord displacement (“capping defect” appearance); contrast enhances

iii. extradural tumor causes thinning of the dural sac (“paint brush” appearance) (Fig. 5–13); tumors also cause cord edema and can occur at multiple levels 2.

Types of tumors a.

intraparenchymal (5%): low-grade astrocytoma, ependymoma

b.

extraparenchymal–intradural (40%): meningioma, neurofibroma, lipoma

c.

extradural (55%): metastasis (breast, prostate, lymphoma), chordoma, bone tumors (multiple myeloma)

Q. Carcinomatous Meningitis 1.

2.

Pathophysiology: occurs in 8% of all cancer patients on autopsy, although often it is microscopic and was asymptomatic during life a.

causative metastatic tumors: breast (35%), lung (20%), melanoma (20%), gastrointestinal (10%), lymphoma/leukemia (10%), unknown (5%)

b.

causative primary brain tumors: PNETs (i.e., medulloblastoma, ependymoblastoma), choroid plexus papilloma, primary central nervous system (CNS) lymphoma

Symptoms a.

polyradiculopathy (80%)

b.

multiple cranial neuropathies (65%)

Figure 5–13 Extradural spinal tumor. Note compression of the spinal cord parenchyma. (From McKhann GM et al. Q&A Color Review of Clinical Neurology and Neurosurgery. Stuttgart, Germany: Georg Thieme; 2003:160, Fig. 139. Reprinted by permission.)

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multifocal neurological injury (50%)

d.

endocrine abnormalities from hypothalamic involvement (5%)

e.

headache, nausea, and poorly defined visual changes

f.

stroke, from invasion of Virchow-Robins spaces by tumor

Diagnostic testing

5 Tumors of the Nervous System

lumbar puncture shows mildly increased pressure with Lundberg waves (see p. 35), mild pleocytosis (occasionally eosinophilic with leukemias and lymphomas), elevated protein, and decreased glucose ( 10 g/dL is nearly pathognomonic); rarely xanthochromia or frank hemorrhage with carcinomatous meningitis from melanoma i.

b.

5.

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c.

a.

4.

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repeat lumbar puncture for large-volume cytological analysis at least twice before accepting a negative result ( 90% accuracy)

MRI: nonspecific findings of dural thickening and enhancement on contrast T1 images; may involve nerve root enhancement, filling of the subarachnoid space, or small tumor masses or clumping of nerve roots in the cauda equina because of tumor-induced fusion

Treatment: irradiation to symptomatic areas  intrathecal chemotherapy (methotrexate, cytarabine, thiotepa) a.

may require ventricular access device (e.g., Ommaya reservoir) for intrathecal chemotherapy administration or ventriculoperitoneal shunt for hydrocephalus

b.

most intraventricular drugs are rapidly eliminated by bulk flow and poorly penetrate tissue

Prognosis: treatment nonresponders  2-month-mean survival; treatment responders  6-month-mean survival

R. General Medical Therapies of Brain Tumors 1.

Glucocorticoids: reduces tumor edema within hours of administration, which can improve focal neurological symptoms as well as reduce intracranial pressure a.

should be used prophylactically for 2 weeks after any irradiation

b.

cancer patients should simultaneously receive prophylaxis for Pneumocystis carinii (i.e., with Bactrim or dapsone) when on prolonged glucocorticoid treatment for  3 weeks

2.

Anticonvulsants: no evidence for prophylactic use in patients who have not had a seizure

3.

Anticoagulation: not contraindicated irrespective of type of tumor and its hemorrhage risk a.

no established benefit of using inferior vena cava filter instead of anticoagulants

II. Pituitary Tumors (Box 5.15) A. Adenomas 1.

2.

Pathophysiology: develop in anterior pituitary may be hormone-secreting or nonsecreting a.

poorly differentiated tumors rarely secrete multiple hormones

b.

most adenomas are a hypertrophic response to prolonged stimulation by hypothalamic-releasing hormones

c.

nonsecreting macroadenomas are incidental findings in 20% of the population

d.

posterior pituitary tumors tend to be astrocytomas

Histology: often exhibit evidence of small hemorrhages or amyloid deposits from collection of excess hormone protein (an endocrine amyloidosis) a.

132

rarely exhibits cellular features of malignancy but adenomas reliably invade bone and dura

Box 5.15 Empty sella syndrome: ✧ Chronic compression of the pituitary by a protrusion of the subarachnoid space forces the pituitary into posterior sella ✧ Occurs mostly in obese women; incidental finding in 5% ✧ Causes headache, visual field cuts, pituitary failure only in children

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Genetics a.

mutations of the GSPT1 gene, which encodes for stimulatory G-protein that limits growth hormone-releasing hormone (GHRH) stimulation of pituicytes; occurs in 40% of growth hormone- (GH) secreting adenomas

b.

many aggressive adenomas exhibit loss of chromosomal heterogeneity at several sites

4.

Epidemiology: common in adults 30 to 50 years of age

5.

Symptoms a.

bitemporal hemianopsia

b.

microadenoma ( 1 cm) or pituitary hypertrophy: symptoms caused by hormone secretion (in order of occurrence) i.

prolactin: causes amenorrhea and galactorrhea in women; impotence in men

ii.

GH: causes

Pituitary Tumors

(1) gigantism in children; acromegaly in adults (2) nerve entrapment (3) hyperthyroidism secondary to goiter formation (4) heart failure iii. adrenocorticotropic hormone (ACTH): causes Cushing’s syndrome often with hyperpigmentation due to coincident secretion of melanocyte stimulating hormone c.

macroadenomas ( 1 cm): symptoms are from hormone secretion and mass effect i.

mass effect causes headache, bitemporal hemianopia, and/or multiple cranial nerve palsies from involvement of the cavernous sinuses

ii.

hormone effects (75% of macroadenomas) (1) follicle stimulating hormone (FSH)/luteinizing hormone (LH): causes decreased libido, usually identified in men (2) thyroid stimulating hormone (TSH): causes hyperthyroidism

d.

6.

pituitary apoplexy—caused by hemorrhage or infarction into a pituitary adenoma; symptoms include acute-onset headache, ophthalmoplegia, bilateral vision loss, and somnolence progressing to coma

Treatment a.

bromocriptine for prolactin-secreting tumors

b.

surgery  irradiation for all other types

c.

propylthiouracil or methimazole can be used temporarily to control hyperthyroidism

B. Craniopharyngioma 1.

Pathophysiology: In adults, likely develops after dedifferentiation of pituicytes into squamous epithelial-like cells that then form a tumor; in children, may be derived directly from Rathke’s pouch (Box 5.16) a.

usually have a cystic component filled with cholesterol-rich fluid {crank case oil}

2.

Tumor location: develop from the top of the pituitary near the optic chiasm, and often extend into the 3rd ventricle

3.

Symptoms: obstructive hydrocephalus with 3rd ventricle extension (rare in adult cases); variable visual field cuts; endocrine dysfunction; chemical meningitis with cyst rupture

4.

Treatment: complete surgical removal

5.

Prognosis: high operative morbidity and mortality with hypothalamic damage; significant recurrence tendency, which requires irradiation as well as repeat surgery

Box 5.16 Rathke’s pouch also gives rise to the nonneoplastic Rathke’s pouch cyst, which can be treated just by drainage.

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5 Tumors of the Nervous System

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Figure 5–14 Schwannoma. Transition between the cellular Antoni A area and the looselyarranged Antoni B area. Palisading Schwann cells with elongated nuclei characteristic of a Verocay body (arrow). (From Bernstein M, Berger M. Neurooncology: The Essentials. Stuttgart, Germany: Georg Thieme; 2000:28, Fig. 2–10. Reprinted by permission.)

III. Peripheral Nervous System Tumors A. Schwann Cell Tumors 1.

Schwannoma a.

histology: neoplastic Schwann cells are surrounded by small amounts of connective tissue that is encapsulated and largely external to the nerve i.

tumor exhibits different areas that are highly cellular (Antoni type A) or loose myxoid connective tissue (Antoni type B) (Fig. 5–14) (1) Verocay body: cellular palisades that occur in Antoni type A areas

ii.

minimal risk of malignant transformation

iii. exhibits intense staining for the astrocyte marker protein S-100 throughout the tumor b.

tumor location: most occur on peripheral nerves but 8% are intracranial on cranial nerves at the cerebellopontine angle (i.e., the acoustic neuroma, which actually develops from the vestibular portion of CN VIII) i.

2.

c.

symptoms: usually are asymptomatic swellings, although pressure on the tumor causes pain; rarely cause motor or sensory dysfunction in the affected nerve despite stretching of the nerve fibers around the outside of the tumor

d.

treatment: surgical resection of symptomatic tumors

Neurofibroma a.

134

schwannomatosis: condition of multiple schwannomas without achieving the diagnostic criteria for neurofibromatosis

histology: tumors are composed neoplastic Schwann cells encased in a large amount of connective tissue similar to Antoni type B area of schwannoma (Fig. 5–15); tumors grow into the nerve i.

rarely undergoes anaplastic transformation, and then usually only after irradiation

ii.

exhibits patchy staining for the astrocyte marker protein S-100

b.

tumor location: cutaneous branches of peripheral nerves

c.

subtypes i.

solitary (90%)

ii.

multiple: tumors usually are large and involve deep nerves

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iii. plexiform: solitary neurofibromas that grow along the length of the nerves causing fusiform enlargements; associated mostly with neurofibromatosis

3.

diffuse: associated with neurofibromatosis

d.

symptoms: painful swelling, but pressure on tumor does not exacerbate pain; motor and/or sensory dysfunction in distribution of the nerve

e.

treatment: difficult to excise surgically

Malignant peripheral nerve sheath tumor a.

b.

pathophysiology: generally develop de novo or rarely from degeneration of a neurofibroma i.

4% prevalence in neurofibromatosis

ii.

target large nerves (e.g., sciatic) and the plexuses; metastasizes to lung, liver, and bone

Figure 5–15 Neurofibroma demonstrating intrinsic nerve fascicles. (Courtesy of Dr. Yamada)

histology: hypercellular tumors with mitotic figures and areas of necrosis; tumors form fusiform masses that invade surrounding tissues i.

Paraneoplastic Syndromes

iv.

may express S-100 protein, which is commonly considered an astrocyte marker

c.

symptoms: pain, swelling, motor and sensory dysfunction of involved nerve

d.

treatment: irradiation  surgical removal involving limb amputation or en-bloc resection

e.

prognosis: 40% 5-year survival

IV. Paraneoplastic Syndromes 1.

2.

Epidemiology: develops in  0.01% of cancer patients, except a.

Lambert-Eaton myasthenia  3% of small-cell lung cancer (SCLC)

b.

myasthenia gravis  15% of thymomas

General pathophysiology a.

the paraneoplastic syndrome is often the presenting feature of the tumor by months or even years because the autoantibodies that cause it are also effective against tumor antigens and thereby limiting tumor growth i.

b. 3.

4.

tumors in patients with paraneoplastic syndromes are better recognized by the immune system (e.g., infiltrated with leukocytes), in comparison with similar tumors in patients without paraneoplastic syndromes

development of a paraneoplastic syndromes may indicate tumor recurrence after an effective treatment

General diagnostic testing: evaluation for primary tumor is best done with PET scanning a.

serum antibodies (see below)

b.

lumbar puncture demonstrates mild T lymphocyte pleocytosis early in course

General treatment: eliminations of causative tumor may improve paraneoplastic syndrome in 30%, but treatment of paraneoplastic syndrome should be initiated immediately as they may limit further neurological injury a.

immunosuppression: glucocorticoids, cyclophosphamide, tacrolimus, mycophenolate

b.

IVIg plasmapheresis: particularly effective in myasthenia gravis, LambertEaton myasthenia, and stiff-man syndrome

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Table 5–3 Antibody-Mediated Paraneoplastic Syndromes* Syndrome

Antibodies

Associated tumor

Myasthenia gravis (see Chapter 10)

Nicotinic ACh receptor

Thymoma

Striated muscle Titan Ryanodine calcium channel

5 Tumors of the Nervous System

Isaac syndrome/neuromyotonia (see Chapter 10)

Nicotinic ACh receptor

SCLC, thymoma, lymphoma

Voltage-gated potassium channels Lambert-Eaton myasthenia (see Chapter 10)

P/Q-type V-gated calcium channel

SCLC

PCA-2 Cerebellar degeneration

Hu

SCLC, neuroblastoma, prostate

Yo/PCA-1

SCLC, ovary, breast

PCA-2

SCLC

Ma-1

SCLC

CV-2

SCLC, thymoma

Tr

Hodgkin’s disease

Metabotropic Glu receptor type 1

Hodgkin’s disease

Ma-1

SCLC

Ta/Ma-2

Testicle

Limbic encephalitis

Voltage-gated potassium channels

SCLC

Encephalomyelitis

Amphiphysin

SCLC, breast

Hu

SCLC, neuroblastoma, prostate

PCA-2

SCLC

CV-2

SCLC

MAG

Waldenstrom’s macroglobulinemia

Hu

SCLC, neuroblastoma, prostate

CV-2

SCLC

Retinopathy

Antiretinal

Melanoma

Stiff-man syndrome (see Chapter 8)

Amphiphysin

SCLC, breast

Opsoclonus–myoclonus

Ri

SCLC, breast, bladder, neuroblastoma

Brainstem encephalitis

Neuropathy

*Best bets for testing  Hu/ANNA1, Yo/PCA-1, and CV-2. Abbreviations: ACh, acetylcholine; SCLC, small-cell lung cancer.

5.

General prognosis: patients with paraneoplastic syndrome generally have a better oncologic outcome than do tumor patients without paraneoplastic syndromes

6.

Subtypes (Table 5–3): symptoms evolve over a period of days to weeks

Appendix 5–1 Imaging Characteristics of Tumors

136

Calcified tumors

Contrast-enhancing tumors

Hemorrhagic tumors

Meningioma

Metastases

Metastases, particularly melanoma and choriocarcinoma

Oligodendroglioma

Meningioma

Astrocytoma (high-grade)

Astrocytoma (low-grade)

Astrocytoma (high-grade)

Lymphoma

Ependymoma

Schwannoma/acoustic neuroma

Craniopharyngioma

Pituitary tumors

Pituitary tumors

Vascular tumors

Vascular tumors

Vascular tumors

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6 Headache and Pain Disorders

Note: Significant diseases are indicated in bold and syndromes in italics.

Episodic Headache

I. Episodic Headache A. Episodic Headaches Lasting More than Four Hours 1.

Migraine a.

symptoms: attacks last between 4–72 hours (but may be only 1 hour long in children), and typically involve i.

at least two of the following: unilateral location; pulsating quality of the pain; severe intensity; aggravation by movement (1) nonpulsatile pain does not exclude the diagnosis of migraine

ii. b.

at least one of the following: nausea, photophobia, phonophobia

subtypes of migraine: patients may have any combination of the various subtypes i.

migraine with aura (classic migraine) and without aura (common migraine): phases include (1) prodrome phase (60%): involves psychological, neurological, and/or constitutional symptoms that develop hours to days before the headache onset (a) psychological symptoms include depression, euphoria, and restlessness (b) neurological symptoms include photo/phonophobia and dysphasia (c) constitutional symptoms include anorexia or hunger, sluggishness, fluid retention, and diarrhea/constipation (2) aura phase (in  30% of all migraine cases): auras evolve gradually, last 4–60 minutes, and involve positive and negative symptoms such as (Box 6.1) (a) visual phenomenon: account for 99% of auras; includes the sensation of flashes of light {photopsia}, bilateral scotoma, or a fortification spectrum {teichopsia} (b) complex visual disturbances, including macro/micropsia or metamorphopsia

Box 6.1 In comparison with migranous auras, complex partial seizure auras are shorter ( 5 minutes), produce a change in consciousness, and include automatisms or myoclonic jerks.

(c) paresthesias and sensory loss (30%); clumsiness (20%); apraxias; speech disturbances; déjà vu/jamais vu; delirium (i)

usually these occur in conjunction with a visual aura

(3) headache phase: pain can be bilateral in 40%, and consistently is on one side of the head in only 20% of cases (a) 40% of cases involve sharp stabbing pains lasting a few seconds (i.e., idiopathic stabbing headache; see p. 143) (4) postdrome phase: involves impaired concentration, fatigue, and/or irritability lasting for several hours following the headache

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aura without migraine/migraine equivalent/acephalgic migraine— development of migraine aura phenomena without progression to the headache phase; usually occurs late in life (1) abdominal migraine—episodes of abdominal pain and nausea often without headache that occur in children with a strong family history of migraine; all other causes of abdominal pain must be excluded prior to establishing the diagnosis

6 Headache and Pain Disorders

iii. complicated migraine/migraine with prolonged aura—migraines in which the aura phenomena persist beyond the duration of headache, or in which stroke-like focal neurological deficits develop (1) migrainous infarction: persistence of the neurological deficits of a complicated migraine for  1 week or neuroimaging evidence of infarction iv.

migraine variants (1) basilar migraine—the migraine aura is followed by any combination of dysarthria, vertigo, tinnitus, hearing loss, diplopia, ataxia, bilateral paresthesias or weakness, or confusion; the headache is usually bilateral and located over the occiput (a) hemianopic visual auras may become bilateral, leading to complete vision loss (2) confusional migraine—generally are mild classic migraines that are associated with confusion or agitation; sometimes are triggered by mild head trauma and they rarely recur thereafter (a) usually a disorder of children who have a history of typical migraine; it also is the typical migraine that occurs in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL; see p. 67) (3) ophthalmoplegic migraine—unilateral retroorbital eye pain associated with a cranial nerve palsy (III  IV, VI); episodes occur over a period of days to months before spontaneously resolving; however, they are likely to recur (a) may be related to the Tolosa-Hunt syndrome (see p. 34) because the involved nerves contrast enhance on magnetic resonance imaging (MRI) and both disorders respond to steroids (4) hemiplegic migraine—migraine associated with acute-onset weakness and usually confusion, typically lasting  24 hours; often triggered by mild head trauma (a) subtypes of hemiplegic migraine (i)

familial hemiplegic migraine (75% of cases): involves visual phenomena as well as paresthesias (100%) or aphasia (45%) as auras 1.

138

autosomal dominant inheritance with variable penetration, linked to mutation of the P/Q-type voltagegated calcium channel gene located on chromosome 19 (Box 6.2)

2.

20% of patients also exhibit slowly progressive nystagmus and ataxia between hemiplegic migraine attacks

3.

may develop into a regular migraine syndrome in adulthood

4.

sporadic hemiplegic migraine: indistinguishable from familial form

(ii) hemiplegic migraine associated with benign familial infantile convulsions (rare): mutation of ATP1A2 sodium-potassium ATPase on chromosome 1 (not the mutation that causes benign familial infantile convulsions without migraine—which is on chromosome 16)

Box 6.2 Other mutations of the P/Q voltage-gated calcium channels cause episodic ataxia type 2.

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(5) menstrual/menopausal migraine: not associated with aura; headaches typically have a longer duration than regular migraine syndromes (a) migraine during pregnancy does not affect the rate of spontaneous abortion, toxemia, or fetal malformations in comparison with pregnant women without migraine headaches (6) status migrainosus—headache phase that lasts for more than 72 hours with headache-free intervals  4 hours (not including sleep) c.

pathophysiology i.

the aura is likely a primary neuronal phenomenon that is triggered by a preceding period of vasoconstriction; reduced blood flow may trigger a brief period of neuronal hyperactivity followed by a prolonged inactivation that spreads outward as a wave moving at 2–6 mm/min across the cortex surface {neuronal spreading depression}

ii.

the headache is likely due to a combination of (1) extracranial arterial vasodilation: initiated by an unknown trigger, but may be promoted by release of calcitonin gene-related peptide (CGRP) and substance P from unmyelinated fibers of CN V (2) neurogenic inflammation: develops in the region of vasodilation due to plasma protein extravasation as well as the inflammatory effects of neurokinin, CGRP, and substance P released from CN V sensory fibers

Episodic Headache

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(3) decreased inhibition of central pain neurotransmission: abnormal function of second-order neurons in the caudal trigeminal nucleus and cervical dorsal horn (“trigeminocervical complex”) may account for headaches that overlap the trigeminal and cervical innervations iii. risk factors for migraine (1) right-to-left cardiac shunt and patent foramen ovale (2) genetic: tumor necrosis factor (TNF) gene polymorphisms; polymorphisms in upstream regulatory region of serotonin transporter (3) psychiatric comorbidities: depression (a) dysthymia and bipolar disorders are associated specifically with migraine with aura

d.

iv.

epidemiology: age of onset is typically between 10–15 years of age; new-onset migraine is common in women after age 30, but by that age it becomes very rare in men

v.

triggers include bright light, cigarette smoke, fasting, emotional stress, exercise, poor sleep, alcohol, caffeine, aged cheeses or other foods containing tyramine, chocolate, monosodium glutamate, nitrates, and menstruation

diagnostic testing i.

neuroimaging: not indicated for classic or common migraine unless it is atypical (1) MRI demonstrates small T2 hyperintensities in the subcortical white matter that accumulate over time; occasionally infarctionlike changes (i.e., increased diffusion-weighted imaging [DWI] signal) may be seen acutely in cases of complicated migraine (2) EEG can demonstrate any of several focal abnormalities during attacks (e.g., reduced and asymmetric alpha and theta rhythms, poor reactivity), none of which have diagnostic or predictive value

e.

treatment i.

classic and common migraines (1) acute treatment (a) triptans: first-line medication for migraines that are of severe intensity; act as agonists of multiple subtypes of the 5-HT1 receptor both on the vasculature and in brain nociceptive pathways (Table 6–1)

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6 Headache and Pain Disorders

Table 6–1 Triptans Medication

Routes

Benefits and limitations

Metabolism

Almotriptan

PO

Minimal side effects

Hepatic (MAO-A)

Eletriptan

PO

High efficacy; low-recurrence rate

Hepatic (non-MAO)

Frovatriptan

PO

Long half-life; low-recurrence rate but low efficacy; minimal side effects

Hepatic (MAO-A)

Naratriptan

PO

Low-recurrence rate; minimal side effects

Mostly renal excretion; no MAO interaction

Rizatriptan

PO, disintegrating tablet

High efficacy

Hepatic (MAO-A)

Sumatriptan

PO, SQ, nasal spray

High efficacy, particularly for SQ preparation

Hepatic (MAO-A)

Zolmitriptan

PO, disintegrating tablet, nasal spray

High efficacy

Hepatic (MAO-A)

Abbreviations: MAO, monoamine oxidase

(i)

most triptans cause vasoconstriction via 5-HT1B receptors, and lipophilic triptans (eletriptan, naratriptan) may also act to reduce the activity of the second-order neurons via 5-HT1B/1D inhibitory receptors

(ii) general side effects of triptan agents include chest pain and paresthesias, therefore triptans should not be given to patients with known or suspected coronary artery disease considering the risk of coronary vasospasm (b) nonsteroidal antiinflammatory drugs (NSAIDs): may be used as first-line medications for migraines of moderate intensity; act as inhibitors of the constitutive (COX-1) and/or inducible (COX-2) cyclooxygenase enzymes that produce prostaglandins (i)

prostaglandins are involved in neurogenic inflammation component of migraine; they also may cause vasodilation and increase the sensitivity of nociceptive pathways

(ii) NSAIDs can be used in low-dose combinations or in combined preparations with caffeine or opioids (Box 6.3)

Box 6.3

(iii) side effects include GI ulceration and renal hypoperfusion causing reduced filtration and renal failure

Acetaminophen does not have a clear benefit in migraine treatment.

(c) opioids: as effective as triptan agents (d) ergots: generally are considered as rescue medications because of severe side effects (nausea, diarrhea, psychosis, vasoconstriction in the extremities), strict dose limitations, and parenteral administration routes; act on serotonin, adrenergic, and dopaminergic receptors (i)

ergotamine: not consistently shown to be better than triptans or NSAIDs

(ii) dihydroergotamine: can be administered by nasal spray (e) antiemetics: should be used in conjunction with other treatments when nausea is a significant feature of the migraine (2) prophylactic treatments (a)  blockers (b) antidepressants: amitriptyline, fluoxetine (c) antiepileptics: valproate, gabapentin, topiramate (d) methysergide, which is an ergot that acts on 5-HT2 receptors (i)

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cannot be used for more than 6 months at a time because of retroperitoneal fibrosis

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(e) dietary supplements: riboflavin, butterbur extract, coenzyme Q10 (f) relaxation therapy ii.

migraine during pregnancy: to avoid harming the fetus, limit treatments to IV fluids, acetaminophen, opioids, and metoclopramide (for nausea)

iii. status migrainosus (1) fluid and electrolyte replacement (2) medication detoxification (3) IV therapy (Box 6.4) (a) headache: dihydroergotamine (DHE)  glucocorticoids, ketorolac

Box 6.4 Both headache and nausea treatments should be used together, even if the nausea is minor.

(b) nausea: prochlorperazine, metoclopramide 2.

Tension-type headache a.

symptoms: lacks any prodrome- or aura-like symptoms i.

diffuse pain of mild-to-moderate intensity and aching or squeezing quality that is not incapacitating or worsened by head movements; pain often involves the neck and/or jaw (Box 6.5) (1) the pain often develops a pulsatile quality if it becomes severe (2) occasionally involves mild migrainous symptoms (nausea, photo/ phonophobia); more commonly is associated with fatigue or lightheadedness (3) can be triggered by sleep deprivation or emotional stress

ii. b.

Box 6.5 Distinguish tension-type headache from cervical spine disease by the lack of exacerbation with movements; from temporomandibular joint disease by the lack of jaw clicking or exacerbation with chewing; both disorders will have joint tenderness.

Episodic Headache

(4) establish migraine prophylaxis thereafter

tenderness of the pericranial muscles and/or temporomandibular joint is an unreliable finding

pathophysiology i.

headaches are associated with a mild diffuse vasoconstriction and low serum magnesium levels (which can cause vasoconstriction); similar abnormalities are also observed in other types of headache as well

ii.

headache frequency and severity are associated with high levels of anxiety and depression that are not necessarily pathological in severity

c.

diagnostic testing: the spontaneous activity of the cranial muscles on an EMG is not higher in patients with tension-type headaches than it is in normal controls

d.

treatment i.

regular sleep and exercise; relaxation therapy

ii.

medical treatments (1) NSAIDs; acetaminophen; caffeine-containing compounds; codeine (a) triptan agents are effective against tension-type headaches only in patients who have coincident migraines (2) anesthetic or botulinum toxin injection into tender cranial muscles

B. Episodic Headaches Lasting Less than Four Hours 1.

Cluster headache a.

symptoms: severe throbbing or stabbing pain located around the eye and orbit that may radiate to the jaw, neck, or temporal area; attacks last 45–90 minutes and occur regularly and repetitively over a period of 6–12 weeks before spontaneously remitting (Box 6.6) i.

attacks occur at the same time of day and clusters of attacks occur at the same time of the year, although they become less regular over time (1) headache can be triggered by sleep deprivation, alcohol, organic solvents, or emotional stress

ii.

patients are agitated and restless during the headache (unlike migraine)

Box 6.6 The Cluster Headache Phenotype ✧ Deep nasolabial furrows, peau d’orange

skin, telangiectasias {leonine face} ✧ Masculinized face in women ✧ High-stress (type A) personality

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iii. pain is strictly unilateral, always occurring on the same side iv.

migrainous features (e.g., nausea, phono/photophobia) occur in  50%; rarely associated with aura

v.

attacks are triggered by REM sleep, which is shortened by sleep deprivation, therefore patients may avoid sleep

vi. attacks are associated with multiple autonomic features: ptosis (70%); conjunctival injection (80%); lacrimation (80%); nasal congestion and rhinorrhea; bradycardia leading to syncope; hypertension

6 Headache and Pain Disorders

b.

pathophysiology: likely involves the cavernous segment of the carotid artery and the suprachiasmatic nucleus of the supraoptic region of the hypothalamus because i.

attacks are associated with dilation of the ophthalmic artery and cavernous carotid, although this is not specific to cluster headache and can be induced to a lesser degree by pain applied to the CN V-1 region of the face (1) patients exhibit a narrow middle cranial fossa, suggesting venous drainage abnormalities in the cavernous sinus

ii.

c.

d.

patients exhibit an abnormal circadian rhythm of melatonin release from the pineal gland, which is under the control of the suprachiasmatic nucleus

epidemiology: typical onset between 25–30 years of age; 5:1 male predominance i.

occasional families exhibit autosomal dominant inheritance

ii.

associated with heavy alcohol and tobacco use

treatment i.

good sleep hygiene with regular hours

ii.

acute medical treatment (1) oxygen inhalation: 100% oxygen at 7 L/min for 15 minutes via non-rebreather mask gives relief in 70% (2) sumatriptan: effective in 70% when given by the SQ route; not effective as an abortive therapy when given orally (3) dihydroergotamine (DHE) IV (4) intranasal lidocaine, as an adjunct therapy

iii. prophylactic medical treatments: to be used during the cluster, then discontinued (1) glucocorticoids: effective at headache prevention but headaches frequently recur during tapering (2) lithium (3) DHE (4) valproate: particularly effective in patients with migrainous features (5) topiramate (6) methysergide (7) intranasal capsaicin (8) melatonin, as an adjunct therapy iv. 2.

Paroxysmal hemicrania a.

142

surgical treatment: trigeminal rhizotomy or microvascular decompression of the trigeminal/gasserian ganglia

symptoms: severe throbbing or stabbing pain that is usually located in the orbital, supraorbital, and/or temporal areas; may have anywhere from a few to dozens of attacks lasting 2–45 minutes each i.

pain is strictly unilateral, always occurring on the same side

ii.

attacks are associated with at least one of the following autonomic features: conjunctival injection; lacrimation; nasal congestion; rhinorrhea; ptosis; eyelid edema

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iii. attacks can be triggered by pressure on the cervical nerve roots or cervical vertebrae pathophysiology: headaches are related to pronounced increases in ipsilateral ocular blood flow and intraocular pressure

c.

treatment: scheduled indomethacin is uniformly effective, and this responsiveness is necessary to establish the diagnosis

Short-lasting unilateral neuralgiform headaches with conjunctival injection and tearing (SUNCT) syndrome a.

symptoms: unilateral stabbing or electrical pain of sudden onset lasting  2 minutes, centered around the eye but radiating to the forehead, face, temple, and oropharyngeal cavity; upwards of 100 attacks per day may occur i.

periods of headaches last from several days to months followed by spontaneous remission ranging from weeks to years

ii.

attacks are triggered by tactile stimulation to the head or neck (i.e., involving CN V and C2 distributions)

Chronic Headaches

3.

b.

(1) no refractory period exists after a triggered attack, unlike trigeminal neuralgia iii. attacks are associated with at least one of the following autonomic features: conjunctival injection; lacrimation; nasal congestion and rhinorrhea; ptosis; eyelid edema

4.

5.

b.

pathophysiology: unknown

c.

treatment: carbamazepine, which has limited effectiveness; verapamil actually worsens the condition

Hypnic headache a.

symptoms: unilateral or bilateral throbbing headache without associated migrainous or autonomic features that last  60 minutes, occurring 1–3 times per evening; headaches develop only during REM sleep, rarely during daytime naps

b.

pathophysiology: unknown

c.

epidemiology: occurs only in patients  60 years of age

d.

treatment: lithium

Idiopathic stabbing headache/ice-pick headache/abs-and-jolts syndrome/ ophthalmodynia a.

symptoms: sharp pain lasting  1 second that causes a shock-like response (“jolt”); pain is typically unilateral, located in the orbit, forehead, and/or temple i.

attacks usually occur in clusters lasting a few days, followed by a period of remission

ii.

involves migrainous or autonomic symptoms, and triggers

iii. 60% have an additional subtype of headache, usually migraine iv.

10% have episodes involving ipsilateral conjunctival hemorrhage

b.

pathophysiology: unknown, but has a high coincidence of ocular pathology (glaucoma, cataracts, amblyopia)

c.

treatment: indomethacin, verapamil

II. Chronic Headaches 1.

Definition: any headache type occurring more than 15 days per month

2.

General pathophysiology (Box 6.7) a.

development of chronic headache: 75% of cases develop from episodic migraine {transformed migraine}, 10% of cases develop from episodic tensiontype headache, and 15% of cases develop without a previous headache history i.

chronic headache that does not develop from an existing episodic headache disorder is worrisome for having an underlying pathophysiology process (secondary chronic headache)

Box 6.7 Secondary Chronic Headaches ✧ Posttraumatic headache ✧ Cervical spine disorders ✧ Cranial nerve injuries ✧ Ophthalmic disorders: glaucoma, corneal

✧

✧

✧ ✧

erosions, refractive errors, heterotropia/ phoria Vascular cranial disorders: arteriovenous malformation, giant cell arteritis, cerebral dissection, subdural hematoma Nonvascular cranial disorders: high- or low-intracranial pressure, infection, neoplasm, Chiari malformation, inflammatory disorders (sarcoidosis, Bechet’s syndrome) Oromandibular and temporomandibular disorders Sinus infections, ear disorders

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b.

c.

6 Headache and Pain Disorders

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genetics i.

chronic tension-type headache exhibits multifactorial inheritance

ii.

chronic cluster headache exhibits autosomal dominant inheritance

epidemiology: 4% prevalence for all subtypes in the general population versus 12% for episodic migraine and 38% for episodic tension-type headache i.

d.

10:13 AM

sex: overall relative risk in females  2–9 depending upon the subtype; male predominance is observed only with chronic cluster headache

associated conditions i.

psychiatric disorders: most common are anxiety disorders (45%), mood disorders (35%), and somatoform disorders (5%); coexisting psychiatric disorders often remit following successful chronic headache treatment

ii.

medication overuse (40%) (1) defined as the use of (a) at least three simple (e.g., single-agent, nonbarbiturate, nonsedative) analgesic medications per day for at least 5 days per week (b) triptans and/or multiagent analgesics on at least 3 days per week (c) opioids and/or ergots on at least 3 days per week (2) medication overuse leads to (a) “rebound headaches” that are confused with the underlying headache disorder, thereby encouraging additional medication usage (b) headaches that are refractory to prophylactic medications (c) systemic toxicities of excessive analgesic use

3.

Primary chronic headache  4 hours in duration a.

chronic migraine/transformed migraine—accounts for 65% of chronic headache i.

symptoms: chronic headache that is persistent for  3 months, and typically has (1) a period of increasing headache frequency with decreasing severity of migrainous symptoms (2) pain that is still throbbing in nature, although it is less severe than episodic migraine and involves features of other types of headaches (a) chronic headaches with migraine and tension-type features should be considered as chronic migraine and treated as such (3) persistence of triggers from the episodic migraine

ii.

treatment (1) prophylaxis: amitriptyline, fluoxetine, doxepin,  blockers, anticonvulsants (valproate, topiramate)

tizanidine,

(2) acute attack: triptans, long-acting NSAIDs (e.g., diflunisal, naproxen, nabumetone, oxaprozin, piroxicam, phenylbutazone) b.

chronic tension-type headache—accounts for 30% of chronic headache i.

symptoms: chronic headache must be persistent for  6 months, and typically has (1) pain that is pressing or tightening in quality, mild to moderate in severity, and bilaterally located; pain is not aggravated by routine physical activity (2) pain that is associated with at most only one migrainous symptom

144

(3) tenderness of pericranial muscles that also exhibit increased electromyographic activity at rest

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treatment (1) prophylaxis: amitriptyline, tizanidine, botulinum toxin injection into tender cranial muscles (2) acute attacks: long-acting NSAIDs

c.

hemicrania continua—does not reliably develop from an episodic headache condition (i.e., often is chronic at its onset) i.

symptoms: chronic headache persistent for  1 month that is characterized by (1) unilateral, continuous pain of varying nature and severity (2) at least one autonomic symptom (conjunctival injection, ptosis, lacrimation, nasal congestion, rhinorrhea, eyelid edema, miosis, facial sweating) during periods of severe headache

ii.

treatment: indomethacin PRN (as needed) for acute attacks, or scheduled for prophylaxis (1) complete symptomatic relief following indomethacin treatment is essentially a diagnostic test for hemicrania continua

4.

Chronic headaches  4 hours in duration: rarely cause chronic headache a.

chronic cluster headache i.

symptoms: 1–8 attacks of pain per day lasting 15–180 minutes (versus 45–90 minutes for episodic cluster headache) with clusters of daily attacks occurring regularly at the same time, wherein the clusters last  1 year in duration with  14 days of remission

Chronic Headaches

(3) an absence of triggers

(1) pain has a compressive or boring quality (2) pain is strictly unilateral, and always on the same side; pain is typically located around the orbit and temporal region and occasionally radiates to the jaw and neck (3) attacks are associated with autonomic symptoms (conjunctival injection, ptosis, lacrimation, nasal congestion, rhinorrhea, eyelid edema, miosis, facial sweating), but migrainous symptoms occur in  50%; rarely is associated with an aura (4) headache triggers include REM sleep, alcohol, and nitrates ii.

treatment (1) medical treatment (a) prophylaxis: lithium, verapamil, methysergide, anticonvulsants (valproate, topiramate) (b) acute attacks: oxygen supplementation, triptans, intranasal lidocaine (2) surgical treatment: gamma-knife radiosurgery, trigeminal rhizotomy, or trigeminal root section for medically refractive cases

b.

chronic paroxysmal hemicrania i.

symptoms:  4 attacks per day of headache lasting 2–45 minutes, wherein the attacks (1) involve severe periorbital and temporal region boring or throbbing pain, which causes agitation and restlessness (a) the pain is strictly unilateral, and always on the same side of the head (2) are associated with autonomic symptoms (conjunctival injection, ptosis, lacrimation, nasal congestion, rhinorrhea, eyelid edema, miosis, facial sweating) ipsilateral to the pain; migrainous symptoms absent (3) occur irregularly throughout the day or night, and can be triggered by head movements or pressure applied to cervical region (in 10% of cases)

ii.

treatment: indomethacin should completely alleviate the headache, as in hemicrania continua

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General diagnostic testing a.

neuroimaging i.

brain MRI or CT scan (1) chronic migraine does not require neuroimaging if it developed from episodic migraine, if it is symptomatically stable, and if the patient’s neurological examination is normal

6 Headache and Pain Disorders

(2) chronic tension-type headache: neuroimaging identifies a surgically treatable abnormality in  1.5% of patients compared with 0.4% of patients without headaches (3) other chronic headaches: undefined yield of neuroimaging; they are all so rare; that they are aggressively evaluated ii.

b.

6.

MR venogram: venous sinus thrombosis can be observed in 10% of chronic migraine or chronic tension-type headache patients, although its significance is unclear

lumbar puncture: opening pressure may be  20 cm H2O in 20% of chronic headache patients but only half of chronic headache patients with elevated intracranial pressure have papilledema

General treatment a.

patient education i.

encourage regular sleep habits, exercise involving stretching, and regular meals

ii.

dietary supplementation with L-5-hydroxytryptophan may reduce analgesic use during detoxification

b.

identify comorbid psychiatric factors and treat appropriately

c.

medication detoxification (Box 6.8)

d.

i.

gradually taper barbiturates, benzodiazepines, and opioids

ii.

butalbital-containing analgesics can be substituted with phenobarbital, which can then be gradually tapered

adjunctive treatment i.

psychotherapy: stress management, relaxation therapy, and biofeedback has been proven efficacious

ii.

physiotherapy: cervical spine manipulation, massage, transcutaneous electrical neural stimulation (TENS), and ergonometric review have limited evidence supporting their use in the treatment of chronic tension-type headache

a.

response to preventative medication takes up to 10 weeks following detoxification

b.

60% of patients will revert to an episodic headache disorder

c.

failure to improve following aggressive management is highly suggestive of an untreated psychiatric disorder

Pseudotumor cerebri pathophysiology: a condition of elevated intracranial pressure that is idiopathic by definition; may be caused by reduced cerebrospinal fluid resorption or increased cerebrospinal fluid production i.

146

monitoring

✧ Failed outpatient detoxification

General prognosis

a.

✧ Comorbid medical conditions that require ✧ Detoxification from opioids, barbitu-

III. Special Headache Disorders 1.

Indications for In-Hospital Detoxification

iii. gradually switch from short-acting NSAIDs (including most overthe-counter medications except for naproxen) to long-acting NSAIDs

iii. acupuncture is proven ineffective 7.

Box 6.8

risk factors include obesity, female sex, withdrawal from glucocorticoid use, Addison’s disease, and the use of certain medications (nalidixic acid, nitrofurantoin, ketoprofen, vitamin A, isotretinoin, anabolic steroids)

rates, benzodiazepines, or ergots

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(1) no relation to pregnancy or menstruation (2) no proven relation to glucocorticoid use, only glucocorticoid withdrawal ii.

symptoms i.

daily headache, usually diffuse and throbbing in nature; pain is exacerbated by eye movements and is associated with neck stiffness

ii.

visual symptoms (1) acute: transient unilateral loss of vision {visual obscurations} due to optic nerve ischemia; diplopia caused by CN VI palsy (2) chronic: enlargement of the blind spot, peripheral visual field constriction, and scotomas caused by papilledema

iii. pulsatile tinnitus c.

d.

diagnostic testing i.

neuroimaging to evaluate for mass lesions and MR venography to evaluate for venous sinus thrombosis

ii.

lumbar puncture demonstrates elevated intracranial pressure with Lundberg waves (see p. 35), but no abnormalities of the cerebrospinal fluid

treatment i.

weight loss with fluid and salt restriction

ii.

medical treatment: diuretics (acetazolamide, furosemide), digoxin, glucocorticoids

Special Headache Disorders

b.

occasionally associated with Behçet’s syndrome (iritis, oral and genital ulcers)

(1) lumbar puncture lowers intracranial pressure only for a few hours, so repeated lumbar puncture is unlikely to be of much benefit iii. surgical treatment (1) optic nerve sheath fenestration, which is effective only for visual symptoms (2) lumboperitoneal shunt 2.

Spontaneous intracranial hypotension a.

b.

c.

pathophysiology: can be caused by decreased intracranial pressure or low ventricular volume resulting from i.

leaks in the meninges that develop most commonly in the spine but occasionally in the skull base (e.g., cribriform plate); leaks can develop as a consequence of minor trauma (even from injury caused by bony or vertebral disk abnormalities of the spine), the Valsalva maneuver, or congenital weakness of the meninges (e.g., as in Marfan’s syndrome, autosomal dominant polycystic kidney disease)

ii.

peripheral hypovolemia

symptoms i.

headache when standing that is relieved by lying and that often involves the neck and upper back

ii.

tinnitus and/or vertigo, possibly because of traction on CN VIII or abnormalities of the perilymphatic fluid in the inner ear

diagnostic testing i.

lumbar puncture demonstrates a low opening pressure that may even be negative; mildly elevated protein and pleocytosis levels may occur

ii.

cisternography demonstrates the site of radiolabel leakage or its accumulation in a meningeal diverticula, as well as the lack of accumulation of the radiolabel over the cerebral convexities 24 hours after administration; early accumulation ( 4 hours after administration) of the radiolabel in the kidneys is also suggestive of a cerebrospinal fluid leak

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iii. neuroimaging may demonstrate reduced ventricle sizes, meningeal enhancement, and descent of the cerebellar tonsils through the foramen magnum (Chiari I malformation; see p.); extraaxial subdural fluid collections representing meningeal diverticula are rarely observed

6 Headache and Pain Disorders

d.

treatment i.

bed rest and increased fluid intake

ii.

caffeine; theophylline; glucocorticoids

iii. epidural blood patching: effective in 30% of cases of lumbar punctureinduced headaches; it is minimally effective in spontaneous cerebrospinal fluid leaks

3.

iv.

intrathecal fluid administration

v.

surgical closure of an identified meningeal defect

Trigeminal neuralgia/tic douloureux a.

pathophysiology: irritation of the nerve root at the site where central and peripheral myelin meet {Obersteiner-Redlich zone}; irritation is typically caused by demyelination (e.g., multiple sclerosis) or compression by a mass lesion (e.g., a vascular loop, meningioma) i.

ii.

pain attacks can be triggered by somatosensory stimulation of the trigeminal distribution may involve ephaptic transmission between mechanoreceptive fibers and nociceptive fibers at the site of irritation (Box 6.9) pain attacks may also involve the increased sensitivity of second-order nociceptive and mechanoreceptive neurons in the spinal trigeminal nucleus

iii. may occur in conjunction with hemifacial spasm {tic convulsif} with large intracranial lesions b.

d.

i.

distribution of pain: CN V2  V3  all three divisions  CN V2 only  CN V3 only

ii.

pain never crosses the midline, nor do patients with bilateral disease have simultaneous bilateral attacks

diagnostic testing i.

neuroimaging: surgically treatable abnormalities are usually only detected by MRI in patients with facial numbness or who exhibit progressive disease; MRA may disclose vascular abnormalities

ii.

trigeminal evoked potentials: an abnormal study is highly indicative of a mass lesion

treatment: all treatments appear to be less effective in those patients who have dull pain between triggered attacks i.

medical treatment: antiepileptics (carbamazepine, gabapentin); pimozide; clonazepam (1) baclofen can be given as an adjunct medication with antiepileptics

ii.

surgical treatment (1) microvascular decompression: separation of the nerve from any aberrant vascular loops (usually from the superior cerebellar artery) by means of a suboccipital craniotomy

148

Other Diseases of Possible Ephaptic Transmission at the ObersteinerRedlich Zone ✧ Hemifacial spasm ✧ Glossopharyngeal neuralgia

symptoms: clusters of severe sharp pain lasting several seconds to a few minutes that is triggered by mild somatosensory stimulation to various parts of the face; patients may have dull pain in the affected regions between triggered attacks

iii. sensory loss in the trigeminal divisions affected by pain (Box 6.10) c.

Box 6.9

(a) the preferred surgical treatment in patients  65 years of age who have more than a 5-year life expectancy; effective in 80% of cases

Box 6.10 Trigeminal Dysesthesia ✧ A continuous burning pain in a region of

the face caused by a mild injury to CN V (e.g., tooth extraction, zoster infection); does not involve triggers ✧ Involved regions of the face exhibit abnormal skin temperature

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(2) percutaneous trigeminal rhizotomy using glycerol or radiofrequency ablation: lesioning of the nerve roots behind the gasserian ganglia is achieved by advancing the surgical tool through the soft tissues of the cheek into Meckel’s cave via the foramen ovale (a) particularly useful in cases of multiple sclerosis (b) often causes significant sensory loss in the CN V distribution (3) stereotactic radiosurgery of the trigeminal ganglia: generally reserved for patients who have failed other surgical treatments 4.

5.

Glossopharyngeal neuralgia

Figure 6–1 Nerves of the occipital area. (From McKhann GM et al. Q&A

a.

pathophysiology: likely an irritative disorder of Color Review of Clinical Neurology and Neurosurgery. Stuttgart, Germany: Georg Thieme; 2003:66, Fig. 57. Reprinted by permission.) the nerve root entry zone of CN IX and/or CN X caused by an aberrant intracranial vascular loop; cases have been associated with extracranial pathology such as oropharyngeal mass lesions

b.

symptoms: sharp pain in the throat or ear, lasting several seconds to a few minutes; attacks may involve bradycardia that causes syncope i.

triggers include swallowing, yawning, and sneezing

ii.

occurs with trigeminal neuralgia in 10% of cases

c.

diagnostic testing: MRI studies should cover the head and neck to evaluate for causative lesions

d.

treatment i.

medical treatment: as per trigeminal neuralgia; topical anesthetics to the oropharynx

ii.

surgical treatment: microvascular decompression

Complex Regional Pain Syndrome (CRPS)

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Greater occipital neuralgia a.

pathophysiology: typically caused by trauma to the greater or lesser occipital nerves, as prolonged compression or after whiplash movements (Fig. 6–1)

b.

symptoms: paroxysmal attacks of sharp pain radiating upward along the occiput from the neck or skull base that is usually triggered by neck extension or other neck movements; sensory loss over the C2 dermatome may occur

c.

treatment: cervical collar; NSAIDs, muscle relaxants; local anesthetic or glucocorticoid injections

IV. Complex Regional Pain Syndrome (CRPS) 1.

Subtypes a.

CRPS-1/reflex sympathetic dystrophy i.

pathophysiology: develops after minor injury (e.g., trauma, surgery) in the absence of an obvious nerve lesion; the injury may occur in the limbs, thorax, or abdomen, and the symptoms can extend outside of the distribution of a single nerve (1) some but not all patients have abnormal baseline sympathetic activity (e.g., abnormal local skin temperature) and responsiveness (e.g., inappropriate sweating) in the affected regions

ii.

specific symptoms (1) pain that is out of proportion to the severity of the inciting injury {hyperpathia} that often spreads to neighboring areas, which is perceived to be deep in the extremity; usually pain attacks occur spontaneous but they also are inducible by movement and palpation of the affected area

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(2) dysesthesias and sensory loss to all modalities in the painful area (50%) (3) skin changes, meaning hyperhidrosis and warm skin (acutely after injury) or hypohidrosis and cold skin (chronic state) (4) weakness, decreased range of motion, tremor, and/or dystonia in the affected area

6 Headache and Pain Disorders

b.

CRPS-2/causalgia i.

pathophysiology: develops after injury to a large nerve; abnormal sympathetic activity and reactivity are apparent in the affected region, as per CRPS-1

ii.

symptoms (1) hyperpathia, dysesthesia, and sensory loss as per CRPS-1, but no movement abnormalities (2) skin changes: cold skin; hyperhidrosis; edema; smoothing and mottling; increased hair growth occurs in chronic state

2.

3.

4.

General symptoms a.

psychiatric dysfunction: patients exhibit poor coping skills, depression, and/or anxiety disorders

b.

symptoms are sensitive to emotional factors, stress, changes in environmental temperature, and limb position

Diagnostic testing: no tests are of proven accuracy in establishing the diagnosis a.

subcutaneous norepinephrine injection causes pain in cases of CRPS that involve sympathetic hyperactivity

b.

nerve conduction studies demonstrate no evidence of nerve injury in CRPS-1, unlike CRPS-2

c.

quantitative sensory testing to determine any asymmetry in sensory thresholds

d.

autonomic testing: laser Doppler flowmetry, infrared thermography, quantitative sudomotor axon reflex test

Treatment a.

medications: clonidine; tricyclic antidepressants; carbamazepine; type Ib antiarrhythmic agents (lidocaine, mexiletine, tocainide); glucocorticoids

b.

regional sympathetic blockade: ineffective for pain control but may be useful against edema

c.

TENS

d.

physical therapy

V. Fibromyalgia 1.

Pathophysiology a.

biological i.

subjective reporting of increased pain sensitivity and an increased temporal summation of repetitive painful stimuli is paralleled by (1) lowered threshold for activation of pain-sensitive brain regions, as demonstrated by PET scan (2) increased cortical somatosensory evoked potential amplitudes to standard stimuli

ii.

increased substance P levels in cerebrospinal fluid suggest hyperactive nociceptive neurotransmission

iii. baseline hypoperfusion of the caudate and thalamus is also seen in other chronic pain conditions b.

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psychological: unclear causative relationship to emotional stress, although it seems to exacerbate the symptoms; fibromyalgia is more common in patients with depression, anxiety disorders, and somatoform disorders

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2.

Epidemiology: more common in women

3.

Symptoms a.

multifocal musculoskeletal pain, generally continuous in nature although the location of the painful sites can change over time i.

b.

generally develops after a focal, chronic pain condition (e.g., low back pain)

fatigue and nonrestorative sleep

4.

Diagnostic testing: polysomnography demonstrates reduced time spent in slow-wave sleep stages 3 and 4

5.

Treatment

6.

a.

graded exercise programs, which are particularly useful in the subgroup of fibromyalgia patients that demonstrates phobic-like avoidance of physical activity

b.

behavioral psychotherapy

c.

medications: antidepressants; muscle relaxants; adenosyl-methionine and niacin supplementation

Prognosis:  10% exhibit long-term improvement

VI. Chronic Fatigue Syndrome/Neurasthenia 1.

2.

3.

4.

5.

6.

Pathophysiology a.

biological: patients exhibit an increase—(not the normal decrease) in adrenocorticotropic hormone (ACTH) and cortisol levels in response to serotonin agonists and exhibit reduced ACTH and cortisol responses to CRH, suggesting abnormal hypothalamic-pituitary function

b.

psychological: patients have an increased use of avoidance-escape behavioral strategies, suggesting maladaptive coping skills

Low Back Pain

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Epidemiology: more common in women; unclear relation to socioeconomic status a.

increased risk in family members of an affected individual

b.

high coincidence with fibromyalgia, irritable bowel syndrome, and multiple chemical sensitivities

Symptoms a.

fatigue  6 months in duration, typically beginning after a nonspecific flu-like illness and that is disproportionately exacerbated by exercise

b.

at least four of the following: polyarthralgia, polymyalgia, impaired memory or concentration, headache, nonrestorative sleep, sore throat, lymph node tenderness

Diagnostic testing a.

neuropsychological testing: minimal impairment of concentration and memory function is usually delectable

b.

polysomnography does not reliably demonstrate any abnormality

Treatment a.

graded exercise programs

b.

behavioral psychotherapy

c.

low-dose glucocorticoids; tricyclic antidepressants; NSAIDs; magnesium supplements

Prognosis:  10% exhibit long-term improvement;  60% have impaired work performance

VII. Low Back Pain 1.

Pathophysiology: cause for pain can be identified in only 20% of cases a.

soft tissue and bone disorders: includes vertebral body disease, spinal stenosis, degenerative facet disease, and muscle injury (either primary or due to overuse from stabilization of misaligned bony structures)

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6 Headache and Pain Disorders

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Figure 6–2 Disk herniations. (A) Central disk herniation compresses the dural sac (e.g., cauda equina). (B) Intermediate disk herniation compresses the dural sac and the nerve root from the level below the disk. (C) Extreme lateral disk herniation compresses the nerve root from the

b.

level above the disk and occasionally the level from the level of the disk. (From Hosten N, Liebig T, CT of the Head and Spine. Stuttgart, Germany: Georg Thieme; 2002:346, Fig.12.58. Reprinted by permission.)

disk herniation: rupture or protrusion of the nucleus pulposus through the annular fibers of the disk occurs after tearing of the inner annular fibers from rotational or sliding (not compressive) movements of the adjacent vertebral bodies; pain is generated by injury to the disk itself and/or by compression of nearby structures (e.g., spinal ligaments, dura, nerve roots) i.

location of disk herniations (Fig. 6–2) (1) extreme lateral herniation hits the nerve root from underneath (e.g., an L4–5 disk hits the L4 nerve root) (2) intermediate lateral herniation hits the nerve root from the top (e.g., an L4–5 disk hits the L5 nerve root) (3) central herniation hits multiple nerve roots in the cauda equina that are derived from several spinal cord levels below the vertebral level of the herniation

c.

2.

Symptoms (Table 6–2) a.

b.

3.

nerve root compression {radiculopathy}: can be caused by facet hypertrophy, osteophyte formation, disk herniation, or diseases that involve the ganglia (Box 6.11) pain radiating down the lower extremity that is relieved by knee and hip flexion and that is exacerbated by straight leg raises, immobility, or the Valsalva maneuver referred pain and paresthesias to the flank and buttocks in cases with significant soft tissue disease; the pain reliably does not extend below the knee, but its location does not identify the site of the lesion

Box 6.11 Noncompressive but Painful Diseases of the Nerve Roots ✧ Diabetes (proximal diabetic neuropa-

thy, see p.) ✧ Human immunodeficiency virus (HIV),

Lyme disease, syphilis (tabes dorsalis) ✧ Guillain-Barre syndrome

Diagnostic testing: In the absence of neurological deficits or any likelihood of a secondary cause for the back pain, no neuroimaging should be performed until several weeks of medical management has failed a.

in asymptomatic persons, 50% exhibit degenerative joint disease and 20% exhibit disk herniations on neuroimaging

b.

disk herniations can resolve spontaneously on sequential neuroimaging studies

Table 6–2 Lumbar Radiculopathies Pain is located in

Weakness is in

Decreased reflex in

L4 nerve root

Anterior thigh

Knee extension

Patellar tendon

L5 nerve root

Posterior thigh and calf

Foot dorsiflexion; ankle inversion and eversion; hip extension/abduction (Box 6.12)

Quadriceps femoris

Foot plantar flexion

Ankle

S1 nerve root

152

Posterior thigh, calf, and foot

Box 6.12 Inversion and hip extension distinguish an L5 lesion from peroneal nerve injury.

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Treatment a.

medical treatment i.

minimal, if any, bed rest; continue with nonexertional daily activities

ii.

NSAIDs, muscle relaxants

iii. no benefit of traction or TENS b.

Prognosis: 80% of cases improve with NSAIDs, muscle relaxants, and physical therapy

VIII. Neck, Shoulder, and Arm Pain (Fig. 6–3)

Neck, Shoulder, and Arm Pain

5.

surgical treatment: lumbar spinal fusion; laminectomy; diskectomy; vertebroplasty

Figure 6–3 Common causes of shoulder and arm pain. 1, syringomyelia; 2, root neurinoma; 3, spondylosis with root encroachment; 4, Pancoast tumor; 5, referred pain; 6a, cervical rib; 6b, scalenus tunnel; 7a, first rib; 7b, clavicle; 8a, supraspinatus muscle; 8b, supraspinatus muscle; 9, shoulder arthritis; 10, bone sarcoma; 11, supracondylar humeral process; 12, radial epicondylitis; 13, median nerve–pronator teres muscle; 14, carpal tunnel syndrome. (From Mumenthaler M, Neurological Differential Diagnosis. 2nd ed. Stuttgart, Germany: Georg Thieme; 1992:150, Fig. 55. Reprinted by permission.)

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7 Behavioral Neurology and Psychiatry

7 Behavioral Neurology and Psychiatry Note: Significant diseases are indicated in bold and syndromes in italics.

I. Dementias A. Mild Cognitive Impairment (MCI) (Box 7.1) 1.

Definition: cognitive impairment that does not achieve the criteria for dementia because the degree of impairment does not significantly affect the patient’s activities of daily living

2.

Subtypes a.

amnestic MCI/age-related memory loss: an objective impairment of memory function in comparison with the normal range for the patient’s age, which does not involve significant impairment of other cognitive functions or impair the patient’s activities of daily living i.

15% of cases/year develop into Alzheimer’s disease, which is  10 times the incidence of non-MCI patients; the incidence of progression to Alzheimer’s disease is increased in MCI patients who express the apolipoprotein E (APOE) 4 allele

Box 7.1 Types of Memory by Subject Declarative/episodic—knowledge of events (hippocampus) Procedural—riding a bike (basal ganglia, cerebellum) Conditioning—associative learning (cerebellum) Semantic—factual or definitional knowledge (hippocampus-independent)

Types of Memory by Duration Immediate/working (seconds) Short-term/anterograde ( 10 minutes) Long-term/remote ( 10 minutes)

(1) small hippocampal and/or entorhinal cortex volumes on a MRI scan may also predict progression of MCI to Alzheimer’s disease, although the rate of volume loss is not helpful

3.

b.

MCI with impairment in a nonmemory domain (Box 7.2)

c.

MCI with impairment in multiple domains

Treatment: none yet established

B. Definition of Dementia 1.

In general, impairment of at least two of five functional domains (memory, language, visuospatial, emotion, executive) that affects the patient’s activities of daily living a.

dementia is usually suspected in patients who have a mini-mental status exam (MMSE) score  24, but performance is dependent upon the patient’s age and education background; therefore, use the MMSE only for screening, not for establishing the diagnosis i.

2.

MMSE  24 often does not identify non-Alzheimer’s dementias

Subtypes of dementia: cortical versus subcortical dementias (Table 7–1)

C. Reversible Causes of Dementia 1.

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Reversible causes exist in 10% of dementia cases, and include a.

metabolic abnormalities: hyponatremia, hypocalcemia, hypoglycemia

b.

organ-failure: respiratory failure (hypoxia or hypercarbia); liver, renal, or cardiac failure

Box 7.2 Non-amnestic MCI may progress to a nonAlzheimer’s type dementia.

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Table 7–1 Cortical versus Subcortical Dementias Cortical dementia

Subcortical dementia

Memory

Learning  retrieval deficit

Retrieval  learning deficit

Language

Aphasic

Dysarthric

Emotion

Disinhibited

Depressed

Visuospatial

(Indistinguishable)

Executive

Impaired and does not improve with cues

Impaired, but improves with cues

c.

endocrine disorders: hypo- and hyperthyroidism, hyperparathyroidism, adrenal failure or Cushing’s syndrome

d.

toxin-induced: heavy metal exposure, drugs, alcohol

e.

vitamin deficiency, particularly B1/thiamine or B12

f.

medication use, particularly benzodiazepines, opioids, and anticholinergic agents

g.

chronic brain infections (e.g., HIV, syphilis) or inflammatory conditions

h.

intracranial mass lesions or hydrocephalus

i.

normal pressure hydrocephalus

A

B Figure 7–1 Epidemiology of major dementing disorders. (A) 65 years old; (B) 65 years old. (AD, Alzheimer’s dementia; Lewy, Lewy body dementia)

D. Epidemiology of Major Dementing Disorders (Fig. 7–1)

Dementias

Functional domain

E. Alzheimer’s Dementia (AD) 1.

Histology: primary cortical atrophy involving the loss of synapses, and neurons, and the shrinkage of surviving neurons; atrophy initiates in the mesial temporal and posterior cingulate cortex (cortex layers V-VI) (Box 7.3), but eventually involves the hippocampus and all of the cortex sparing only the primary motor, sensory, and visual cortices a.

neurons in the nucleus basalis of Meynert, locus coeruleus, and raphe are also reduced in number early in the disease

b.

hippocampal atrophy is predominant in the CA1 area (unlike Lewy body dementia, which affects CA2–3)

c.

the cortex and hippocampus lose choline acetyltransferase  nicotinic and muscarinic acetylcholine receptors well into the course of the disease, therefore these are not the primary defects; also exhibit reduced acetylcholine release and decreased choline reuptake (necessary for acetylcholine synthesis), which may relate to a decreased trophic responsiveness to nerve growth factor

d.

plaques and tangles (Fig. 7–2) i.

Box 7.3 Cortical histopathology in AD is in comparison to the loss of layers I–III in frontotemporal lobar degeneration disorders

neurofibrillary tangle: intraneuronal inclusions of hyperphosphorylated tau protein (a microtubuleassociated protein) and ubiquitin (which binds and marks other proteins for degradation) (1) neurofibrillary tangles are associated with an early age of disease onset and a more severe disease course (2) neurofibrillary tangles may not occupy the whole neuron, and may only fill a dendrite {neuropil thread}

ii.

plaques: all are extracellular (1) neuritic/senile plaque: composed of abnormal neuronal processes (dystrophic neurites), and glial processes surrounding an amyloid core; also

Figure 7–2 Neurofibrillary tangles (arrowhead) and neuritic plaque (arrow) in Alzheimer’s disease. (From McKhann GM et al. Q&A Color Review of Clinical Neurology and Neurosurgery. Stuttgart, Germany: Georg Thieme; 2003:123, Fig. 121. Reprinted by permission.)

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includes tau and other molecules (acetylcholinesterase, ubiquitin, chymotrypsin, complement proteins, glycosaminoglycans)

7 Behavioral Neurology and Psychiatry

(2) ghost plaque: develop only after cell death when extracellular proteases degrade the neurofibrillary tangle, leaving only the dense amyloid core (3) diffuse plaque: similar histological appearance to senile plaques; composed of amorphous nonfibrillar -amyloid or finely fibrillar -amyloid deposits iii. Hirano bodies (Fig. 7–3): eosinophilic intracellular inclusions in hippocampal pyramidal cells that have a “herringbone” appearance on electron microscopy iv.

e. 2.

Lewy bodies (see p. 162): more commonly found in the synucleinopathies (Parkinson’s disease, Lewy body dementia, multisystem atrophy), but are present in the substantia nigra in 20% of AD

amyloid angiopathy caused by the -amyloid protein coexists in 90% of AD patients (see p. 65)

Subtypes a.

sporadic AD (95% of cases): symptomatic onset  65 years of age, typically with a slowly progressive course at time of diagnosis (i.e., at the time of diagnosis, the patient is 2–3 years into the course of the disease) i.

risk factors

Figure 7–3 The Hirano body (arrow). (From Hirano A. Color Atlas of Pathology of the Nervous System, 2nd Ed. Tokyo/New York: Igaku-Shoin Press; 1988:94, Fig. 222. Reprinted by permission.)

(1) increasing age (2) APOE alleles: APOE is component of very low-density lipoprotein (VLDL) and chylomicron particles, which facilitates their uptake by muscle and fat cells (Box 7.4) (a) the APOE 4 allele is present in 50% of sporadic AD cases; no clear association with the 4 allele and the severity of the disease

Box 7.4 Other apolipoprotein disorders–APOA1 deposits in some types of amyloidosis; APOB deficiency in abetalipoproteinemia

(b) APOE 4 binds -amyloid, creating an insoluble complex that may form plaques (c) APOE 3 allele may stabilize tau protein thereby preventing neurofibrillary tangle formation, but only the rare APOE 2 allele is known to be protective against AD (3) family history of AD without clear inheritance pattern (4) low level of education (5) female gender (6) history of severe head trauma (7) stroke and vascular risk factors (8) small head size (9) Down’s syndrome b.

familial/early-onset AD (5% of cases): patients are generally  65 years old at onset, and exhibit a more rapid progression of symptoms than do sporadic AD patients; although the disease course is still insidious i.

causative genetic mutations (Fig. 7–4): all have autosomal dominant inheritance (1) the AD1 mutation in the amyloid precursor protein (APP) gene (chromosome 21), which occurs in a region that codes for the -amyloid protein, accounts for 2% of familial AD (a) overexpression of the APP in trisomy 21/Down’s syndrome may account for the early-onset AD in these patients

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(2) presenilin 1 (PS1, chromosome 14): accounts for 75% of familial AD (Box 7.5)

Box 7.5 Presenilin 1 forms the catalytic subunits of the  secretase complex that cleaves APP

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Figure 7–4 Key enzymes of Alzheimer’s disease. (APP, amyloid precursor protein)

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(3) presenilin 2 (PS2, chromosome 1) (4) 2 macroglobulin (chromosome 12) 3.

4.

Epidemiology a.

age distribution: prevalence at 60 years of age  3%; prevalence at 90 years of age  50%

b.

prevalence as a cause of dementia is likely underestimated because i.

Lewy body dementia has a high coincidence with AD

ii.

 50% of vascular dementia cases have elements of AD histology on postmortem examination

Symptoms: course of impairment is typically memory loss before involvement of any other cognitive functions or behavioral impairment a.

memory loss: early and severe impairment of short-term memory  longterm or immediate memory i.

episodic memory is most severely affected

ii.

procedural memory is well-preserved, although mild apraxia can be detected early in the disease

b.

language impairment: initial language abnormality is anomia (due to lateral temporal dysfunction, not memory impairment) that progresses to a transcortical sensory aphasia

c.

behavioral impairment: more common late in the disease i.

agitation and aggressive behaviors (70%), but rarely sexual disinhibition (10%)

ii.

depression (50%), which is proportionate to cell loss in locus coeruleus

iii. simple delusions (30%) that are often paranoid in nature iv.

hallucinations (20%)

d.

visuospatial impairment: manifests primarily as difficulty with navigation

e.

executive impairment: impaired judgment and reasoning, and poor abstraction and decision-making abilities occur late in the disease as frontal lobes become involved (Box 7.6)

Box 7.6 Agnosias can occur in AD, but they are distributed topographically (e.g., visual agnosias to the occipital lobe).

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f.

5.

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generally does not involve focal neurological signs, seizures, motor disturbances (i.e., parkinsonism), or impairment in the level of arousal until late in the disease; the physical exam generally is nonfocal, although multiple frontal lobe release reflexes (e.g., glabellar reflex, grasp, snout reflex) are often present (Box 7.7) i.

myoclonus occurs in 10% of AD cases, which can be confused with prion diseases

ii.

pyramidal signs (increased reflexes, Babinski reflexes, hypertonus) are unlikely to be due to AD, as the primary motor and sensory cortices are not involved in the disease process until very late

Box 7.7 20% of normal young persons have one frontal lobe release sign, but the palmomental reflex is always pathological

Diagnostic testing: none are well-established or necessary for diagnosis a.

genetic markers: the low incidence of familial AD makes them impractical as screening tools

b.

cerebrospinal fluid protein markers: protein markers correlated with pathologically determined AD include i.

increased tau protein and hyperphosphorylated tau protein levels

ii.

combined increases in -amyloid protein and tau protein levels

c.

EEG: loss of alpha activity and increased theta and delta frequencies in 80% of AD cases with  4-year disease duration; useful for differentiating against the frontotemporal lobar degeneration disorders in which EEG is relatively normal

d.

neuroimaging i.

SPECT scans demonstrate hypoperfusion in the temporal and parietal lobes

ii.

PET scans demonstrate hypometabolism in the temporal and parietal lobes

iii. MRI and CT demonstrates reduced hippocampal, entorhinal cortex, and posterior cingulate cortex volumes (Fig. 7–5) 6.

Treatment a.

b.

preventative i.

chronic use of NSAIDs is associated with a decreased risk of developing AD, but it is not an established prophylactic treatment

ii.

hormone replacement therapy appears to increase, not reduce, the risk of dementia

symptomatic treatment i.

acetylcholinesterase inhibitors: donepezil (Aricept), rivastigmine (Exelon), galantamine (Reminyl) (1) improve functional abilities and delay institutionalization in patients with mild or moderate dementia; also appear to be beneficial in severe dementia (2) tacrine also improves cognitive performance but it has a high rate of side effects (particularly hepatotoxicity) and requires q.i.d. dosing, therefore it is rarely used

ii.

memantine: acts as an N-methyl- D -aspartate (NMDA) glutamate receptor antagonist; improves patient’s functional abilities and reduces caregiver burden in patients with moderate or severe dementia

iii. no evidence for use of vitamin E, NSAIDs, or estrogens c.

treatment of behavioral impairment i.

depression: SSRIs or trazodone, which have minimal anticholinergic side effects

ii.

agitation: behavioral modification; buspirone; atypical antipsychotics (olanzapine, quetiapine, risperidone, clozapine) (1) avoid benzodiazepines because they worsen cognitive function

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iii. insomnia: improve sleep hygiene, avoid daytime naps; trazodone

Figure 7–5 Coronal T1 MRI from a patient with Alzheimer’s disease. Note the pronounced hippocampal atrophy (arrows). (From Nestor P, Hodges J. Non-Alzheimer’s dementias. Semin Neurol 2000, 20:443, Fig. 1b. Reprinted by permission.)

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Type

Symptoms different from AD

Signs different from AD

Pseudodementia/ depression with cognitive disturbances

Rapid onset

Good performance on cognitive tests; self-referral to physician

Vascular dementia

Classically (but not commonly) has an abrupt onset and stepwise deterioration

Focal deficits; bulbar signs

Lewy body dementia

Fluctuating cognitive abilities & attention; visual hallucinations; sleep disturbance; frequent falls from syncope

Parkinsonism; high sensitivity to the side effects of antipsychotics

Frontotemporal lobar degeneration/ Pick’s disease

Impulsivity; compulsivity; emotional lability; disinhibition; aphasia

Lack of EEG slowing; lack of visuospatial impairment or other parietal lobe findings

Prion dementias (e.g., CreutzfeldtJakob disease)

Abrupt onset, rapid progression; early aphasia; extrapyramidal symptoms

Cerebellar symptoms; visual loss; myoclonus; CSF positive for 14–3-3 protein; diffuse slow-wave EEG with periodic complexes; neuroimaging abnormalities (see p. 265)

Parkinson’s disease

Subcortical dementia features; subcortical dementia symptoms

Parkinsonism

Huntington’s disease

Impulsivity; hypersexuality; psychosis; subcortical dementia symptoms

Chorea

Dementias

Table 7–2 Differentiating Alzheimer’s Dementia (AD) from Other Dementias

Abbreviations: CSF, cerebrospinal fluid; EEG, electroencephalogram.

7.

Prognosis a.

nursing home placement occurs on average 3 years after diagnosis

b.

70% 5-year mortality, with death usually being attributed to complications of immobility or malnutrition (Table 7–2)

F. Vascular/Multi-Infarct Dementia 1.

2.

Pathophysiology: caused by any combination of cortical infarction, lacunar infarction, and/or leukoaraiosis; also involves microscopic areas of neuron loss and gliosis {microinfarcts} a.

requires  50 cc of tissue loss to achieve symptomatic dementia

b.

risk factors are as per stroke, but also include the cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) gene mutation and the APOE 4 allele (as in AD)

c.

epidemiology: incidence increases with age; 25% of patients will become demented within 3 months of a stroke

Subtypes a.

large infarct dementia: caused by a few cortical and/or subcortical infarcts that are larger than lacunes

b.

small infarct dementia: typically caused by multiple lacunes {l’etat lacunaire}, leukoaraiosis, CADASIL, or amyloid angiopathy

c.

strategically placed infarct dementia: caused by single lesions in the hippocampus/medial temporal lobe, medial thalamus, caudate nucleus, or nondominant parietal lobe; such infarcts tend to have a preference for the dominant hemisphere

d.

hypoxic-ischemic encephalopathy

e.

hemorrhagic dementia secondary to subdural hemorrhage, subarachnoid hemorrhage, or intracerebral hemorrhage

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3.

Symptoms: dementia must be preceded within 3 months by a stroke, and focal neurological deficits should be present; exhibits distinguishable cortical- and subcortical-type dementias

4.

Diagnostic testing a.

the size and exact number of infarcts are not as predictive of dementia as is cortical atrophy

b.

isolated lacunar infarcts occur in 20% of the general population, but are associated with worse cognitive performance and an increased risk of dementia

c.

periventricular white matter T2 hyperintensities on an MRI scan {leukoaraiosis} is not specific for vascular dementia or any dementia, but is associated with worse performance on cognitive tests

5.

Treatment: as per stroke prevention, with particular attention to the reduction of hypertension (reduces incidence of dementia by 50%) and reduction of elevated homocysteine levels; acetylcholinesterase inhibitors; memantine

6.

Prognosis: 30% 5-year survival, which is worse than other types of dementia or nondemented stroke; however, cognitive deterioration progresses more slowly than in AD

G. Frontotemporal Lobar Degeneration/Pick’s Disease (Box 7.8) 1.

Histology: Selective atrophy of the frontal (particularly orbitofrontal) and/or anterior temporal lobes often involving the hippocampus, amygdala, and/or underlying basal ganglia (particularly the caudate); atrophy tends to spare the sensory cortices (as with AD) but also the parietal lobe (unlike AD) a.

pronounced astrocyte gliosis in cortex and subcortical white matter with loss of cortical layers I–III (versus AD that affects layers V–VI predominantly)

b.

loss of acetylcholine receptors  choline acetyltransferase (in comparison with AD)

c.

inclusion bodies: argentophilic cellular inclusions {Pick bodies} and swollen neurons {Pick cells} are fairly specific for the frontotemporal lobar degeneration disorders, although they are found in  50% of cases (Fig. 7–6); cases with Pick bodies and cells tend to be more rapidly progressive

Figure 7–6 The Pick body (arrow). (From Hirano A. Color Atlas of Pathology of the Nervous System, 2nd Ed. Tokyo/New York: Igaku-Shoin Press; 1988:98, Fig. 233. Reprinted by permission.)

Box 7.8 Frontotemporal lobar degeneration is not the same as frontotemporal dementia, which is a subtype of it

2.

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i.

Pick bodies contain ubiquitin and tau protein tau

ii.

in cases without Pick bodies or cells, intranuclear ubiquitin inclusions can often be identified

Pathophysiology a.

b. 3.

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genetics: 20% of cases have a familial pattern that is usually autonomic dominant i.

tau gene mutations: mutations in the tau gene on chromosome 17 are responsible for 10% of familial frontotemporal lobar degeneration disorders, particularly those that involve parkinsonian features (i.e., the FTDP-17 variant)

ii.

tau gene haplotypes: of the two tau haplotypes (H1 and H2) (Box 7.9), the H2 haplotype is particularly common in the semantic subtype of frontotemporal lobar degeneration disorders

associated with Parkinson’s disease and amyotrophic lateral sclerosis (ALS)

Subtypes: all have an insidious progression and symptomatic onset before 65 years of age (Box 7.10); lack of parietal lobe dysfunction differentiates against AD a.

frontotemporal dementia—common symptoms include impersistence of attention, apathy or disinhibition, and irritability; occasionally may also involve i.

Kluver-Bucy syndrome (usually incomplete): placidity, hypersexuality, hyperorality, and/or increased manual exploration

ii.

perseverative behaviors with stereotypies

Box 7.9 H1 haplotype is common in progressive supranuclear palsy and corticobasal ganglionic degeneration

Box 7.10 Eventually all frontotemporal lobar degeneration subtypes will progress to frontotemporal dementia.

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iii. echolalia and perseveration of speech progressing to mutism b.

primary progressive aphasia—caused by disease predominantly in the dominant frontal or temporal lobes i.

symptoms: aphasia of either a nonfluent or fluent type; progresses to dyslexia, agraphia, and apraxias, suggesting parietal lobe involvement (1) isolated aphasia is usually present  2 years before the development of other symptoms

4.

5.

c.

semantic dementia—symptoms include reduced verbal fluency and pronounced naming difficulties; usually seen in patients with anterior temporal lobe atrophy

d.

progressive prosopagnosia—usually seen in patients with nondominant temporal lobe (i.e., fusiform gyrus) atrophy

Diagnostic testing a.

neuroimaging may reveal an asymmetric atrophy pattern (Fig. 7–7)

b.

PET demonstrates hypometabolism and SPECT demonstrates hypoperfusion in the frontal and temporal lobes and often the basal ganglia

Treatment: None with proven efficacy; SSRIs for management of behavioral abnormalities irrespective of depression

H. Lewy Body Dementia 1.

Histology: degeneration of the temporal and parietal cortices (like AD), but also of the occipital cortex; hippocampal atrophy predominantly affects the CA2–3 regions, unlike AD that predominantly affects CA1 a.

exhibit significant loss of acetylcholine but limited loss of neurons in the cholinergic basal forebrain nuclei (i.e., basal nucleus of Meynert), unlike AD

b.

exhibits loss of basal ganglia dopamine as in Parkinson’s disease, but also loss of basal ganglia D2 receptors

c.

80% of cases exhibit some Alzheimer’s-like histological abnormalities, particularly neuritic-like plaques that do not contain tau protein

d.

inclusion bodies

Figure 7–7 Coronal T1 MRI from a patient with semantic dementia. Note the pronounced atrophy of the left temporal lobe (arrows). (From Nestor P, Hodges J. NonAlzheimer’s dementias. Semin Neurol 2000, 20:443, Fig. 1c. Reprinted by permission.)

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Figure 7–8 The Lewy body (arrow). Courtesy of Dr. C. Yamada.

i.

Lewy body (Fig. 7–8): eosinophilic inclusions surrounded by a halo that contain -synuclein and ubiquitin; found predominantly in the hippocampus and parahippocampal gyrus, but are widely distributed throughout the cortex, brainstem, and spinal cord (Box 7.11) (1) Lewy bodies are identical to those found in Parkinson’s disease

ii. 2.

Pathophysiology: Rare familial disease patterns are weakly associated with cytochrome P450 mutations or -synuclein mutations

3.

Symptoms a.

fluctuating cognitive abilities and level of arousal that may relate to cyclic sleep disturbance

b.

autonomic dysfunction: orthostatic hypotension; incontinence; sexual dysfunction (Box 7.12)

c.

visual hallucinations (80%); also illusions and paranoid delusions (Box 7. 13) i.

d.

conversely, an unspecified dementia occurring in conjunction with RSBD is likely to be Lewy body disease

Lewy body-like inclusions occur in Parkinson’s disease, Alzheimer’s disease, multiple system atrophy, corticobasal ganglionic degeneration, Hallervorden-Spatz disease, ataxia telangiectasia, and frontotemporal lobar degeneration  amyotrophic lateral sclerosis.

Box 7.12 Fluctuating cognitive abilities and autonomic dysfunction together account for episodes of loss of consciousness.

Box 7.13 Capgras syndrome—The delusion that imposters have replaced family members

e.

impairment of visuospatial abilities without ophthalmologic abnormality (Box 7.14)

Box 7.14

f.

Parkinsonism: symptoms are symmetric and poorly responsive to dopaminergic agonists; tremor is mild and often involves a positional as well as resting component

Impairment of visuospatial abilities and parkinsonism together may account for frequent falls.

i.

4.

hallucinations may be caused by intrusion of REM sleep while the patient is awake (i.e., as in peduncular hallucinosis)

sleep disturbance, particularly REM (rapid eye movements) sleep behavioral disorder (RSBD) that may precede the dementia by decades i.

the parkinsonism must develop no sooner than 1 year before the dementia to be diagnosed as Lewy body disease and not as Parkinson’s disease dementia

Diagnostic testing a.

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Lewy neurites: intracellular inclusions of ubiquitin and -synuclein, which are limited to dendrites

Box 7.11

polysomnography may demonstrate RSBD (i.e., the lack of atonia during REM sleep)

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b.

SPECT demonstrates parietal and occipital hypoperfusion, and PET demonstrates hypometabolism in these regions

c.

neuroimaging and EEG provide no reliable or specific information

Treatment a.

acetylcholinesterase inhibitors, which do not seem to worsen the disease’s parkinsonian features

b.

atypical antipsychotics (olanzapine, quetiapine, risperidone, clozapine) for treatment of psychosis

c.

low-dose dopamine agonists for parkinsonism, although they are poorly effective and readily exacerbate the hallucinosis and orthostatic hypotension

1.

Pathophysiology: a communicating hydrocephalus that does not involve constantly increased intracranial pressure; potential mechanisms include dilation caused by transiently increased intracranial pressure and/or altered elastic properties of the ventricle walls

2.

Epidemiology: more common in males  60 years old

3.

Symptoms (in order of appearance)

4.

a.

gait disturbance: Bruns’ frontal lobe ataxia (which is really an apraxia; see p. 5)

b.

“dementia” (60%), which is really an attentional deficit (i.e., a confusional state)

c.

urinary incontinence (spastic bladder); urgency may precede incontinence

Diagnostic testing: No test exhibits high diagnostic accuracy a.

5.

6.

Dementias

I. Normal Pressure Hydrocephalus/Hakim-Adams Syndrome

lumbar puncture i.

demonstrates normal pressure but continuous cerebrospinal fluid pressure monitoring may exhibit prolonged or transient pressures  20 mm Hg (Lundberg waves; see p. 35)

ii.

measurement of the resistance to fluid injection into the subarachnoid space is correlated with the severity of symptoms but is not predictive of the response to shunting

b.

radionuclide cisternography: retention of contrast in the ventricles  24 hours after administration is not useful for establishing the diagnosis or predicting the clinical response to shunting

c.

MRI cerebrospinal fluid flow study: absence of flow near the cerebral aqueduct does not predict the clinical response to shunting

Treatment: low-pressure ( 3-mm opening pressure) ventriculoperitoneal shunt a.

patient should be sat upright slowly over several days after shunt placement

b.

lumboperitoneal shunts often results in over-shunting and have high complication rates

Prognosis: incontinence and gait generally improve more than the “dementia”; responsiveness to shunting is predicted by a.

the presence of the classic triad of symptoms with gait disturbance as the first symptom

b.

clinical improvement after lumbar puncture

c.

a near-normal opening pressure

d.

high transient pressures on continuous cerebrospinal fluid pressure monitoring

e.

the absence of periventricular increased T2 signal on MRI

f.

symptoms  1 year in duration

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II. Sleep Disorders A. Normal Sleep 1.

Physiology a.

arousing systems

7 Behavioral Neurology and Psychiatry

i.

mesencephalon (1) ascending reticular activating system (ARAS): the major component is the cholinergic nuclei of the mesencephalic and pontine reticular formation (pedunculopontine tegmental nucleus), but it also includes the noradrenergic locus coeruleus and the serotonergic raphe nuclei (2) ventral tegmental area (dopaminergic) (3) mesencephalic raphe nuclei

ii.

hypothalamus: includes the posterior nucleus (histaminergic) and posterolateral nucleus (orexinergic/hypocretinergic) of the mamillary region

iii. basal forebrain: includes the septal nuclei and the nucleus basalis of Meynert (cholinergic) iv. b.

thalamus, specifically the intralaminar nuclei (glutamatergic)

somnogenic systems i.

hypothalamus: the lateral preoptic nucleus sends inhibitory projections (GABA, galanine) to the arousing centers, thereby inhibiting wakefulness

ii.

medulla (1) dorsolateral region of medullary reticular formation and anterior solitary tract nucleus (a) synchronize the EEG and may induce non-REM sleep (b) also trigger atonia prior to the onset of REM sleep via projections to nucleus gigantocellularis of the medullary reticular formation that forms the lateral reticulospinal tract (2) nucleus reticularis pontis: may trigger REM sleep via projections to mesencephalic ARAS nuclei; responsible for ponto-geniculooccipital (PGO) spikes detected by parenchymal electrodes in animals during REM sleep

iii. hypothalamus: lateral preoptic nucleus sends inhibitory projections (GABA, galanin) to the arousing centers of the brainstem, basal forebrain, and hypothalamus, thereby inhibiting wakefulness iv.

thalamus: the reticular nucleus sends GABAergic projections to the other thalamic nuclei, thereby inhibiting their excitation of the cortex

v.

basal forebrain: exhibits changes in adenosine levels (a somnogenic compound) that increase with wakefulness and decrease with sleep; adenosine receptors in this region may mediate caffeine’s alerting effects as an antagonist on these receptors

vi. pineal: produces melatonin (Fig. 7–9) from serotonin and begins releasing it during the evening with a peak at 3–5 AM; may act to fix sleep–wake behaviors with the light–dark cycle (1) the melatonin cycle is regulated by projections from the suprachiasmatic nucleus and sympathetic afferents from the superior cervical ganglia c.

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circadian systems: the suprachiasmatic nucleus of the hypothalamus acts as the major circadian pacemaker and regulates other hypothalamic nuclei including the histaminergic and orexinergic portions of the posterior hypothalamus; affects melatonin release by sympathetic nervous system projections from the superior cervical ganglion

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Sleep Disorders

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Figure 7–9 Biosynthesis of melatonin and serotonin.

2.

Sleep stages a.

b.

wakefulness: EEG demonstrates desynchronized activity of predominant  frequency;  frequency is normally reduced by mental activity or by drowsiness i.

closing the eyes results in a synchronization and increased amplitude of the occipital alpha frequency

ii.

all three neurotransmitter systems of the ARAS (acetylcholine, catecholamines, and serotonin) are active

non-REM/slow-wave sleep (Fig. 7–10) (Box 7.15): all exhibit synchronized, high-voltage low-frequency background and are associated with a low level of motor activity and decreased muscle tone; all neurotransmitter systems of the ARAS are reduced

Box 7.15 non-REM sleep can have dreams, but they are relatively unformed.

Figure 7–10 The EEG in wakefulness and the various slow-wave sleep stages. Transition from wakefulness to stage I sleep (arrow, top line). K-complexes (arrow, third line) and sleep spindles (underline) are characteristic of stage II sleep. (From Sinton CM, McCarley RW. Neurophysiological mechanisms of sleep and wakefulness. Semin Neurol 2004, 24: 213, Fig. 1A. Reprinted by permission.)

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Figure 7–11 REM sleep. Courtesy of Dr. P. Manthena.

i.

stage 1 sleep exhibits  50% alpha frequency (versus being awake with eyes closed) and vertex waves

ii.

stage 2 sleep exhibits sleep spindles and K complexes, as well as vertex waves

iii. stage 3 sleep exhibits 20–50% delta frequency of at least 75 mV amplitude iv. c.

stage 4 sleep exhibits  50% delta frequency of at least 75 mV amplitude

REM sleep: exhibits desynchronized, low-voltage mixed frequency background involving theta  alpha and beta frequencies (Fig. 7–11); acetylcholine levels from the ARAS are relatively high, but catecholamines and serotonin levels are reduced i.

PGO spikes are seen during REM sleep in animals prior to the appearance of rapid eye movements, but it is not known if they exist in humans

ii.

bursts of hippocampal theta waves {sawtooth waves} are characteristic

iii. somatic activity: atonia and absence of movements except in the ocular muscles and diaphragm, but including oropharynx; rarely twitching can be observed in the facial muscles (1) paralysis of nondiaphragmatic respiratory muscles may lead to collapse of the rib cage in infants or to airway collapse in adults (as in obstructive sleep apnea) (2) erections occur in REM sleep; absence of erections during REM sleep supports the diagnosis of biogenic (versus psychogenic) impotence iv. d.

dreams: are relatively complex and involve emotions

sleep stage distribution: in normal sleep, there is an orderly progression through slow-wave sleep stages, which is followed by REM sleep; this cycle repeats itself 4–5 times/night, although the majority of slow-wave sleep occurs during the first half of the night and the majority of REM sleep occurs during the second half

B. Dyssomnias (Box 7.16) 1.

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Disorders of initiating and maintaining sleep {insomnias} a.

subtypes

Box 7.16 Dyssomnias require the complaint of daytime sleepiness.

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i.

transient insomnias ( 1-month course): usually caused by psychological stress, anxiety disorders, depression, changes in the patient’s sleep schedule, or medications/drug use

ii.

chronic insomnias ( 1-month course) (1) primary insomnia

b.

symptoms: difficulty falling asleep and/or difficulty staying asleep with early morning awakenings; nonrestorative sleep

c.

treatment i.

improve sleep hygiene: daytime exercise; avoid daytime naps; avoid light exposure at night; avoid caffeinated beverages; avoid heavy meals or drinking 3 hours before bedtime; strictly limiting the use of the bed to sleeping; regular bed and waking times

ii.

relaxation therapy; biofeedback; cognitive–behavioral therapy

iii. sleep restriction therapy: limiting the time spent in bed until 85% of the time is in sleep; after this is achieved, the patient can increase the total time spent in bed iv.

benzodiazepines (Box 7.17), which cause significant morning sleepiness (1) act by increasing the duration of sleep stage 2 and increasing the number of sleep cycles at the expense of REM sleep, which produces a refreshing sleep but which may lead to REM rebound when the medication is discontinued

v.

Box 7.17 Benzodiazepines use only sparingly, never scheduled, and always in conjunction with behavioral modification.

Sleep Disorders

(2) insomnia secondary to chronic medical condition, psychiatric disorders, or medications/drugs

hypnotics: zolpidem (Ambien) and zaleplon (Sonata), which are GABA receptor agonists (1) exhibit minimal respiratory or cognitive side effects, and significantly less tolerance or rebound than benzodiazepines (2) hypnotics do not decrease REM sleep as much as benzodiazepines, therefore there may be no REM rebound phenomenon upon discontinuation

vi. sedating antidepressants (amitriptyline, trazodone, amoxapine); other antidepressants (e.g., SSRIs) are less likely to be effective unless the patient has a psychiatric disorder 2.

Disorders of excessive daytime sleepiness: The most common cause is selfimposed sleep restriction, which must be excluded by a careful history a.

narcolepsy i.

pathophysiology: destruction (possibly autoimmune) of the hypocretin/ orexin-containing neurons in the posterolateral nucleus of the mamillary region of the hypothalamus, which normally act to stimulate the cholinergic, histaminergic, and monoaminergic components of the reticular activating system; this causes instability between waking and REM sleep, and allows one to intrude into the other (1) associated with HLA-DQ and -DR types

ii.

symptoms: develops at 20–30 years of age (1) excessive daytime sleepiness with the sudden onset of sleep {sleep attacks}, which are refreshing for the patient; sleep attacks are not specific for narcolepsy (2) sudden-onset diffuse weakness that is precipitated by intense emotional responses, particularly laughter {cataplexy}; pathognomonic for narcolepsy (a) cataplexy may develop years after the other symptoms of narcolepsy (b) cataplexy likely represents development of REM atonia while awake (c) may only last a few seconds and involve the face and/or arms

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(3) paralysis at the onset of sleep or upon awakening, with intact consciousness {sleep paralysis} (4) hallucinations at sleep onset {hypnagogic} or upon awakening {hypnopompic} (a) hallucinations may or may not be accompanied by sleep paralysis

7 Behavioral Neurology and Psychiatry

(b) hallucinations may be of any type but are usually visual (c) some awareness of surroundings is preserved (5) fragmented sleep patterns with frequent arousals iii. diagnostic testing (1) multiple sleep latency test: in narcoleptics, evaluation of 4–5 daytime naps (one every 2 hours) will demonstrate sleep-onset latencies of  5 minutes and two or more naps with REM sleep beginning immediately after sleep onset {sleep-onset REM}; nonnarcoleptics do not exhibit sleep-onset REM and have longer sleep-onset latencies (a) should be performed with an overnight polysomnogram the previous evening to rule-out other sleep disorders (2) maintenance of wakefulness test: determines the patient’s ability to stay awake for 40 minutes in a dark, relaxed environment (3) overnight polysomnography to rule-out other causes of excessive daytime sleepiness iv.

treatment (1) behavioral: scheduled naps; avoid heavy meals and alcohol consumption (2) for daytime sleepiness: modafinil (Provigil) or amphetamines (3) for cataplexy: tricyclic antidepressants, fluoxetine, venlafaxine, sodium oxybate

b.

sleep breathing disorders (Box 7.18) (Box 7.19) i.

subtypes (1) obstructive sleep apnea—may be caused by pharyngeal collapse, dysfunction of the airway dilator muscles, or anatomical narrowing of the airways (a) risk factors include increased body mass index, neck circumference  17 inches, hypothyroidism, witnessed sleep apneas, gasping during waking, and hypertension (b) exhibits continued respiratory activity during apneic episodes (2) central sleep apnea: caused by bilateral medullary lesions, usually in the context of postanoxic brain injury, encephalitis, Leigh’s disease (see p. 48), or disorders of the autonomic nervous system (e.g., Hirschsprung’s disease) (a) occurs normally several times during each sleep cycle (b) does not exhibit respiratory activity during apneic episodes

ii.

symptoms: transient arrest of breathing during sleep that can be complete {apnea} or partial {hypopnea} that must be  10 seconds in duration and occur  5 times per hour to be considered pathological; other symptoms include (1) excessive daytime sleepiness (2) snoring, gasping, or snorting during sleep; dry mouth or sore throat upon awakening (3) grinding of teeth during sleep (4) mood changes: irritability, apathy

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(5) sleep terrors

Box 7.18 Ondine’s curse—Repeated central sleep apneas during early postnatal life, caused by abnormal function of chemoreceptors in the central nervous system

Box 7.19 The number of apneic episodes does not correlate with daytime sleepiness.

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iii. treatment (1) nonsurgical treatment: weight loss, continuous positive airway pressure (CPAP), and oral appliances to promote airway patency (2) surgical treatment: uvulopalatopharyngoplasty; tonsillectomy; adenoidectomy; tracheostomy in severe refractory cases c.

restless legs syndrome i.

pathophysiology: unknown, but may be related to abnormal transport and storage of iron in the brain

ii.

subtypes (1) idiopathic: most common subtype (2) secondary: associated with iron deficiency, chronic renal failure, pregnancy, peripheral vascular disease, and Parkinson’s disease

(3) iatrogenic: caused by antidepressants (particularly the SSRIs), caffeine, amphetamines, lithium iii. symptoms (1) paresthesias and dysesthesias of the limbs that create the urge to move the affected limb {akisthesia}; paresthesias and dysesthesias are temporarily relieved by movement of the akisthetic limb (a) pronounced at rest and while inactive, but may be present during the day

Sleep Disorders

(a) iron is a necessary cofactor for tyrosine hydroxylase, which is involved in the synthesis of dopamine

(2) periodic limb movements (80%) iv.

diagnostic testing: serum iron and ferritin levels to identify ironresponsive patients

v.

treatment (1) dopaminergic agonists: pramipexole (Mirapex), ropinirole (Requip) (a) initiation or increasing the dosage often exacerbates symptoms (2) gabapentin, particularly for patients with painful symptoms (3) iron supplementation (4) opiates (hydrocodone, methadone) for refractory cases

d.

periodic limb movement disorder i.

pathophysiology: unknown, but likely involves decreased dopaminergic activity that causes disinhibition of the spinal cord (1) may not even be a distinct disease, but may rather be a feature of other diseases (e.g., restless legs syndrome, sleep apnea, narcolepsy)

ii.

symptoms: involuntary movements of the lower  upper extremities lasting  5 seconds, typically occurring during sleep stages 1–2; must be repetitive and disruptive of sleep to be considered pathological

iii. treatment: dopaminergic agonists 3.

Circadian rhythm disorders a.

pathophysiology: caused by a loss of synchronization between the internal circadian rhythm and the light–dark cycle of the environment, usually from jet lag or shift work but may be due to irregularity of the internal circadian rhythm in patients with hypothalamic lesions or severe vision loss

b.

subtypes i.

advanced sleep phase syndrome—symptoms include early sleep onset (before 9 PM) and early awakening (before 5 AM)

ii.

delayed sleep phase syndrome—symptoms include a late sleep onset (after 2 AM) and a late awakening

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treatment i.

bright light exposure (1) in the evening for an advanced sleep phase (2) in the morning for a delayed sleep phase

7 Behavioral Neurology and Psychiatry

ii.

melatonin, given 4–5 hours before the onset of bedtime

C. Parasomnias 1.

Non-REM parasomnias a.

pathophysiology: caused by partial arousal from sleep stages 3–4 i.

triggers for parasomnia attacks include (1) an increased amount of slow-wave sleep, e.g., during recovery from sleep deprivation, at the onset of CPAP therapy, or during febrile illnesses (2) sleep fragmentation as caused by stress, pain, sleep-related breathing disorder (snoring, sleep apnea), pregnancy, alcohol use, or new sleep site (e.g., hotel)

b.

epidemiology: male predominance except for nocturnal eating/drinking behavior; more common in the young and in patients with a family history of non-REM parasomnias

c.

subtypes i.

sleep terrors

ii.

sleep walking {somnambulism}

iii. nocturnal eating/drinking behavior

2.

3.

d.

symptoms: episodes last  15 minutes and develop early during sleep when slow-wave sleep is more abundant; patients are poorly responsive to external stimuli during an episode and have only a vague or no recollection of the event

e.

treatment: avoid triggers; prevent injuries during attack (door alarms, motion sensors); clonazepam

REM parasomnias: REM sleep behavior disorder (RSBD) a.

pathophysiology: may relate to dysfunction of the pedunculopontine tegmental nucleus of the mesencephalic reticular formation that disrupts the atonia generated by the nucleus gigantocellularis and the lateral reticulospinal tract

b.

subtypes i.

acute-onset RSBD: typically caused by withdrawal of sedative-hypnotic drugs or alcohol, caffeine use, or a new medication (particularly SSRIs or cholinergic medications)

ii.

insidious-onset RSBD: likely a neurodegenerative disorder involving reduced striatal dopamine transporters and dopamine innervation; associated with the synucleinopathies (e.g., Parkinson’s disease, multiple system atrophies, Lewy body dementia), which may develop decades after the onset of RSBD

c.

epidemiology: male predominance; increasing incidence with advanced age

d.

symptoms: violent behavior directed against an apparent enemy following a brief period of autonomic and behavioral arousal; the patient will have excellent recall of a vivid dream that underlies the event

e.

diagnostic testing: polysomnography demonstrates a lack of atonia during REM sleep with intrusion of complex motor behaviors

f.

treatment: clonazepam

Transitional parasomnias: rhythmic movement disorder/jactatio capitis nocturna a.

pathophysiology: unknown; occurs during sleep onset and during transitions to and from sleep stage 2 i.

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b.

common in young children but spontaneously resolves by 4 years of age

symptoms: violent movements (head banging, thrashing, kicking) often associated with vocalizations; movements can cause injury

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persistence of movements into adulthood is common only in patients with autism and mental retardation, in whom the movements may resemble the patient’s waking stereotypies

III. Psychosis A. Schizophrenia Pathophysiology: unknown cause, but predominant hypotheses include a.

2.

neuroanatomical abnormalities i.

a migrational defect of cortical layers I–III

ii.

diffuse brain atrophy with both neuronal and glial cell loss

b.

prefrontal cortex dysfunction {hypofrontality}

c.

increased mesolimbic dopamine activity

d.

genetic factors: strong familial patterns of schizophrenia have been associated with numerous chromosomal abnormalities; increased incidence of schizophrenia occurs in monozygotic twins  dizygotic twins  nontwin siblings

e.

psychosocial factors i.

stress-diathesis model: an environmental stress induces schizophrenia in biologically vulnerable patients (e.g., viral infection, obstetrical complication, hypoxia)

ii.

sociocultural and economic factors likely influence the course of schizophrenia rather than directly causing the disorder

Symptoms: average age of onset at 21 years of age for men and 27 years of age for women (Box 7.20) (Box 7.21) a.

diagnostic symptoms i.

over a 6-month period, at least two of the following (1) delusions (2) hallucinations (3) disorganized speech with reduced content (similar to mild form of Wernicke’s aphasia) (4) disorganized behavior, which must impair social activities, work, or self-care

Psychosis

1.

Box 7.20 Subtypes of Schizophrenia Paranoid—Mostly hallucinations and delusions Disorganized—Mostly disorganized speech and behavior Catatonic—Negativism, motiveless resistance to orders, posturing, echolalia, and echopraxia; may be hypoactive or agitated

(5) flat affect, apathy, anhedonia, social withdrawal

Box 7.21

or ii.

b.

bizarre delusions, auditory hallucinations involving two or more voices, or an auditory hallucination making a running commentary on the patient’s activities/thought

other symptoms i.

preoccupation with religious, philosophical, or abstract thought

ii.

ideomotor apraxia, sensory aprosody, right–left confusion, denial of illness (all are indicative of parietal lobe dysfunction)

Good prognostic signs in schizophrenia: Late onset; acute onset; married; positive symptoms Bad prognostic signs in schizophrenia: Early onset; gradual onset; single; negative symptoms

iii. abnormal movements: grimacing, stereotypies, abnormal smooth pursuit eye movements

3.

iv.

polysubstance abuse: cigarette smoking (75%), alcohol (50%), cannabis, cocaine

v.

depression, particularly after psychotic episodes (25%)

Diagnostic testing no laboratory values are diagnostic for schizophrenia and a diagnosis is made solely on clinical features a.

EEG: demonstrates reduced alpha and increased delta and theta frequencies during waking, frequent spikes after sleep deprivation, and increased desynchronization induced by mild auditory stimulation

b.

somatosensory evoked potentials exhibit increased early waveforms (N100) and reduced delayed waveforms (P300) that may represent subcortical and cortical processing, respectively

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Table 7–3 Antipsychotic Medications Class

Receptor effect

Typical antipsychotics

D2  D1 antagonism

Parkinsonism, tardive disorders, neuroleptic malignant syndrome

High potency

Sundowning

Gynecomastia, impotence

chlorpromazine (Thorazine)

Low potency

Antipruritic, hiccups

Anticholinergic effects

D2 and 5HT2 antagonism

Minimal Parkinsonism; tics Effective for treatment refractory cases; ↓ suicide risk

Clozapine (Clozaril)

Risperidone (Risperdal)

5HT2  D2 affinity

Agranulocytosis; ↓ seizure threshold

Gynecomastia, raises prolactin levels

Olanzapine (Zyprexa)

Hyperglycemia, ↑ weight

Quetiapine (Seroquel)

Sedation

Ziprasidone (Geodon) Aripiprazole (Abilify)

D2 partial agonists

Minimal weight gain and hyperglycemia

QT prolongation

Treatment a.

5.

Side effects

haloperidol (Haldol)

Atypical antipsychotics

4.

Specific benefits

antipsychotics (Table 7–3): sudden withdrawal may provoke a transient chorea ( tardive dyskinesia) i.

typical antipsychotics good for positive symptoms while relatively ineffective for negative symptoms

ii.

atypical antipsychotics: efficacy for positive and negative symptoms with minimal or no potential for extra pyramidal symptoms (EPS)

b.

adjuvants: anticonvulsants (carbamazepine, valproate), lithium, benzodiazepines

c.

psychosocial treatment including supportive psychotherapy, social skills training, and assertive community treatment

Prognosis: symptoms may be continuous, episodic with or without symptoms between episodes a.

15% mortality from suicide, most commonly in the well-educated and young

B. Schizophreniform Disorder

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1.

Pathophysiology: exhibits abnormalities similar to schizophrenia (poor activation of the prefrontal cortex, diffuse atrophy)

2.

Symptoms: at least 1 month, but  6 months, of a.

hallucinations and delusions

b.

flat affect

c.

absence of a concurrent mood disorder (which indicates schizoaffective disorder)

3.

Treatment: antipsychotics, typically for 3–6 months

4.

Prognosis: by definition, symptoms must resolve within 6 months; the postpsychosis period is typified by depression and an increased suicide risk

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IV. Mood Disorders A. Major Depressive Disorder 1.

Biological pathophysiology a.

monoamine hypermetabolism and depletion

b.

neuroendocrine abnormalities i.

hypothalamic-pituitary-adrenal axis: 50% of patients with major depression do not suppress adrenal cortisol secretion in response to administration of dexamethasone (i.e., in the dexamethasone suppression test), reflecting persistent hypothalamic CRH secretion (1) failure of dexamethasone suppression is not specific for major depression

2.

c.

circadian rhythm abnormalities: major depression patients exhibit delayed sleep onset, rapid onset of REM sleep, and increased REM density; sleep deprivation may actually improve depressive symptoms

d.

genetics: exhibits a multifactorial inheritance pattern, although no candidate genes have been identified

Psychosocial pathophysiology a.

stressful life events often precede the initial major depressive episode, but they do not necessarily precede subsequent episodes of depression i.

3.

4.

development of depression is particularly associated with certain stressful events (i.e., death of a parent or spouse)

Symptoms: onset commonly between 20–50 years of age; onset  20 years of age is often associated with drug abuse a.

at least 2 weeks of five of the following symptoms (with at least one being depressed mood or anhedonia inflated self-esteem, decreased need for sleep, distractibility, increased talkativeness, racing thoughts, increased physical and mental activity, over-involvement in pleasurable activities (typically sex and/or shopping)

b.

no mania or hypomania

Treatment a.

psychotherapy: cognitive–behavioral, psychodynamic (insight-oriented), interpersonal, and family therapies

b.

medical: antidepressants (Table 7–4) i.

5.

hypothalamic-pituitary-thyroid axis hypoactivity, which is a nonspecific finding that occurs in many psychiatric disorders

may supplement with lithium, triiodothyronine (T3), mood stabilizers, or atypical antipsychotics if the patient does not respond to antidepressant treatment

Prognosis: 30% may remit after successful treatment of the first episode; in nonremitters, subsequent episodes of depression become more severe and prolonged

B. Bipolar Disorders (Box 7.22) 1.

Symptoms of manic and hypomanic episodes a.

both types of episodes require at least three of the following i.

2.

Mood Disorders

ii.

mood must be either euphoric, expansive, or irritable

b.

manic episode:  1 week of symptoms that impair social or occupational functioning

c.

hypomanic episode: at least 4 days of symptoms that do not impair social or occupational functioning

Box 7.22 Dysthymia:  2 years of depression-like symptoms that do not meet criteria for major depression; treat as per depression Cyclothymia:  2 years of hypomanic episodes and depressive symptoms that do not meet criteria for a major depressive episode; treat as per bipolar disorder

Subtypes a.

bipolar I disorder—multiple manic episodes with or without major depressive episodes i.

pathophysiology (1) biological: linked to polymorphisms on chromosomes 11 and X

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Table 7–4 Antidepressant Medications Class/drug

Specific benefit

Major side effects

Selective serotonin reuptake inhibitors:

Low potential for lethality in overdose; few anticholinergic effects, orthostatic hypotension, and cardiac arrhythmias; also useful for obsessive-compulsive, panic, and eating disorders

Insomnia, tremor, sexual dysfunction; increased suicide risk in children

Anxiety disorders

Hypertension

Tricyclics:

Phobias, hypochondriasis, chronic pain, anxiety, & panic disorders

Overdose → prolonged QT, anticholinergic effects

Amitriptyline (Elavil)

Headache prophylaxis, sleep disorders, chronic pain conditions

Orthostatic hypotension, sedation

Clomipramine

Obsessive–compulsive disorder

Orthostatic hypotension, ↑ seizure risk*

Desipramine

Attention-deficit disorders

Nortriptyline

Lowest incidence of orthostatic hypotension among TCAs

Arrhythmia

Attention deficit, low incidence of sexual dysfunction

Lowers seizure threshold

Citalopram (Celexa)

7 Behavioral Neurology and Psychiatry

Escitalopram (Lexapro) Fluoxetine (Prozac) Paroxetine (Paxil) Sertraline (Zoloft) Serotonin-norepinephrine reuptake inhibitors: Venlafaxine (Effexor) Duloxetine (Cymbalta)

Second generation: Bupropion (Wellbutrin)

Sedation, weight gain, increased appetite, sedation

Mirtazapine (Remeron) Monoamine oxidase (MAO)-A inhibitors:

“Atypical” depression (e.g., with hypersomnia and hyperphagia), phobias

Phenelzine

hypochondriasis

Hypertensive reaction to tyramine ingestion; overdose toxicity due to serotonin syndrome (see p. 202)

Tranylcypromine *“increased” seizure risk is still  1%. Abbreviations: TCAs, tricyclic antidepressants.

(2) psychosocial: stressful life events often precede the initial manic episode ii. b. 3.

b.

lithium, anticonvulsants (carbamazepine, valproate, lamotrigine), antipsychotics i.

bupropion may be less likely to induce mania/hypomania in bipolar depressed patients

ii.

side effects of lithium include hypothyroidism, tremor, and nephrogenic diabetes insipidus

cognitive–behavioral therapy

Prognosis: bipolar II disorder patients are at higher risk for suicide than bipolar I patients a.

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bipolar II: episodes of major depression mixed with hypomanic episodes but not manic episodes

Treatment a.

4.

increased risk in patients with family members who have major depression or bipolar I disorder

rapid cycling (four episodes per year) occurs in bipolar I or II patients; may be triggered by use of antidepressants (most often by tricyclic antidepressants)

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V. Anxiety Disorders 1.

Pathophysiology a.

biological: the sensation of anxiety may be related to dysfunction of the septohippocampal pathway that is caused by hyperactive noradrenergic input from the locus coeruleus and/or serotonergic input from the raphe nucleus i.

anxiety disorders are associated with (1) an abnormal hypothalamic-pituitary-adrenal hormone response (2) an increased baseline sympathetic nervous system activity that over-responds to stimuli and that poorly adapts to repeated stimuli

2.

genetics: associated with polymorphisms of serotonin transporter genes

b.

behavioral: the fear response to specific stimuli become generalized

c.

cognitive: learned response from repeated exposure to anxiety inducing situations (similar to classic conditioning)

d.

psychodynamic: anxiety is related to unresolved unconscious conflict or an unsuccessful attempt to diffuse anxiety laden impulses

Subtypes a.

panic attacks—symptoms include recurrent, discrete periods of intense fear with four or more of the following i.

angina-like symptoms

ii.

choking sensation or shortness of breath

Anxiety Disorders

ii.

iii. lightheadedness iv.

numbness or paresthesias

v.

depersonalization or derealization of the situation

vi. fear of loosing sanity or sensation of dying b.

phobias: a fear that involves the avoidance of certain situations; the patient recognizes the fear is not rational i.

subtypes (1) specific phobia—the fear of certain objects or scenarios, or the anticipation thereof (2) social phobia—the fear of humiliation or embarrassment when in social situations (3) agoraphobia—the fear of being in any place where escape is difficult; if the fear is related to a specific place, then it is considered a specific phobia

ii.

treatment (1) exposure therapy, desensitization and rehearsal therapy (2) SSRIs, beta blockers, benzodiazepines

c.

generalized anxiety disorder i.

symptoms:  6 months of anxiety and worry related to numerous poorly defined issues; may be associated with mild panic attack-like symptoms (1) fatigue occurs due to sleep discontinuity, more frequent transitions into stage 1 sleep, and a lower REM density

ii.

highly associated with substance abuse

iii. treatment: psychotherapy, benzodiazepines, SSRIs, buspirone d.

posttraumatic stress disorder i.

a person is exposed to a traumatic event with a response that involves fear, helplessness, or horror; symptoms must be present for at least 1 month including

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(1) reexperiencing the trauma (nightmares, flashbacks) (2) avoiding recollections of the traumatic event (3) persistent symptoms of hyperarousal including an exaggerated startle response or hypervigilance

7 Behavioral Neurology and Psychiatry

ii.

short-lived symptoms are suggestive of an acute stress disorder ( 4 weeks duration)

iii. highly associated with substance abuse iv.

treatment: SSRIs, serotonin and norepinephrine reuptake inhibitors (SNRIs; i.e., venlafaxine), beta blockers, MAOIs; psychotherapy

VI. Somatoform Disorders and Factitious Disorders A. Somatization Disorder (Box 7.23) 1.

Pathophysiology a.

b.

psychological: may relate to behavioral patterns of emotional expression that are learned in unstable social settings; 50% coincidence with personality disorders, major depression, bipolar I disorder, anxiety disorders, and/or substance abuse biological: reports of patients exhibiting decreased metabolic activity in several brain regions i.

2.

genetics: exhibits familial patterns

Symptoms: almost always begins  30 years of age a.

diagnostic symptoms: at least a 2-year period of multiple medically unexplainable symptoms including i.

at least four different pain complaints (e.g., pain with menstruation, during urination, or during sexual intercourse)

ii.

at least two gastrointestinal symptoms (e.g., bloated sensation, flatulence, food intolerance)

iii. at least one symptom related to sexual function (including abnormal menstrual bleeding) iv.

3.

4.

at least one “pseudoneurological” symptom (e.g., dysphagia, glomus sensation), usually milder than those of conversion disorder and nonspecific

Treatment: after a thorough medical evaluation (particularly for patients  30 years of age) a.

evaluation and treatment of other underlying psychiatric comorbidities, with careful monitoring of medication use due to poor compliance

b.

regularly scheduled clinic visits with a single physician

c.

psychotherapy

Prognosis: Chronic, undulating, and relapsing disorder; symptoms are exacerbated by stress, and the patient is chronically debilitated by the symptoms

B. Conversion Disorder 1.

Pathophysiology a.

psychological: may be caused by repression of an unconscious intrapsychic conflict and its representation as a physical symptom i.

b.

2.

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associated with major depression, anxiety disorders, and schizophrenia

biological: SPECT scanning can occasionally demonstrate hypoperfusion of the basal ganglia (particularly the caudate) and thalamus contralateral to the side of sensorimotor conversion symptoms

Symptoms: excludes pain-related symptoms such as those of somatization disorder

Box 7.23 Other Symptoms of Somatization Disorder ✧ Multiple positives during review-of-

systems ✧ History of multiple surgeries ✧ Receiving medical care from multiple

physicians ✧ Self-perception of sickly nature

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motor dysfunction i.

weakness may involve muscle atrophy in long-standing conversion disorder

ii.

extrapyramidal-like motor dysfunction (e.g., dystonia, tremor)

b.

sensory loss: classically in a neuroanatomically inconsistent pattern (e.g., stocking or glove distribution) or precisely splitting the midline

c.

vision loss: commonly involves tunnel vision or blindness without significant functional impairment

d.

pseudoseizures (see p. 99)

e.

inappropriate lack of concern for symptoms {la belle indifference} although it is not considered an accurate indicator of conversion disorder

3.

Treatment: Psychomotor and sensory rehabilitation; psychotherapy; may require anxiolytics or antidepressants

4.

Prognosis: The majority of symptoms spontaneously resolve but 25% recur a.

upwards of 50% of patients diagnosed with conversion disorder may subsequently be found to have focal neurological disease or a causative medical condition

Substance Dependence and Abuse

iii. astasia-abasia—exceptionally ataxic gait with minimal falling that often involves thrashing of the trunk and arm movements that would only seem to worsen an unsteady gait

C. Hypochondriasis 1.

Pathophysiology: may represent misinterpretation of, and elaboration upon, common sensations, or a learned behavioral pattern of emotional expression a.

associated with major depression or anxiety disorders in 80%

2.

Epidemiology: equally common in men and women; more common in Blacks; not related to socioeconomic status

3.

Symptoms: at least 6 months of the false belief that the patient suffers from a disease based upon the misinterpretation of benign physical sensations or signs, wherein the patient cannot be convinced that there is no underlying disease despite normal diagnostic evaluations a.

typically involves only a few physical sensations or signs, unlike somatization disorder

b.

hypochondriac beliefs must cause emotional distress and impair the patient’s activities of daily living

4.

Treatment: evaluation and treatment of other underlying psychiatric comorbidities; avoid medications except for treatment of psychiatric comorbidities

5.

Prognosis: often exhibits episodic course that is exacerbated by stress;  50% spontaneously resolve

VII. Substance Dependence and Abuse 1.

2.

Definitions a.

substance abuse: a maladaptive pattern of drug use that interferes with a person’s activities of daily living

b.

substance dependence: severe pattern of drug use leading to clinically significant impairment or distress; involves tolerance, withdrawal, unsuccessful attempts to cut down, and continued drug use despite physical or psychological problems that it causes

General epidemiology: psychiatric comorbidities occur in 70% of substance abuse patients, particularly polysubstance abuse, antisocial personality disorder, and major depression

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Specific drugs-of-abuse a.

7 Behavioral Neurology and Psychiatry

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alcohol i.

biochemical effects: acute use increases cell membrane fluidity that indirectly may activate nicotinic acetylcholine-, 5-HT3-, and GABAA-receptors, and inhibit glutamate receptor and voltage-gated calcium channels

ii.

acute alcohol intoxication (1) symptoms include (a) behavioral disinhibition (Box 7.24), mood lability, and impaired judgment (b) dysarthria, ataxia, and nystagmus from cerebellar dysfunction (c) autonomic dysfunction: hypoglycemia, hypothermia (d) respiratory depression (e) somnolence progressing to coma (f) episodes of pure anterograde amnesia {blackouts} (2) treatment: respiratory support; correction of electrolyte and acidbase abnormalities

iii. chronic alcohol use (1) neurological complications (a) malnutrition due to dietary changes and inhibition of vitamin uptake in the intestines, particularly vitamins B1/thiamine and B12 (b) alcoholic neuropathy: a length-dependent axonal sensorimotor neuropathy that frequently involves pain and dysesthesias, trophic changes of the skin (hyperpigmentation, edema, ulceration, cellulitis), and joint injuries (i)

involvement of the vagus nerve (25%) causes hoarseness and orthostatic hypotension

(ii) treatment: abstinence and multivitamin supplementation provides slow, partial recovery (c) midline cerebellar degeneration—pronounced atrophy of the anterior and superior cerebellar vermis that includes all cell types; mild atrophy of the cerebellar hemispheres, deep cerebellar nuclei, and inferior olive nucleus (i)

symptoms include subacute development of gait and truncal ataxia with minimal limb ataxia (present in the lower extremities, if at all); no nystagmus or ocular dysmetria, dysarthria, hypotonia, or tremor 1.

symptoms worsen during periods of active drinking or during intercurrent illness

(ii) treatment: improves significantly with abstinence and multivitamin supplementation (d) tobacco-alcohol/nutritional amblyopia—likely a multivitamin deficiency state and not a direct toxic effect of alcohol because it occurs in nonalcoholic malnourished patients (i)

symptoms include bilateral painless scotoma and loss of acuity

(ii) treatment: multivitamin supplementation (e) demyelinating disorders: Marchiafava-Bignami disease involves progressive degeneration of the corpus callosum; rarely central pontine myelinosis (see p. 112) (2) general treatment

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(a) support groups (i.e., Alcoholics Anonymous); psychotherapy focused on situations leading to drinking (most effective if family is involved); behavioral therapy involving operant conditioning

Box 7.24 Alcoholic behavioral disinhibition can result in violent outbursts, which may be an idiosyncratic reaction to the alcohol; rarely occurs with barbiturate intoxication.

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(b) disulfiram (Antabuse) prophylaxis: inhibits the second metabolic step in the breakdown of alcohol by alcohol dehydrogenase, which allows accumulation of acetaldehyde that causes flushing and nausea (c) acamprosate, naltrexone, lithium, topiramate, and SSRIs may reduce alcohol craving and help maintain abstinence iv.

alcohol withdrawal (1) tremor (develops  8 hours after abstinence) (2) psychosis (develops 8–12 hours after abstinence) (3) seizures (Box 7.25) (develops 12–24 hours after abstinence): typically are multiple but  3% develop status epilepticus; may be related to concurrent hypoglycemia, hyponatremia, or hypomagnesaemia (a) treatment: benzodiazepines

Box 7.25 Patients suspected of alcoholic seizures still should be evaluated for an underlying disease of the CNS; 3% will have a surgically treatable brain lesion.

(4) delirium tremens (3–4 days after abstinence): involves delirium, tremor, autonomic instability, wildly fluctuant psychomotor activity, and hallucinations (visual and tactile); typically develops in binge drinkers with  5-year history of alcohol use and some degree of liver failure (a) treatment: scheduled benzodiazepines (preferably chlordiazepoxide) for prophylaxis; beta blockers for autonomic instability; antipsychotics for persistent psychotic symptoms b.

Substance Dependence and Abuse

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sedative-hypnotic drugs i.

includes (1) benzodiazepines (2) barbiturates: pentobarbital (Nembutal), secobarbital, pentobarbital secobarbital (Amytal) (3) barbiturate-like drugs: methaqualone (Quaalude)

ii.

biochemical effects: barbiturates are direct agonists of GABAA receptors; differ from benzodiazepines by potentiating GABA-induced chloride currents by prolonging periods of activity rather than increasing frequency of channel opening (1) long-term use causes downregulation and desensitization of GABAA receptors (2) all sedative-hypnotics exhibit cross-tolerance with alcohol

iii. acute sedative-hypnotic intoxication: symptoms include (1) behavioral disinhibition, mood lability, impaired judgment (2) cerebellar dysfunction: dysarthria, ataxia, nystagmus (3) memory impairment (4) somnolence, coma (Box 7.26)

Box 7.26

(5) respiratory depression

Death by overdose-respiratory suppression with benzodiazepines generally occur only when they are used together with other sedative-hypnotic drugs or alcohol.

(6) hypotension iv.

sedative-hypnotic withdrawal: symptoms include (1) anxiety, dysphoria (2) insomnia (3) photo- and phonophobia (4) nausea/vomiting (5) seizures (6) visual, tactile, or auditory hallucinations or illusions

v.

treatment (1) acute intoxication treatment with (a) benzodiazepines: flumazenil; gastric lavage with charcoal (b) barbiturates: gastric lavage with charcoal

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(2) detoxification (a) gradually taper benzodiazepines (b) convert barbiturates to equivalent doses of long-acting phenobarbital, then gradually taper (c) psychotherapy or behavioral therapy c.

cocaine

7 Behavioral Neurology and Psychiatry

i.

biochemical effects: blocks the reuptake transporters primarily for dopamine, but also for norepinephrine, and serotonin, thereby increasing neurotransmitter levels in the synaptic cleft; dopamine activity is increased particularly in the ventral tegmental projections to the limbic system (mesolimbic dopaminergic “reward pathway”) where it acts on D1 and D2 receptors (similar to amphetamines) (1) use of high-potency forms (i.e., crack) may induce craving after a single use

ii.

acute cocaine intoxication: symptoms are the same as for amphetamine intoxication, but overdoses can easily be fatal due to arrhythmia (1) euphoria, impaired judgment (2) autonomic dysfunction (e.g., hypertension, hyperthermia) (3) agitation, insomnia (4) stereotypies, automatisms (5) dystonias, dyskinesias (6) paranoia, psychosis (7) delirium, particularly in patients with preexisting brain injuries (8) seizures (9) stroke (hemorrhagic or ischemic), myocardial infarction

iii. chronic cocaine use: complications include hypertension, vasculitis, and cardiomyopathy iv.

cocaine withdrawal: symptoms include dysphoria, anxiety, fatigue, hypersomnolence, nightmares, and depression

v.

treatment (1) acute intoxication: antipsychotic medications, except in cases with hyperthermia, which they can exacerbate; benzodiazepines (2) amantadine, bromocriptine may be used to ease withdrawal symptoms (a) evaluation for underlying psychiatric comorbidities after detoxification, particularly depression and attention-deficit disorder

d.

amphetamines i.

include dextroamphetamine, methamphetamine, methylphenidate, and numerous synthetic compounds (e.g., ecstasy, crank, methylenedoxymethamphetamine [MDMA]); ephedrine and propanolamine have similar effects but are not considered true amphetamines

ii.

biochemical effects: all amphetamines reverse the dopamine reuptake transporter thereby increasing extracellular dopamine, particularly that of the ventral tegmental projections to the limbic system (mesolimbic dopaminergic “reward pathway”) (1) the synthetic amphetamines also increase extracellular serotonin levels, which may account for their hallucinogenic properties

iii. acute amphetamine intoxication: symptoms are as for acute cocaine intoxication; it rarely is fatal (unlike cocaine overdose) (1) MDMA is frequently associated with hyperthermia iv.

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chronic amphetamine use: complications include anorexia and cachexia, hypertension, and vasculitis

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amphetamine withdrawal: as per cocaine withdrawal

vi. treatment (1) acute intoxication: antipsychotics; benzodiazepines (2) chronic use: inpatient supportive care marijuana/cannabis i.

biochemical effects: tetrahydrocannabinol (THC), which is the active compound in marijuana, binds two specific G-protein-linked cannabinoid receptors that are located predominantly in the basal ganglia, hippocampus, and cerebellum; the endogenous ligands are anandamide and 2-arachidonylglycerol, which are breakdown products of phosphatidylcholine and phosphatidylinositol, respectively (1) THC does not appear to induce craving, but does induce tolerance

ii.

symptoms (1) acute intoxication (a) euphoria, disorientation to time, impaired judgment (b) increased sensitivity to sensory inputs but slowed reaction times (c) conjunctival injection, hunger, dry mouth (2) withdrawal: mild irritability, insomnia, and nausea

iii. treatment: none specific f.

Substance Dependence and Abuse

e.

opioids i.

include (1) natural products or their derivatives: morphine, heroin, codeine, hydromorphone (Dilaudid) (2) synthetic drugs: meperidine (Demerol), methadone, propoxyphene (Darvon)

ii.

biochemical effects: appear to involve the ventral tegmental dopamine projections to the limbic system (i.e., the mesolimbic dopaminergic “reward pathway”), but unlike cocaine and amphetamines, opioids may also directly act in the nucleus accumbens through dopamine-independent mechanisms (1) withdrawal produces rebound noradrenergic activity that is responsible for most of the unpleasant symptoms, which can be reduced by presynaptic 2 receptor agonists (i.e., clonidine) that likely act in the locus coeruleus

iii. symptoms (1) acute intoxication: euphoria progressing to apathy; psychomotor agitation or retardation; analgesia; impaired memory; dysarthria; somnolence, coma; seizures (with meperidine use) (2) withdrawal: dysphoria, insomnia; nausea, rhinorrhea, increased lacrimation, diarrhea; sympathetic hyperactivity (pupillary dilation, piloerection, diaphoresis, hyperthermia); diffuse myalgias and arthralgias iv.

treatment (1) acute intoxication: reverse with naloxone (Narcan) or naltrexone carefully dosed so as not to precipitate a withdrawal reaction (2) detoxification: conversion to methadone followed by gradual tapering; clonidine; buprenorphine (a partial opioid agonist associated with limited physical dependence and minimal withdrawal symptoms)

g.

phencyclidine (PCP) and ketamine i.

biochemical effects: both are NMDA glutamate receptor antagonists; PCP also increases release of dopamine, particularly the ventral tegmental projections to the limbic system (“reward pathway”)

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ii.

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acute intoxication: aggression and impulsiveness; impaired judgment; psychosis with auditory and visual hallucinations, delirium; cerebellar dysfunction (ataxia, dysarthria, horizontal and vertical nystagmus); autonomic dysfunction (hypertension, hyperthermia); rigidity with rhabdomyolysis; reduced pain sensitivity; hyperacusis; amnesia; seizures

7 Behavioral Neurology and Psychiatry

iii. treatment

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(1) urine acidification to increase excretion (2) benzodiazepines, antipsychotics; supportive care is generally insufficient

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8 Movement Disorders

I. Parkinson’s Disease (Box 8.1) 1.

Pathophysiology: increased inhibition of the ventral anterior and lateral thalamic output to the motor cortex caused by loss of dopaminergic input to the striatum (Fig. 8–1) a.

D2 receptors in the striatum are expressed on aspiny and spiny neurons (see p. 11); activation of the D2 receptor causes acetylcholine release onto muscarinic receptors that inhibits glutamatergic input to the striatum from the cortex and the GABAergic neurotransmission within the basal ganglia (i.e., D2 receptor activation inhibits most of the basal ganglia circuit)

b.

histology: degeneration of the dopaminergic substantia nigra pars compacta neurons and, to a lesser extent, the basal forebrain (e.g., nucleus basalis of Meynert), the hypothalamus, and brainstem pigmented neurons (locus coeruleus, dorsal vagal motor nucleus) probably due to dysfunction in the ubiquitin–proteosome system i.

neuron loss is pronounced in lateroventral part of pars compacta, and is usually asymmetric; symptoms appear typically when 80% of substantia nigra pars compacta neurons are lost

ii.

surviving neurons often exhibit eosinophilic inclusions surrounded by a halo that contain -synuclein and ubiquitin {Lewy body (see p. 162)} (Box 8.1)

Box 8.1 Synucleinopathies Parkinson’s disease, multisystem atrophy, Lewy body dementia

Parkinson’s Disease

Note: Significant diseases are indicated in bold and syndromes in italics.

(1) -synuclein is a presynaptic protein thought to be involved in dopamine release and/or synaptic plasticity; in Parkinson’s disease it becomes insoluble and aggregates into fibrils that attract ubiquitin and neurofilaments, thereby forming Lewy bodies c.

genetics: the majority of cases are sporadic, but several inherited forms exist (Table 8–1) i.

parkin: acts to covalently link proteins targeted for destruction to ubiquitin, which then can be recognized by proteosomes; mutations cause accumulation of intracellular proteins that form Alzheimer’s-like neurofibrillary tangles instead of Lewy bodies (1) accounts for the majority of early-onset Parkinson’s disease

ii.

ubiquitin C-terminal hydrolase L1 acts to release ubiquitin from its conjugated protein after delivery of the conjugated protein to the proteosome

iii. PINK1: a mitochondrial protein kinase that regulates the electron transport chain 2.

Epidemiology: exhibits increased incidence according to geographic (industrialized countries  nonindustrialized countries) and racial factors a.

risk factors for sporadic Parkinson’s disease include drinking well water, rural residence, farming (possibly related to pesticide exposure in industrialized countries), and employment in wood pulp mills or steel industries; risk may be reduced by cigarette smoking and caffeine use

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A

B Figure 8–1 (A) normal basal ganglia function. (B) Basal ganglia function in Parkinson’s disease.

Table 8–1 Familial Parkinson’s Disease Major subtypes

Chromosome

Mutated gene/protein

Notes

Usually a de novo mutation

Autosomal dominant PARK 1,4

4

-synuclein

PARK 3

2

?

PARK 5

4

Ubiquitin C-terminal hydrolase L1

6

Parkin (E3 ubiquitin ligase)

Autosomal recessive PARK 2

184

PARK 6

1

PINK-1

PARK 7

1

DJ-1

Onset 20–40 years of age

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3.

Symptoms: onset is typically 50–60 years of age in patients with sporadic Parkinson’s disease; a younger age of onset suggests an inherited form a.

initially presents as a unilateral resting tremor, bradykinesia, or limb stiffness; progressive rigidity and bradykinesia eventually will become bilateral and will involve freezing episodes and dysphagia i.

progression involves hypophonia, dysarthria, dysphagia, and an expressionless face

ii.

symptoms are slowly progressive, presenting asymmetrically or unilaterally

b.

depression (50%)

c.

dementia (30%): half of demented Parkinson’s disease patients have no other pathological cause, but 35% exhibit Alzheimer’s-like histological changes

d.

restless legs syndrome; akathisia; REM sleep behavioral disorder (see pp. 169–170)

e.

autonomic symptoms (urinary urgency, constipation {intestinal pseudoobstruction}, sexual dysfunction) and oculomotor abnormalities are mild and develop only late in the disease course i.

f. 4.

20% of patients develop significant orthostatic hypotension often due to medication side effects, but this can represent the misdiagnosis of a multisystem atrophy disorder

Parkinson’s Disease

iii. symptoms most commonly begin in the upper extremities, but occasionally may initiate in the lower extremities or jaw (particularly with tremor)

dementia develops in 30% of patients with advanced disease

Treatment (Table 8–2) i.

management of autonomic dysfunction (1) orthostatic hypotension (a) nonpharmacological treatments: graded position changes; avoid Valsalva maneuvers; squatting or flexing of the lower extremity musculature prior to standing; increase fluid and salt intake; lower extremity compressive garments (b) pharmacological treatments (i)

fludrocortisone

(ii) midodrine, ephedrine, pseudoephedrine, methylphenidate (iii) desmopressin acetate (ddAVP); erythropoietin; caffeine (2) bladder hyperactivity: reduce drinking in the evening; anticholinergic medications (oxybutynin, propantheline) (3) constipation: dietary modification and stool softeners; discontinuing anticholinergic medications ii.

management of side effects of medical treatment (1) “off”/freezing phenomenon (a) combine a dopamine agonist with Sinemet (b) increase the frequency of combined medications (c) substitute or add a sustained-release preparations of Sinemet (2) dyskinesia/dystonia (a) occurring with the peak in drug levels (“on” dyskinesia/ dystonia) (i)

lower the dose of dopamine agonists or Sinemet

(ii) substitute sustained-release preparations of Sinemet for shorter-acting medications (iii) add a catechol-O-methyltransferase (COMT) antagonist (iv) consider neurosurgical intervention (b) occurring a minimal drug levels (“off” dyskinesia/dystonia) (i)

evening “off” dyskinesia: add sustained-release Sinemet in the evening

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Table 8–2 Medications for Bradykinesia, Tremor, and Rigidity in Parkinson’s Disease Drug

Mechanism of action

Side effects

Notes

L-dopa  carbidopa (Sinemet)

Dopamine precursor (L-dopa)  peripheral MAO inhibitor (carbidopa)

Nausea, dystonia, orthostatic hypotension, hallucinations (late in disease)

Regular Sinemet effect lasts 6 hr (less in late disease)

Add domperidone if carbidopa is ineffective at a 1 : 4 ratio

Keep carbidopa  150 mg/d to avoid CNS penetration Low-protein diet improves absorption from GI system

Agonists of 5-HT and  adrenoceptors, as well as

As per Sinemet; anorexia, confusion

Bromocriptine

D2 agonist, partial D1 agonist

Painful swollen feet

Pergolide (Permax)

D1 and D2 agonist

8 Movement Disorders

Ergot DA agonists

Side effects with pergolide are more mild than those with bromocriptine

Non-ergot DA agonists Nausea

Can be given as a nasal spray, sublingually, SQ, or PR

D2 receptor agonist; minimal on D1 receptors

As per Sinemet; drowsiness and sleep attacks

Cause less motor fluctuations than Sinemet, but more cognitive and hypotensive side effects

Inhibits MAO-B breakdown of L-DOPA in the brain

As per Sinemet

May be neuroprotective, therefore is initial treatment for young patients

Apomorphine Pramipexole (Mirapex) Ropinirole (Requip) Selegiline (Deprenyl)

Many drug interactions (particularly antidepressants) COMT inhibitors Entacapone

Inhibit COMT breakdown of L-DOPA in the GI system and liver

As per Sinemet; liver failure with tolcapone

Increase “on” time duration of Sinemet

Muscarinic acetylcholine receptor antagonists

Dry mouth, blurred vision, urinary retention, confusion

Generally are more effective against tremor and rigidity than bradykinesia

? NMDA receptor antagonist, anticholinergic, MAO-B inhibition, ↑ DA release

Restlessness, insomnia, depression, hallucinations

Modest effect, useful in early/mild disease

Tolcapone Benztropine (Cogentin) Trihexyphenidyl (Artane) Amantadine

May reduce freezing in late disease

Abbreviations: CNS, central nervous system; COMT, catechol-O-methyltransferase; GI, gastrointestinal; MAO, monoamine oxidase; NMDA, N-methyl-D-aspartate; SQ, subcutaneous.

(ii) between dose “off” dyskinesia 1.

add dopamine agonist or amantadine

2.

increase the frequency of medication administration

3.

consider neurosurgical intervention

(3) treatment-induced hallucinations (a) identify and discontinue the offending medication in order of likely causation: anticholinergics  amantadine  selegiline  dopamine agonists  Sinemet (b) lower the dose of dopamine agonists or Sinemet (c) add a low-dose atypical antipsychotic medications (clozapine, quetiapine) (Box 8.2) b.

surgical treatment: best response to medication postoperatively is equal to the patient’s best response to medication preoperatively, and the chief improvement is in terms of reduced fluctuations and dyskinesias i.

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lesion procedures: usually done with stereotactic and intraoperative electrophysiological confirmation of location, but can be done by means of radiosurgery (e.g., gamma knife)

Box 8.2 Lewy Body dementia’s Parkinsonism is very sensitive to antipsychotics.

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(1) thalamotomy: targets the ventral intermediate nucleus (a) improves only tremor, therefore not often used in Parkinson’s disease (b) not effective against bradykinesia, and may exacerbate hypophonia and gait abnormalities; avoid bilateral procedures due to cognitive impairment

Progressive Supranuclear Palsy (PSP)

(2) pallidotomy: targets the posterolateral region of the internal globus pallidus to avoid impairment of memory and cognitive function (a) effective against all major Parkinson’s disease symptoms and dyskinesias (b) limited to a unilateral procedure due to high incidence of cognitive impairment with bilateral procedures ii.

deep brain stimulator procedures: over stimulation may produce dyskinesias (1) thalamic stimulation: effectiveness as per thalamotomy, but fewer side effects (2) globus pallidus stimulation: effectiveness as per pallidotomy, but fewer side effects; bilateral stimulation has pronounced benefits for gait abnormalities (3) subthalamic stimulation: most effective surgical procedure for bradykinesia, and is effective for all other major Parkinson’s disease symptoms; bilateral stimulation has pronounced benefits for gait abnormalities

II. Progressive Supranuclear Palsy (PSP) (Box 8.3) 1.

Pathophysiology: Gliosis and neuron loss predominantly in the frontal cortex, globus pallidus, substantia nigra, and mesencephalic nuclei a.

histology: affected areas exhibit Alzheimer’s disease-like neurofibrillary tangles (with hyperphosphorylated tau protein) and neuropil threads i.

b.

2.

Box 8.3 The tau-opathies—Alzheimer’s disease, frontotemporal lobar degeneration/Pick’s disease; cortical-basal ganglionic degeneration; progressive supranuclear palsy

D2 receptors in the basal ganglia are reduced, unlike Parkinson’s disease where they are increased; this likely reflects the loss of cholinergic striatal interneurons in PSP (see p. 11)

genetics i.

90% of sporadic cases are associated with homozygous H1 alleles of the tau gene, although 60% of normal people also are homozygous for the H1 allele

ii.

families with autosomal dominant inheritance patterns have been described

Symptoms: develop between 60–70 years of age a.

axial rigidity  limb rigidity, leading to an abnormal gait and falls early in the disease (particularly backward falls, unlike Parkinson’s disease patients who fall forward)

b.

cortical-type dysarthria; hypophonia

c.

reduced voluntary saccades, particularly a vertical gaze palsy involving downward  upward gaze; voluntary smooth pursuit movements become impaired thereafter i.

involuntary (vestibulo-ocular) eye movements are preserved until late in the disease

3.

Diagnostic testing: loss of saccadic fast-phase on optokinetic testing may distinguish early PSP from Parkinson’s disease

4.

Treatment: none specific

5.

Prognosis: usually fatal within 6 years

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III. Cortical-Basal Ganglionic Degeneration 1.

8 Movement Disorders

2.

Pathophysiology: Gliosis with neuronal loss and vacuolation in cortical layers III–V (like frontotemporal lobar degeneration/Pick’s disease), the basal ganglia, and the substantia nigra; depigmentation of the substantia nigra also occurs a.

surviving neurons exhibit accumulations of hyperphosphorylated tau

b.

genetics: associated with the H1 allele of the tau gene, as per PSP

Symptoms: develop  60 years of age; symptoms occur in a random order and may relapse and remit, but they all are concentrated initially in one limb a.

subcortical symptoms: Parkinsonism; postural and/or action tremor; limb dystonia; reflex myoclonus

b.

cortical symptoms: dementia similar to frontotemporal lobar degeneration (see p. 160); apraxia (e.g., constructional dyspraxia); cortical sensory loss; weakness i.

Gerstmann’s syndrome and alien-hand syndrome is a rare complication of corticobasal ganglionic degeneration

3.

Diagnostic testing: MRI may reveal regional degeneration in frontal and parietal cortex

4.

Treatment: none specific

5.

Prognosis: symptoms remain focally in one limb for several years, but eventually progress to involve other limbs; severe dysphagia eventually develops

IV. Multiple System Atrophy (MSA) 1.

2.

3.

General histology: exhibits multiple types of inclusion bodies to varying degrees; the most typical for MSAs are a.

an argentophilic cytoplasmic inclusion in neurons and glia that resemble neuropil threads but that contain only ubiquitin and no tau protein

b.

a flame-shaped glial cytoplasmic inclusion similar to the neurofibrillary tangles of Alzheimer’s disease but that do not contain tau protein

The old classification scheme a.

olivopontocerebellar degeneration (OPCD)—idiopathic degeneration of the inferior olivary nuclei, ventral pontine nuclei, and cerebellar cortex with relative preservation of the substantia nigra and striatum

b.

striatonigral degeneration—idiopathic degeneration of the putamen and substantia nigra with relative preservation of the globus pallidus, caudate, and subthalamic nucleus

c.

Shy-Drager syndrome—idiopathic degeneration of the intermediolateral cell column in thoracic and lumbar spinal cord, the dorsal motor nucleus of the vagus, and in the sympathetic chain ganglia

The new classification scheme: The Shy-Drager syndrome has been eliminated because autonomic dysfunction is present in all types of multiple-system atrophy a.

multiple system atrophy with predominant parkinsonian features (MSA-P)/striatonigral degeneration form of MSA i.

histology: the pattern of degeneration is as for striatonigral degeneration  Shy-Drager syndrome (1) despite pronounced Parkinsonian features, does not have Lewy bodies, neurofibrillary tangles, or even many of the MSA inclusion bodies in the surviving neurons of substantia nigra

ii.

epidemiology: sporadic occurrence only

iii. symptoms: bradykinesia, rigidity, autonomic dysfunction; less commonly involves myoclonus, neck anteroflexion, or dysarthria

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(1) autonomic dysfunction usually predates parkinsonian features (2) hyperpigmentation of the extremities iv.

diagnostic testing: late in the disease, MRI demonstrates (1) T2 hypointensity in the globus pallidus with a lateral linear hyperintensity, and putamen atrophy (Fig. 8–2) (2) loss of pontine fibers {hot-cross bun sign} (Fig. 8–3)

v.

multiple system atrophy with predominant cerebellar features (MSA-C)/OPCD form of MSA i.

histology: pattern of degeneration is as for olivopontocerebellar degeneration  Shy-Drager syndrome

ii.

epidemiology: peak incidence at 50–60 years of age; usually sporadic, but may have autosomal dominant or recessive patterns of inheritance (usually such cases are classified under spinocerebellar ataxias)

Figure 8–2 T2 MRI of MSA-P. (From Kaufmann H, Biaggioni I. Autonomic failure in neurodegenerative disorders. Semin Neurol 2003, 23:357, Fig. 3A. Reprinted by permission.)

iii. symptoms: ataxia in the lower extremities  upper extremities; cerebellar-type dysarthria; autonomic dysfunction (Box 8.4)

Box 8.4

(1) subtypes of MSA-C include

Dystonias

b.

treatment: dopaminergic agents usually have little effect against the parkinsonism because D2 receptors are lost in the striatum; management of autonomic dysfunction as per Parkinson’s disease

MSA-C usually occur in a hereditary pattern, and thus are considered spinocerebellar ataxias (see p. 198).

(a) parkinsonian symptoms (50%) (b) retinal degeneration (c) spastic paraplegia and areflexia (d) dementia, ophthalmoplegia, and extrapyramidal signs iv.

diagnostic testing: late in the disease, neuroimaging demonstrates atrophy of the brainstem and cerebellum

v.

treatment: none specific; management of autonomic dysfunction as per Parkinson’s disease

V. Dystonias 1.

Pathophysiology: primary dystonias result from dysfunction the dopaminergic systems (Fig. 8–4) in the of basal ganglia without apparent neuron loss or neurochemical deficit; abnormal function of the motor and sensory cerebral cortex and in lower motor neuron reflexes are likely reactions to the basal ganglia dysfunction a.

b.

primary and secondary motor and sensory cerebral cortex exhibit abnormal activation patterns even when dystonic movements are not occurring lower motor neuron reflexes are apparently abnormal because the dystonic movements involve unnecessary activation of co-agonist muscles and also antagonist muscles i.

c.

even when dystonic movements are not occurring, dystonia patients exhibit reduced skeletal muscle inhibition (e.g., reduced reciprocal inhibition of antagonist muscles during voluntary movement in focal dystonia patients, reduced suppression of the blink reflex in blepharospasm patients)

focal lesions can cause dystonia when they are located in the contralateral putamen  globus pallidus  caudate, thalamus, brainstem i.

2.

Figure 8–3 Hot-cross bun sign of MSA-P. (From Kaufmann H, Biaggioni I. Autonomic failure in neurodegenerative disorders. Semin Neurol 2003, 23:357, Fig. 3C. Reprinted by permission.)

rarely dystonia presents after peripheral nerve injury, likely by altering basal ganglia function in genetically susceptible individuals

Causes of dystonia

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Figure 8–4 Biosynthesis of dopamine, norepinephrine, and epinephrine.

a.

primary dystonias (Table 8–3)

b.

secondary dystonias i.

neurodegenerative disorder-related dystonias: Parkinson’s disease, multiple-system atrophies, progressive supranuclear palsy, corticobasal ganglionic degeneration, spinocerebellar atrophies (particularly

Table 8–3 Primary Dystonias Type

Genetics

Notes

Early-onset dystonia (DYT1)

Mutation in torsin A gene, an ATP-binding protein

Childhood onset Progresses to other limbs

(AD, 60% penetrance)

Accounts for most primary dystonia

Dystonia-Parkinsonism/ Lubag syndrome

Unknown gene (X-linked)

Segmental or diffuse dystonia

DOPA-responsive dystoniaParkinsonism

Mutation in GTP cyclohydrolase I gene

Common only in Philippines Treat with levodopa–carbidopa (Sinemet)

Box 8.5) (AD) (B Segawa syndrome

Mutation in tyrosine hydroxylase gene (AR) Box 8.6) (B

Treat with levodopa–carbidopa (Sinemet)

Rapid-onset dystoniaparkinsonism

(AD)

Adult onset

Paroxysmal nonkinesigenic choreoathetosis

(AD)

Dystonia is not triggered by activity

Paroxysmal choreoathetosis with spasticity and ataxia

(AD)

Dystonia occurs with diplopia, paresthesias, and ataxia

Dystonia is worse in evening, better or absent in morning

Develops over several hours to weeks

Spastic paraplegia develops between episodes of dystonic symptoms Myoclonic dystonia Box 8.7) (B

190

Mutation of -sarcoglycan Box 8.8) gene (AD) (B

Symptoms reduced by alcohol use

Note: Dark gray  primary dystonias with parkinsonian features; light gray  primary dystonias with choreoathetosis. Abbreviations: AD, autosomal dominant; GTP, guanosine 5-triphosphate.

Box 8.5 GTP cyclohydrolase I synthesizes tetrahydrobiopterin cofactor for DA synthesis.

Box 8.6 Tyrosine hydroxylase is directly involved in DA synthesis.

Box 8.7 Localize to the same region of chromosome 16 as benign familial infantile convulsions

Box 8.8 Other sarcoglycans are mutated in autosomal recessive limb-girdle muscular dystrophy

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Machado-Joseph’s disease/SCA-3), ataxic telangiectasia, Huntington’s disease, dentatorubropallidoluysian atrophy (DRPLA) ii.

autoimmune: related to antibasal ganglia antibodies, which occur in 65% of patients with atypical dystonia; probably these antibodies are a reaction to a Streptococcus infection similar to Sydenham’s chorea and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS syndrome; see p. 193)

iii. disorders of metal overload: Wilson’s disease, Hallervorden-Spatz disease iv.

leukodystrophies, particularly metachromatic leukodystrophy

v.

metabolic diseases of the nervous system: ceroid lipofuscinosis, methylmalonic academia, aromatic amino acid decarboxylase deficiency, homocystinuria, Lesch-Nyhan’s disease

vi. acquired conditions: biopterin deficiency (due to failure of dopamine synthesis), basal ganglia injury vii. neuroacanthocytosis (see p. 193) viii. complex regional pain syndrome I/reflex sympathetic dystrophy

3.

4.

Dystonias

ix. iatrogenic: dopamine antagonists (cocaine, amphetamines, antipsychotics); dopamine agonists Subtypes of dystonia by age groups a.

childhood- and adolescent-onset dystonias typically develop in lower extremities and progress to involve other body parts

b.

adult-onset dystonias typically develop in the upper extremities or head, and do not progress

Symptoms a.

slow, sustained, and repetitive twisting and flexion movements and/or posturing, with normal muscle tone between episodes; may involve a degree of tremulousness, but unlike true tremor dystonic movements have a significant directional component i.

often dystonia movements become painful, particularly if they are prolonged

ii.

dystonic movements can be triggered by specific activities involving the affected muscles (e.g., writer’s cramp triggered by the act of writing) or by emotional states

iii. dystonic movements may be aborted or broken by sensory stimulation (usually touch) to specific parts of the body (usually the dystonic region) b.

subtypes of dystonia by symptoms i.

focal dystonias (1) cervical dystonias: rotation {torticollis}, extension {retrocollis}, flexion {anterocollis}, or abduction {laterocollis} of the head (2) blepharospasm—blinking and squeezing of the orbicularis oculi muscles, may be preceded by sensation of eye irritation: often triggered by bright light (a) typically bilateral but with a significant asymmetry (3) Meige’s syndrome—orolingual dystonias with blepharospasm

Box 8.9

(4) Brueghel syndrome—jaw opening with lip retraction, tongue protrusion, and platysma contraction

Status dystonicus—A severe, prolonged period of dystonic posturing often preceded by increasingly frequent and prolonged episodes ✧ Can develop out of any type of dystonia, often precipitated by changes in medications or intercurrent illness ✧ May develop rhabdomyolysis due to prolonged muscle contraction ✧ Requires sedation or even paralysis and ventilation if fatigue or severe pain develop

(5) facial/oromandibular dystonias—can involve facial, masticatory, lingual, and/or oropharynx muscles; commonly occurs with blepharospasm or cervical dystonias (6) spastic dysphonia—dystonia of the laryngeal muscles causing the voice to become hypophonic and strained with frequent tone breaks (7) limb dystonias ii.

multifocal dystonia, segmental dystonia, hemidystonia (rare)

iii. generalized dystonia (Box 8.9)

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5.

Diagnostic testing a.

levodopa–carbidopa or anticholinergic medication trial to distinguish DOPA-responsive dystonias

b.

genetic analysis for torsin-A gene (DYT1) mutations

c.

routine evaluations to evaluate for the possibility of secondary causes of dystonia i.

ii. 6.

ceruloplasmin, slip-lamp evaluation for Kayser-Fleischer rings, and 24-hour urine copper to evaluate for the possibility of Wilson’s disease

neuroimaging to evaluate for basal ganglia lesions

Treatment a.

medical treatment

8 Movement Disorders

i.

botulinum toxin: effective in 75% of focal dystonias (1) clinical resistance may develop due to blocking antibodies, especially with frequent injections; this can be overcome by changing botulinum toxin serotypes (2) the only frequent side effect is excessive local weakness or weakness in neighboring muscles

ii.

carbidopa–levodopa: effective in 15% of dystonias

iii. anticholinergic agents (benztropine, trihexyphenidyl): effective in 40% of dystonias but limited use because of side effects iv.

muscle relaxants: baclofen, tizanidine, cyclobenzaprine (1) intrathecal baclofen is unlikely to be of benefit if baclofen given orally was not effective

v. b.

clonazepam, gabapentin

surgical treatment: for patients who have failed medical therapy i.

lesion procedures (1) rhizotomy, myomectomy: for focal dystonia (2) thalamotomy: has a high rate of complications, particularly dysarthria and cognitive impairment (a) bilateral thalamotomy for generalized dystonia (b) contralateral thalamotomy for segmental dystonia (3) pallidotomy: fewer side effects than thalamotomy

ii.

deep brain stimulation in the globus pallidus: particularly effective for early-onset dystonia (DYT1), cervical dystonias, and blepharospasm

VI. Tic Disorders 1.

Pathophysiology: likely related to abnormal dopaminergic activity in the basal ganglia, leading to inappropriate cortical arousal; mild abnormalities in the size and symmetry of the basal ganglia and cortical regions are apparent, as are abnormal accumulations of dopamine and D2 receptors in the basal ganglia

2.

Subtypes a.

idiopathic tic disorders i.

simple or multiple motor tics: e.g., blinking, snarling, tongue protrusion, neck stretching, finger or toe curling

ii.

complex motor tics: e.g., spitting, foot stomping, teeth grinding, obscene gesturing {copropraxia}

iii. simple phonic tics: e.g., grunting, throat clearing, coughing

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iv.

complex phonic tics: e.g., unintelligible word- or stuttering-like utterances

v.

Tourette’s syndrome: combination of multiple motor tics and at least one phonic tic that begins at  20 years of age (1) most cases are sporadic, but can exhibit polygenic inheritance with variable penetrance

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b.

secondary tic disorders i.

posttraumatic

ii.

postinfectious: occurring after group A -hemolytic Streptococcus infections, typically pharyngitis (1) PANDAS infection syndrome: develops acutely shortly after an infection; no relation to rheumatic fever (a) neuropsychiatric symptoms is typically an obsessive– compulsive disorder

(a) typically occurs in conjunction with symptoms of rheumatic fever (carditis, arthritis, subcutaneous nodules, erythema marginatum), and chorea may recur within a few years (b) particularly common in patients with B cell alloantigen D8/17 iii. neuroacanthocytosis—a disorder characterized by spiny erythrocytes {acanthocytes} caused by an abnormality in membrane lipids; neurological abnormalities include orofacial dystonias involving mutilation of the facial soft tissues, choreiform movements, tic behaviors, behavioral changes, and a motor neuropathy (1) autosomal recessive inheritance with linkage to chromosome 9 iv. 3.

Huntington’s Disease

(2) Sydenham’s chorea—develops several months after an infection, spontaneously resolves after several weeks; involves both chorea and tic behaviors

drug-induced: amphetamines, dopaminergic agonists, antipsychotics, antiepileptics

Symptoms: idiopathic and postinfectious tic disorders generally have onset in childhood, whereas noninfectious secondary tic disorders have an adult onset a.

involuntary movements or vocalizations that can be transiently suppressed although they are associated with a subjective urge to perform them that builds up over time as they are suppressed; movements are jerky in nature (i.e., resembling myoclonus or clonus), but are characteristically stereotypical and coordinated i.

the type of tic behavior and its severity may change over time

ii.

tics are exacerbated by stress (as are all dyskinesias), but also by relaxation

iii. vocalization of understandable words indicates Tourette’s syndrome, which also must involve multiple motor tics b.

4.

Treatment: antipsychotics (haloperidol, pimozide, risperidone), clonidine, clonazepam a.

5.

tic disorder is associated with choreiform movements, dystonias, learning disorders, attention-deficit hyperactivity disorder, and obsessive–compulsive disorder (50%)

selective serotonin reuptake inhibitors (SSRIs) reduce obsessive–compulsive behaviors but they do not reduce tic severity

Prognosis: idiopathic forms usually peak in severity during adolescence then spontaneously remit in early adulthood

VII. Huntington’s Disease 1.

Pathophysiology: expansion of a trinucleotide repeat in the huntingtin gene on chromosome 4 that appears to cause cell death by NMDA excitotoxicity and/or abnormal activity of mitochondrial oxidative phosphorylation a.

requires  40 repeats for symptoms; 30–45 repeats may not produce symptoms, but are thought likely to increase in size in future generations i.

a larger number of repeats causes symptomatic presentation at a younger age {anticipation} and also a more severe course

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8 Movement Disorders

2.

3.

4.

5.

b.

an autosomal dominant inherited disease; inheritance of the affected huntingtin gene on the paternal chromosome produces more severe disease

c.

histology: loss of spiny neurons (see p. 11) and glia in the striatum and of deep cortical neurons (particularly layer V, like Alzheimer’s disease) causes generalized atrophy that is characteristically pronounced in the caudate nuclei; surviving neurons exhibit intranuclear inclusions containing huntingtin protein and ubiquitin

Symptoms a.

chorea, which is pronounced during ambulation

b.

psychiatric disturbance: personality change, hypersexuality, psychosis

c.

progressive dementia

d.

oculomotor abnormalities i.

hypometric saccades progressing to a complete inability to initiate voluntary saccades, thereby requiring head thrusting to change visual fixation

ii.

inability to suppress involuntary saccades causes gaze impersistence

e.

orolingual apraxia

f.

parkinsonism: develops late in disease and replaces the hyperkinetic features of chorea

g.

dysarthria, dysphagia, and respiratory insufficiency are preterminal symptoms

Figure 8–5 Huntington’s disease, with diffuse cortical atrophy and caudate atrophy identified by rounded lateral surfaces of the frontal horns. (From McKhann GM et al. Q&A Color Review of Clinical Neurology and Neurosurgery. Stuttgart, Germany: Georg Thieme; 2003:23, Fig. 13. Reprinted by permission.)

Diagnostic testing a.

genetic testing for the trinucleotide repeat

b.

neuroimaging demonstrates caudate atrophy (Fig. 8–5), similar to some frontotemporal lobar degeneration disorders

c.

positron emission tomography (PET) scan demonstrates hypometabolism in the striatum

d.

blood smear shows no acanthocytes, to rule out acanthocytosis

Treatment a.

antipsychotic medications for severe chorea

b.

nondopaminergic anti-Parkinsonian medications for Parkinsonian features

c.

psychiatric disturbances are managed as per routine

Prognosis: Death within 15 years from onset

VIII. Wilson’s Disease/Hepatolenticular Degeneration 1.

Pathophysiology: Autosomal recessive mutations in a membrane-bound copper-transporting ATPase that secretes excess copper into the bile; accumulation of copper causes degeneration of the putamen  globus pallidus, caudate, cortex  mesencephalic nuclei, dentate nucleus a.

histology: hyperpigmented areas from copper deposition are associated with neuronal degeneration and local demyelination that eventually will form cavitary lesions; reactive gliosis in these areas involves i.

Alzheimer glia type 1: a multinucleated astrocyte; specific for Wilson’s disease

ii.

Alzheimer glia type 2: greatly enlarged astrocytes with oval nuclei (Box 8.10)

iii. Opalski cells: large cells with coarsely granular cytoplasm that are possibly derived from histiocytes (Fig. 8–6) 2.

194

Epidemiology: Bimodal distribution i.

early-onset (7–15 years of age): rapidly progressive symptoms

ii.

late-onset (21–40 years of age): slowly progressive symptoms

Box 8.10 Alzheimer glia type 2 are also seen in Canavan’s disease, hepatic encephalopathy, and urea cycle disorders.

Wilson’s Disease/Hepatolenticular Degeneration

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Figure 8–6 Opalski cell (left) characterized by its large size and lobulated nucleus. (From Hirano A. Color Atlas of Pathology of the Nervous System, 2nd Ed. Tokyo/New York: Igaku-Shoin Press; 1988:117, Fig. 283. Reprinted by permission.)

3.

Symptoms: majority of patients begin with liver disease; however, neurological and/or psychiatric symptoms can be the initial presentation a.

neurological symptoms: dysarthria progressing to anarthria; mood lability, psychosis; rest and wing-beating tremor, ataxia, dystonia; loss of postural reflexes; seizures

b.

systemic symptoms i.

eye: copper deposits in Descemet’s membrane of cornea {KayserFleischer rings} are asymptomatic (Fig. 8–7) (Box 8.11)

ii.

hepatitis leading to liver cirrhosis

iii. splenomegaly with hemolytic anemia iv.

Box 8.11 Kayser-Fleischer rings are present in 100% of patients with neuropsychiatric Wilson’s disease, 85% of patients with liver disease

bone fragility due to osteoporosis

4.

Diagnostic testing: decreased serum ceruloplasmin levels (Box 8.12); elevated urine copper excretion

5.

Treatment: tetrathiomolybdate; chronic penicillamine  vitamin B6; zinc supplements; low copper diet

6.

Prognosis: uniformly fatal without treatment; with treatment, neuropsychiatric disease improves in 50% and remains stable in 15%, whereas liver disease is reversible in only 25%

Figure 8–7 Kayser-Fleischer ring. (From Lee DA, Higginbotham. Clinical Guide to Comprehensive Ophthalmology. Stuttgart, Germany: Georg Thieme; 1999:9, Fig. 1–10. Reprinted by permission.)

Box 8.12 Aceruloplasminemia is similar to Wilson’s disease, but central nervous system damage is due to iron accumulation.

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IX. Amyotrophic Lateral Sclerosis (ALS)

8 Movement Disorders

1.

2.

3.

Pathophysiology: unknown, but may relate to a.

glutamate excitotoxicity: patients exhibit increased cerebrospinal fluid (CSF) glutamate levels, reduced levels of the astrocyte excitatory amino acid transporter (EAAT-2), and abnormal messenger ribonucleic acid (mRNA) processing of the EAAT-2; excessive glutamate stimulation of S-alphaamino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors may increase intracellular calcium and allow the generation of free radicals that then damage cellular proteins by tyrosine nitration, causing apoptosis

b.

autoimmune injury: patients exhibit an increased incidence of paraproteinemia; some patients exhibit specific antibodies against the L-type voltage-gated calcium channels, and leukocyte invasion of the affected spinal cord

Subtypes a.

sporadic: includes all those disorders listed under ALS variants

b.

familial: 20% are caused by mutations in superoxide dismutase (SOD)-1 gene, which can be inherited in an autosomal dominant or recessive pattern

Histology: loss of motoneurons in anterior horn, motor cranial nerve nuclei, and primary motor cortex of spinal cord with astrocytosis and macrophage invasion a.

surviving motoneurons are swollen and exhibit high levels of phosphorylated intermediate filaments

b.

surviving motoneurons (particularly in the spinal cord) exhibit three types of inclusion bodies, all of which include ubiquitin i.

Lewy body-like inclusions

ii.

Bunina bodies: eosinophilic inclusions arranged as a chain; stain for cystatin-C

iii. basophilic inclusions 4.

Symptoms a.

slow development of focal weakness, often in the distal extremity (e.g., grip weakness, foot drop); can develop initially in the bulbar muscles causing dysarthria and dysphagia, in the respiratory muscles, or in the axial extensor muscles (causing head drop, like a myopathy) (Box 8.13) i.

spread of weakness occurs along the organization of the motor homunculus, although new weakness often jumps contralaterally into the opposite limb

ii.

progresses to involve pseudobulbar dysfunction (i.e., spontaneous laughing or crying without the perception of emotion), severe dysphagia that prohibits swallowing, and ultimately respiratory impairment

iii. weakness involves fasciculations and cramping, often in unusual places (e.g., the neck muscles) iv.

5.

196

preserves ocular motor and bowel/bladder function

b.

dementia (5%), of a frontotemporal lobar degeneration/Pick’s disease type

c.

absence of pain, sensory impairment, bowel/bladder dysfunction, or impairment of ocular motility

Diagnostic testing a.

EMG: demonstrates fasciculation potentials and a reduced number of active motor units that fire disproportionately fast given the muscle contraction (evidence of denervation), as well as abnormally shaped motor unit potentials (evidence of reinnervation)

b.

neuroimaging, mostly to exclude cervical spine stenosis

c.

serology: may demonstrate anti-GM1 antibodies, paraproteinemia

d.

genetic testing: for SOD-1 mutations, in cases of familial inheritance

Box 8.13 Common causes of head drop—Myasthenia, polymyositis, ALS

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Table 8–4 Amyotrophic Lateral Sclerosis Variants ALS variants: Children (the spinal muscular atrophies [SMA]) Disease

Pathophysiology

Distinguishing features

Infantile-onset SMA/WerdnigHoffman disease

Mutations in the SMN protein, which assembles snRNPs

Death  2 years of age from respiratory failure and aspiration

mutations in NAIP

Diaphragm strength is specifically preserved

Arrested infantile-onset SMA

Can survive to adulthood Delayed motor milestones; rarely can walk Hand tremor

Juvenile-onset SMA/KugelbergWelander disease

Onset 5–15 years of age; survives to adulthood Progressive limb-girdle weakness Preservation of calf muscles

ALS variants: Adults Disease

Pathophysiology

Distinguishing features

Spinal muscular atrophy type IV

Rarely has mutations in SMN or NAIP; autosomal dominant & recessive forms

Onset  20 years of age

Hereditary Spastic Paraplegias

Tongue atrophy, with normal face and eye function

Slow and benign course, mostly in shoulders Spares bulbar muscles

Primary lateral sclerosis

Sporadic occurrence, ? cause

Pure UMN weakness Involves bulbar muscles last Can involve emotional lability (bulbar affect)

Progressive muscular atrophy

As per ALS, including gene mutations

Pure LMN weakness Often occurs in members of families with familial ALS Younger age of onset, slower course than ALS

Progressive bulbar palsy

Autosomal recessive inheritance

Motoneuron loss from lower cranial nerve nuclei and/or cervical spine (e.g., respiratory weakness)

Bulbospinal neuronopathy/ Kennedy’s disease

Trinucleotide repeat in the androgen receptor (X-linked)

Gynecomastia, testicular atrophy LMN weakness in face, tongue, oropharynx, proximal shoulder & hip muscles

Abbreviations: LMN; NAIP, neuronal apoptosis inhibitory protein; SMN, survival of motoneuron; UMN, upper motor neuron.

6.

Treatment: supportive; riluzole (Rilutek) prolongs survival  6 months

7.

Prognosis: rate of spread of weakness is steady but variable from patient to patient a.

average survival from diagnosis  3 years

b.

ALS variants all have a better prognosis (Table 8–4)

X. Hereditary Spastic Paraplegias (Box 8.14) 1.

Pathophysiology: Degeneration of the corticospinal tracts and dorsal columns at their distal ends (e.g., thoracolumbar spinal cord for the corticospinal tract, medulla for dorsal columns); degeneration is primary axonal with minimal neuron loss in motor cortex, anterior horn, or dorsal root ganglion

2.

Symptoms: highly variable severity even among members in an affected family a.

begins as exertion- and cold-triggered calf stiffness and spasms, but progresses to bilateral, symmetric lower extremity weakness with minimal atrophy

Box 8.14 Other diseases with spastic paraplegia— Focal spinal cord disease, subacute combined degeneration, tethered cord syndrome, DOPA-responsive dystonia, leukodystrophies, spinocerebellar ataxia type 3, Friedreich’s ataxia

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8 Movement Disorders

Table 8–5 Hereditary Spastic Paraplegias Locus

Chromosome

Gene name & protein function

Notes

SPG-4

2

SPG-3

14

Atlastin, a GTPase with an unknown function

SPG-17

11

Seipin, an endoplasmic reticulum protein

Silver syndrome: SPG-17 with weakness and atrophy of hand muscles

SPG-11

15

?

Hypoplastic corpus callosum, mental retardation

SPG-7

16

Paraplegin, a nuclear-encoded mitochondrial chaperone protein

Ragged-red muscle fibers, strokes, mental retardation, cerebellar atrophy

SPG-1

X

Box 8.16), a neuronL1CAM (B specific cell adhesion molecule

Mental retardation, hydrocephalus

SPG-2

X

Box 8.17), Proteolipoprotein (PLP) (B an intrinsic myelin protein

Motor aphasia, mental retardation, vision loss

Box 8.15

Box 8.15), a nuclear Spastin (B protein with an unknown function

Spastin is also mutated in distal spinal muscular atrophy.

Note: White  autosomal dominant; light gray  autosomal recessive; dark gray  sex-linked.

i.

weakness is predominantly in tibialis anterior, biceps femoris, and iliopsoas (i.e., muscles of the triple flexion response)

ii.

spasticity, particularly of the biceps femoris that causes a characteristic bent-kneed gait

b.

mild lower extremity large fiber sensory loss, with preservation of small fiber sensation

c.

urinary urgency due to spastic bladder

d.

pes cavus, hyperlordosis

3.

Subtypes (Table 8–5)

4.

Diagnostic testing a.

MRI may show atrophy of thoracolumbar spinal cord

b.

somatosensory evoked potentials demonstrate delayed conduction and cortical potential from the lower extremities but normal responses from the upper extremities

c.

genetic testing: available only for spastic paraplegia genes SPG-4 and SPG-3; SPG-2 does not involve gene duplication of the proteolipid PLP gene as does Pelizaeus-Merzbacher disease, therefore it cannot be tested with the available PLP genetic tests

5.

Treatment: none specific

6.

Prognosis: progressive gait disturbance may ultimately require wheelchair; normal lifespan a.

childhood-onset subtypes generally have mild progression despite their early onset

b.

severity of disease cannot be predicted by course in other family members

XI. Ataxia Disorders 1.

Autosomal dominant ataxia disorders a.

spinocerebellar ataxia i.

198

pathophysiology: atrophy primarily of the cerebellar afferents (inferior olive, pons, spinocerebellar tract, Clarke’s nucleus) and deep cerebellar nuclei, and to a lesser extent the cerebellar cortex and other brain regions (e.g., anterior horn, dorsal columns, substantia nigra, red nucleus, globus pallidus); associated with an axonal neuropathy producing sensory or sensory-motor symptoms (1) does not have inclusions bodies, unlike MSA-C

Box 8.16 LICAM is also mutated in mental retardation, aphasia, shuffling gait, adducted thumbs (MASA) disorder and X-linked hydrocephalus disorders

Box 8.17 PLP is also mutated in Pelizaeus-Merzbacher disease

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Table 8–6 Spinocerebellar Ataxias Subtype

Genetics

Specific symptoms

Notes

SCA-1

Trinucleotide repeat in ataxin-1 gene

Hypermetric saccades, hyperreflexia despite the neuropathy

SCA-1 & SCA-2 account for 50% of all spinocerebellar ataxias

SCA-2

Trinucleotide repeat in the ataxin-2 gene

Hypometric saccades, parkinsonism, myoclonus, neuropathy

SCA-3 (Machado-Joseph disease)

Trinucleotide repeat in the ataxin-3 gene, a ubiquitin-degrading protease

Gaze-evoked nystagmus, spasticity, neuropathy; dementia (type I), exophthalmos (type II)

Type I: German heritage

SCA-6

Trinucleotide repeat in P/Q-type Ca channel (CACNA1A)*

Downbeat and gaze-evoked nystagmus, dysphagia

Onset  50 years of age, usually without a family history

SCA-7

Trinucleotide repeat in ataxin-7 gene

Retinal degeneration, hearing loss

SCA-10

Pentanucleotide repeat

Seizures

SCA-14

Protein kinase C mutation

Myoclonus

ii.

symptoms: onset typically in childhood or young adult; most exhibit anticipation with successive generations (1) general symptoms: gait and limb ataxia, dysarthria

Common in Mexicans

Ataxia Disorders

*CACNA1A gene mutations also cause episodic ataxia type 2 and familial hemiplegic migraine.

Type II: Portuguese heritage

(2) subtypes: all have noncerebellar motor dysfunction and some sort of ocular dysfunction (Table 8–6) b.

dentatorubropallidoluysial atrophy (DRPLA)—could be considered an autosomal dominant spinocerebellar ataxia i.

pathophysiology: caused by a trinucleotide repeat in the DRPLA gene of chromosome 12, which has no known function but is located inside the nucleus (1) histology: atrophy and gliosis in the cerebellum (particularly the dentate nucleus) and globus pallidus  mesencephalon with sparing of the red nucleus, caudate, putamen, substantia nigra, and inferior olivary nucleus (a) cerebellar atrophy may be based upon a preexisting hypoplasia (b) subcortical demyelination is also observed (2) more severe disease occurs with paternal inheritance

ii.

epidemiology: common in Japan

iii. symptoms: onset between 10–60 years of age; involves ataxia, dementia, choreoathetosis (usually in adult-onset disease), seizures (65%), myoclonus (in 55%, usually in juvenile-onset disease), and myelopathy (only in homozygotes with long repeats)

2.

iv.

diagnostic testing: genetic testing for the DRPLA gene repeat

v.

treatment: none specific

Autosomal recessive ataxia disorders a.

Friedreich’s ataxia—could be considered an autosomal recessive spinocerebellar ataxia i.

pathophysiology: caused by mutations in the frataxin gene, the protein of which may function in iron transport into the mitochondria (1) mutations include (a) trinucleotide repeats (95%): age of onset and severity proportionate to number of repeats (b) point mutations (5%) (2) histology: degeneration of projections from dentate nucleus, corticospinal tract, spinocerebellar tract, dorsal columns (a) minimal involvement of cerebral or cerebellar cortices

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ii.

symptoms (Box 8.18) (1) neurological symptoms: ataxia (trunk  limbs), nystagmus, dysarthria; spasticity; large-fiber sensory loss with hyporeflexia (despite a Babinski reflex); weakness

Box 8.18 Friedrich’s ataxia is similar to vitamin E deficiency and to abetalipoproteinemia (which also has vitamin E deficiency)

(2) systemic symptoms: hypertrophic cardiomyopathy, subaortic stenosis; scoliosis, pes cavus; diabetes mellitus iii. diagnostic testing: genetic testing of the frataxin gene

b.

iv.

treatment: none specific for the neurological disorder; idebenone for hypertrophic cardiomyopathy

v.

prognosis: death by 40 years of age; time to wheelchair dependence is shorter in females

ataxia-telangiectasia (AT)

8 Movement Disorders

i.

pathophysiology: caused by mutations of AT mutant (ATM) gene, the protein of which likely acts in the control of mitosis as a tumor suppressor (1) histology: degeneration of cerebellar cortex and dentate nucleus, inferior olive, substantia nigra, and posterior columns

ii.

symptoms: onset at 1–2 years of age (1) neurological symptoms: ataxia (trunk  limbs), dysarthria; oculomotor apraxia; dystonia, choreoathetosis; large-fiber sensory neuropathy with hyporeflexia that can occur in the presence of Babinski signs (2) systemic symptoms (a) ocular and cutaneous telangiectasias (b) cancer (40%), typically leukemia or lymphoma may be presenting feature of the disease (c) diabetes mellitus; gonadal hypoplasia (d) chronic anemia and lymphopenia; recurrent infections (e) hirsutism

iii. diagnostic testing (1) serology demonstrates reduced immunoglobulins (Ig) (except IgM), an oligoclonal or monoclonal gammopathy (10%), and increased -fetoprotein (2) chromosomal analysis for 7 → 14 translocation (3) neuroimaging demonstrates an atrophic cerebellum

c. 3.

iv.

treatment: none specific; frequent evaluation for cancer; avoid radiation exposure

v.

prognosis: 20–50 year lifespan

Cockayne’s syndrome (see p. 286)

Episodic ataxias a.

type I inherited episodic ataxia i.

pathophysiology: caused by mutations of voltage-gated potassium channel (Box 8.19)

ii.

symptoms: onset between 20–30 years of age (1) episodic symptoms: last 1–2 minutes; triggered by changes in position or emotion

Box 8.19 This voltage-gated potassium channel is bound by paraneoplastic antibodies in Isaac’s syndrome/neuromyotonia and limbic encephalitis.

(a) ataxia without nystagmus or vertigo (b) blurred vision (2) chronic symptoms: myokymia iii. treatment: antiepileptics; avoid acetazolamide b.

type II inherited episodic ataxia i.

200

pathophysiology: caused by mutations of P/Q-type voltage-gated calcium channel (CACNA1A) gene (Box 8.20)

Box 8.20 The P/Q-type voltage-gated calcium channel is bound by paraneoplastic antibodies in Isaac’s syndrome/neuromyotonia and limbic encephalitis.

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ii.

symptoms: onset between 20–30 years of age (1) episodic symptoms: last 10 minutes to hours; triggered by exercise or stress (a) ataxia, nystagmus, vertigo (b) dysarthria (c) generalized weakness (d) headache (2) chronic symptoms: nystagmus, ataxia

Iatrogenic Movement Disorders

iii. treatment: acetazolamide

XII. Stiff Man’s Syndrome 1.

Pathophysiology: unknown, but is associated with a.

anti-glutamate decarboxylase (-GAD) antibodies (40%)

b.

autoimmune diseases, particularly diabetes (40%) i.

2.

80% of type I diabetics exhibit antibodies against GAD, as well as other autoantibodies

Symptoms: onset in adulthood a.

painful muscle spasms with rigidity in axial and facial muscles  extremities that initially is intermittent but eventually becomes continuous i.

spasms are exacerbated by voluntary movements and startle, and may be associated with myoclonus

3.

Diagnostic testing: serology for anti-GAD antibodies; EMG demonstrates continuous motor unit potentials in agonist and antagonist muscles at rest

4.

Treatment: benzodiazepines, clonidine, baclofen, prednisone, plasma exchange, IV Ig

XIII. Essential Tremor 1.

Pathophysiology: none established, but may be a neurodegenerative disease a.

2.

risk factors: increasing age, White, family history

Symptoms: Kinetic tremor (Box 8.21) that typically develops in the arms and spreads to the head, neck, and oropharynx over several years; severe disease also involves postural tremor and/or an irregular, jerky resting tremor (20%)

3.

Diagnostic testing: Evaluate for hyperthyroidism and Wilson’s disease

4.

Treatment: Propranolol, primidone

Box 8.21 In comparison to physiological tremor, essential tremor’s amplitude is higher and its frequency is lower.

XIV. Iatrogenic Movement Disorders (Table 8–7) 1.

Tardive dyskinesia a.

pathophysiology: caused by chronic use of typical antipsychotic drugs and other phenothiazines (e.g., metoclopramide, perphenazine, prochlorperazine); rarely caused by atypical antipsychotics i.

20% overall prevalence with typical antipsychotic use, up to 50% in older patients

ii.

5% annual incidence in patients on phenothiazine medications

iii. the previous hypothesis that tardive dyskinesia was due to an upregulation and supersensitivity of dopamine receptors in the basal ganglia is not well substantiated, and instead it may involve dysregulation of the sympathetic nervous system or a direct effect of the musculature b.

symptoms i.

stereotyped movements of the

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Table 8–7 Neuroleptic Malignant Syndrome and Other Hyperthermic Disorders Neuroleptic malignant syndrome

Malignant hyperthermia

Serotonin syndrome

Acute lethal catatonia

Site of disorder

Central nervous system

Muscle

Central nervous system

Central nervous system

Common cause

Antipsychotic drugs, particularly highpotency or depot preparations

Use of halogenated anesthetics or depolarizing anesthetics in patients with mutations in ryanodine calcium channel

Overdose on SSRIs, or combination treatment with MAO inhibitor, TCA, or meperidine

An exacerbated psychotic disorder

Other symptoms

Rigidity

Jaw clenching at the time of medication administration

Shivering

Preceding psychosis and dyskinesias

Respiratory acidosis, cyanosis, myoglobinuria

Nausea, diarrhea

Encephalopathy

8 Movement Disorders

Autonomic instability Dystonia, tremor, or chorea Treatment

Ataxia, hyperreflexia Hypertension Seizures, coma

Withdraw offending drug

Withdraw offending drug

Dantrolene

Bicarbonate

Supportive

Dantrolene

Dopaminergic agonists Abbreviations: MAO, monoamine oxidase; SSRIs, selective serotonin reuptake inhibitors; TCA, tricyclic antidepressant.

(1) face, tongue, and masticatory muscles causing lip smacking or pursing, tongue protrusion, and chewing (2) extremities, producing choreiform movements or (less frequently) dystonias (3) trunk and abdomen, producing pelvic thrusting and grunting ii.

tardive movements are suppressed by voluntary movements of the affected area but are exacerbated by voluntary movements of nonaffected areas or by distraction

iii. movements are rarely bothersome to the patient c.

2.

treatment i.

discontinuation of the offending drug occasionally resolves the tardive movements years after discontinuation but usually they are permanent; tardive movements may dramatically worsen after removal of the drug but this is a transient effect

ii.

benzodiazepines, reserpine, vitamin E

Drug-induced parkinsonism a.

causative medications i.

antipsychotics: the most common offending agents; parkinsonism develops in 15% of patients taking antipsychotics, usually within 3 months of beginning the medication

ii.

GI prokinetic agents, particularly metoclopramide

iii. others: lithium, amiodarone, meperidine, amphotericin, diltiazem b.

management: parkinsonian side effects generally resolve with continued use of medication i.

may lower the dose of typical antipsychotics

ii.

may change to an atypical antipsychotic (clozapine, olanzapine, quetiapine)

iii. may use anticholinergic anti-parkinsonian medications (trihexyphenidyl, benztropine) or amantadine to counteract the effect of the causative medication (1) withdraw anticholinergic medication after 3-month period to determine need of continuing this supplementation

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Waxy flexibility, not true rigidity

Electroconvulsive therapy

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9 Diseases of the Nerves

Note: Significant diseases are indicated in bold and syndromes in italics.

1.

Action potential conduction (Fig. 9–1)

2.

Peripheral nerve organization (Fig. 9–2)

Nerve Physiology

I. Nerve Physiology

Nernst equation for an ion’s reversal potential

Figure 9–1 Action potential conduction. (From Koolman J, Rohm KH. Color Atlas of Biochemistry. Stuttgart, Germany: Georg Thieme; 1996:219. Reprinted by permission.)

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9 Diseases of the Nerves

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Figure 9–2 Peripheral nerve organization. (From Midha R, MacKay M. Principles of nerve regeneration and surgical repair. Semin Neurosurg 2001, 12:82, Fig. 1. Reprinted by permission.)

3.

Peripheral motor axon classification (see p. 231)

4.

Sensory receptors and peripheral sensory axon classification (Table 9–1)

II. Diagnostic Testing 1.

Electromyography (EMG): see p. 232

2.

Nerve conduction studies a.

motor nerve conduction studies (Fig. 9–3) i.

204

measures the muscle response to stimulation of a motor nerve (i.e., the compound muscle action potential [CMAP]); CMAP amplitude, distal latency, and conduction velocity can be used to assess the motor nerve integrity after stimulation of both distal and proximal nerve sites, and these measures should be compared against a reference range developed within the testing laboratory

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Table 9–1 Sensory Neurons and Fibers Types of sensory neurons Classification in cutaneous nerves

Size and conduction velocity

I

A

20 m, 100 m/s

Myelin

Function



Ia

Ia: Muscle spindles

Ib

Ib: Golgi tendon organs

II

A

10 m, 60 m/s



Muscle spindles, cutaneous receptors

III

A

5 m, 20 m/s



Fast localizable pain; temperature

IV

C/wide-dynamic

1 m, 1 m/s



Slow poorly localized (“burning”) pain

Cutaneous sensory terminals Receptor type

Location depth

Adaptation rate

Sensation quality

Meissner’s corpuscle

Superficial

Rapid

Touch

Merkel’s cell

Superficial

Slow

Steady indentation

Pacchionian corpuscle

Deep

Rapid

Flutter

Ruffinian corpuscle

Deep

Slow

Vibration

Diagnostic Testing

Classification in motor nerves

Numerals represent increasing activation threshold

ii.

b.

usually done with the common peroneal and posterior tibial nerves in the lower extremity, and with the medial and ulnar nerves in the upper extremity

sensory nerve conduction studies i.

performed by stimulating a pure sensory nerve and measuring the amplitude and distal latency of the nerve potential (sensory nerve action potential [SNAP]); usually done with the sural nerve behind the lateral malleolus for the lower extremity, and with the median and ulnar nerves for the upper extremity (1) tests only the integrity of the sensory nerve distal to the ganglion; evaluation of the nerve segment proximal to the ganglion requires somatosensory evoked potentials (SSEPs; see p. 108) (2) detects only dysfunction of large sensory fibers, not small fibers

Figure 9–3 Motor nerve conduction study demonstrating partial motor conduction block. The median nerve was stimulated supramaximally at the wrist and elbow and the motor response was recorded from the abductor pollicis brevis muscle. There is a 67% reduction in CMAD comparing distal to proximal stimulation sites. The

antidronic median sensory nerve action potential recorded from the index fingers with ring electrodes was normal note differences in voltage. (From Nagale SV, Bosch EP. Multifocal motor neuropathy with conduction block. Semin Neurol 2003, 23:327, Fig. 1. Reprinted by permission.)

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ii. c.

measurements of SNAPs usually requires averaging because of their small amplitude

nerve conduction tests involving the spinal cord i.

F waves: an internally-generated anterograde potential from the motoneuron soma caused by retrograde conduction of an action potential that is generated by distal, supramaximal axonal stimulation; the F waves are usually observed as a small response with a 20–50-ms delay after the CMAP that was directly activated by the stimulation {M response} (1) useful for testing the integrity of proximal motor nerve segments (2) can be performed on any motor nerve

9 Diseases of the Nerves

ii.

H reflex: specific stimulation of a sensory nerve that causes reflex activation of motoneurons in spinal cord (equivalent to the reflex arc), which can then be measured as a myographic response with a longlatency (30-ms delay) following the M response (1) technically best performed by stimulating the tibial nerve while measuring gastrocnemius and soleus muscles (S1 innervation) (2) sensitive to sensory fiber dysfunction more so than motor fiber dysfunction (3) useful for testing integrity of proximal S1 nerve segments, therefore is good for distinguishing sciatic nerve injury from S1 radiculopathy

d.

technical considerations i.

limb temperature variations: cold extremities slows the conduction velocities, and increases amplitudes and distal latencies

ii.

patient age: slower conduction velocities and reduced amplitudes are normal in young children and in the elderly

iii. limb position should be kept constant and compared against a reference standard that was developed for that limb position 3.

Nerve biopsy a.

diagnostic in some conditions with abnormalities of i.

axons (e.g., giant axon neuropathy)

ii.

myelin (e.g., hereditary neuropathy with liability to pressure palsies, anti-myelin-associated glycoprotein [MAG] antibody neuropathies, leukodystrophies)

iii. connective tissue and supportive elements (e.g., vasculitis, amyloid, sarcoid, leprosy, tumor infiltration) b.

can be supportive, but not diagnostic, of Charcot-Marie-Tooth neuropathies and inflammatory demyelinating polyradiculopathies (Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy [CIDP])

c.

procedure: generally involves both nerve and muscle biopsy simultaneously i.

sites for nerve biopsy (1) sural nerve, 15 cm above the heel: complicated by sensory loss with paresthesias and allodynia around the lateral malleolus that generally resolves over a period of years; avoid nerve biopsy at the ankle because repeated trauma from shoes causes nonspecific changes in the nerve (2) superficial peroneal nerve, at the lower third of the anterior calf (3) superficial radial nerve: used only when the neuropathy is limited to the upper extremities or when severe, chronic neuropathy exists in the lower extremities that would prevent useful histological analysis of the nerve

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(4) intermediate cutaneous nerve of the thigh, at the lower third of the anterior thigh: used mostly to confirm proximal diabetic plexopathy (i.e., diabetic amyotrophy/Bruns-Garland syndrome)

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A

B

Figure 9–4 Wallerian degeneration in situ. (A) Light microscopy demonstrating ovoid myelin debris. (B) Electron microscopy demonstrating degeneration axons in cross-section (arrows). (From Tseng CY et al. Histologic analysis of schwann cell migration and peripheral nerve regeneration in the autogenous venous nerve conduit. J Reconstruct

tissue preparation: sections of the nerve should be evaluated by (1) formalin fixation followed by paraffin embedding, which demonstrates the connective tissue and blood vessels (2) frozen section for immunostaining, which demonstrates leukocytes, complement components, and autoantibodies (3) plastic embedding for high-resolution microscopy

Plexopathies

ii.

Microsurg 2003, 19:338, Fig. 14. From Oliveira EF et al. Correlation between functional index and morphometry to evaluate recovery of the rat sciatic nerve following crush injury. J Reconstruct Microsurg 2001, 17:73, Fig. 5B. Reprinted by permission.)

(4) teased single nerve fibers, which demonstrates demyelination and remyelination, myelin wrinkling, myelin overlap {tomaculae}, and Wallerian degeneration (Fig. 9–4)

III. Plexopathies A. Cervical Plexus 1.

Anatomy: involves only the motor roots of C1–4; the sensory roots from those levels are distributed through lesser occipital, greater auricular, transverse cervical, and supraclavicular nerves a.

innervates the diaphragm (via the phrenic nerves), scalenes, lower trapezius, infrahyoid/ strap muscles, and high cervical paravertebral muscles

2.

Pathophysiology: relatively resistant to injury caused by distortion of the neck; injury is more commonly caused by local tumor growth

3.

Symptoms a.

diaphragm weakness: diaphragm hemiparalysis may present only as orthopnea and exertional dyspnea; complete diaphragm paralysis produces severe dyspnea with inability to cough

b.

infrahyoid/strap muscle paralysis generally does not produce symptoms

B. Brachial Plexus (Fig. 9–5) 1.

Anatomy: composed of motor and sensory roots from C5–T1; variants may involve contributions from C4 or T2

2.

General symptoms: pain in the neck and shoulders with radiation into the distribution of the affected nerves

Figure 9–5 Brachial plexus anatomy. (From Duus P, Topical Diagnosis in Neurology. Stuttgart, Germany: Georg Thieme; 1998:24, Fig. 1.24. Reprinted by permission.)

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Subtypes of lesions a.

supraclavicular lesions: more commonly injured than infraclavicular sites (severe trauma commonly involves all three trunks) i.

upper trunk/C5–6 root injury (1) pathophysiology: caused by (a) traumatic depression of the shoulder (e.g., neck–shoulder distraction, weight-bearing compression) (i)

traction trauma more commonly affects nerve trunks than roots, in comparison with lower trunk/C8–T1 injury

9 Diseases of the Nerves

(b) birth trauma: maternal obesity, multiparity, and large baby size are greater risk factors than obstetrical intervention; can occur even with normal vertex head positioning (2) symptoms (a) weakness in shoulder abduction (supraspinatus and deltoid) and external rotation (infraspinatus), elbow flexion (biceps and brachioradialis), and forearm supination; produces an internally rotated and adducted shoulder with extended elbow and pronated hand {waiter’s tip/Duchenne-Erb palsy} (i)

winging of the scapula (weakness of the serratus) suggests involvement of the C5–7 nerve roots, from which the long thoracic nerve originates

(ii) weakness of scapula elevation (rhomboid) suggests involvement of the dorsal scapular nerve, which originates from the C5 nerve root (b) sensory loss in lateral brachium and antebrachium ii.

middle trunk/C7 root injury (1) pathophysiology: usually occurs in conjunction with upper or lower trunk injuries (2) symptoms (specific for the middle trunk/C7 root) (a) weakness in elbow extension, wrist extension, finger extension, and forearm pronation (pronator teres and quadratus); produces a decorticate-like posture (b) sensory loss in the dorsal brachium, antebrachium, and hand

iii. lower trunk/C8-T1 root injury (Box 9.1) (1) pathophysiology: commonly caused by traumatic extension of the shoulder (e.g., catching oneself while falling), breech delivery, and apical lung tumors {Pancoast’s tumor} (a) traction trauma more commonly affects nerve roots than trunks, unlike upper trunk/C5–6 injury (2) symptoms (a) weakness in wrist flexion and all hand intrinsic muscles, resulting in a claw-like posture of the hand {Klumpke’s palsy} (b) sensory loss in medial brachium, antebrachium, and hand (c) ipsilateral mild ptosis, miosis, abnormal accommodation, and reduced face and neck sweating {Horner’s syndrome}, when the T1 motor root is injured prior to its fusion into the lower trunk, i.e., before the white ramus (i)

Horner’s syndrome may even involve loss of iris pigmentation and a decrease in intraocular pressure

(ii) Horner’s syndrome does not involve a real endophthalmos; it just appears to be so because of the upper and lower lid ptosis b.

208

infraclavicular lesions: less commonly injured than supraclavicular sites; generally are injured by penetrating trauma, shoulder dislocations, clavicular fractures, or irradiation (e.g., for breast cancer treatment)

Box 9.1 Neurological thoracic outlet syndrome— Caused by a fibrous band from the C7 vertebra transverse process to 1st thoracic rib, which compresses C8 and T1 roots; not related to a cervical rib; symptoms include pain in the ulnar forearm, hand weakness, atrophy of the thenar eminence or that involves the whole hand and medial forearm Arterial thoracic outlet syndrome—Caused by compression of the subclavian artery by a cervical rib; symptoms include pain and weakness from ischemia of the hand and forearm Venous thoracic outlet syndrome—Caused by thrombosis of the subclavian vein; symptoms include cyanosis and swelling of the arm

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i.

lateral cord injury—symptoms include weakness in elbow flexion, forearm supination and pronation (pronator teres  quadratus), and wrist flexion toward radial side (flexor carpi radialis), as well as sensory loss in the lateral antebrachium and thumb

ii.

medial cord injury—symptoms include weakness in wrist flexion toward the ulnar side, finger flexion and extension, and hand intrinsic muscles including thumb flexion and opposition (similar to that of Klumpke’s palsy), as well as sensory loss along the whole medial side of the upper extremity

iii. posterior cord injury—symptoms include (1) weakness in shoulder abduction (deltoid) and adduction (latissimus dorsi and teres major), elbow extension, forearm supination, wrist extension, and finger extension

4.

Diagnostic testing a.

5.

neuroimaging: not reliable for lesion localization in the brachial plexus i.

plain radiographs can demonstrate vertebral and clavicular fractures

ii.

CT myelography and MRI can demonstrate nerve root avulsions and traumatic injury to the meninges and spinal cord; CT myelography is superior to conventional myelography, particularly for C5–6 lesions

b.

nerve conduction study: results must be interpreted carefully because the presence of injury to the plexus will hide root injuries

c.

EMG: the absence of fibrillation potentials in paraspinal muscles does not rule-out nerve root injury, but their presence does confirm it

Treatment a.

anastomosis of transected neural elements, although this is generally ineffective for nerve roots or for injuries to lower trunk

b.

destruction of the dorsal root entry zone for elimination of chronic pain of nerve root injury

C. Lumbosacral Plexus (L1–S2) (Fig. 9–6) 1.

2.

Plexopathies

(2) sensory loss that is usually limited to the thumb and deltoid, but it may extend over the entire radial nerve sensory territory (i.e., dorsal webspace between the first and second digits, the dorsal brachium, and dorsal antebrachium)

Figure 9–6 Lumbosacral plexus anatomy. (From Duus P, Topical Diagnosis in Neurology. Stuttgart, Germany: Georg Thieme; 1998:24, Fig. 1.25. Reprinted by permission.)

Pathophysiology: Lesions are caused by a.

tumor compression or invasion (Box 9.2)

b.

retroperitoneal mass (hematoma  abscess)

c.

pregnancy and delivery

d.

pelvic irradiation

e.

trauma (rare), which has to be immensely violent due to soft tissue and bony protection

Box 9.2 Malignant psoas syndrome—lumbar plexopathy caused by tumor infiltration of the psoas muscle Warm dry foot syndrome—pain and anhidrosis of the entire lower extremity, caused by tumor invasion of the sympathetic plexus

Symptoms a.

pain that is worsened with hip extension and often with straight-leg raises (as with radiculopathies); pain is most likely to be absent in radiation-induced plexopathies

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b.

9 Diseases of the Nerves

3.

i.

lumbar plexus lesions: pain is located in the back, pelvis, or anterior thigh

ii.

sacral plexus lesions: pain is located in the posterior thigh, calf, or foot

weakness i.

lumbar plexus lesions: weakness mostly in hip flexion and knee extension

ii.

sacral plexus lesions: weakness mostly in ankle movements and hip extension; involvement of the pudendal nerve function or S2–4 nerve roots causes bowel and bladder dysfunction (rare)

Diagnostic testing a.

neuroimaging: MRI and radionucleotide scanning are useful for localization of tumors; CT is useful for imaging of hematomas

b.

EMG: evidence of denervation in the gluteus muscles and the muscles innervated by the sciatic nerve indicates a sacral plexopathy rather than a sciatic neuropathy

IV. Traumatic and Compression Neuropathies (“Entrapment Neuropathies”) 1.

Pathophysiology: Patients with a preexisting neuropathy are at greater risk for compression neuropathies, but there is no evidence that one focal injury to a nerve increases the susceptibility of that nerve to a second focal injury a.

histology i.

focal compression causes longitudinal sliding of the myelin layers that collect on either side of the site of compression {tomaculae}; accumulations of excess myelin layers may impair axoplasmic transport

ii.

Wallerian degeneration order of progression of historical changes

Figure 9–7 Median nerve anatomy. (From Rohkamm R. Color Atlas of Neurology. Stuttgart, Germany: Georg Thieme; 2004:35. Reprinted by permission.)

(1) Schwann cell retraction and myelin breakdown begin proximal to the injury site; accumulation of mitochondria and transport vesicles occur at the nodes of Ranvier along the length of the axon (2) disintegration of the smooth endoplasmic reticulum in the neuronal soma (3) breakdown of microtubule and intermediate filament structures (4) macrophage invasion of the nerve: a late response, therefore Wallerian degeneration is not a primary inflammatory reaction (5) persistence of Schwann cell tubes and their basal lamina {bands of Bungner} 2.

a.

Ulnar nerve and artery

median nerve compression syndromes (Fig. 9–7) i.

carpal tunnel syndrome (1) pathophysiology: compression occurs in the carpal tunnel of the wrist (Fig. 9–8), which is formed by the transverse carpal ligament superiorly and carpal bones inferiorly (a) risk factors include repetitive uses of the hands (50%), obesity, pregnancy, endocrinopathy (i.e., hypothyroidism, acromegaly), rheumatoid arthritis, osteoarthritis, and previous wrist fractures

210

Flexor digitorum superficialis and profundus tendons

Specific compression neuropathies of the upper extremity

(2) symptoms

Flexor retinaculum

Palmaris longus tendons Median nerve

Flexor carpi radialis tendons

Pisiform

Lateral

Medial

Hamate

Scaphoid Capitate

Figure 9–8 The carpal tunnel. (From Platzere W. Atlas of Topographical Anatomy. Stuttgart, Germany: Georg Thieme; 1985:145, Fig. 153. Reprinted by permission.)

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(a) pain in the wrist at the site of nerve injury; the pain may radiate into the forearm as well as into the fingers (b) paresthesias of hand and fingers, particularly while sleeping or with sustained hand positions (Box 9.3) (i)

only 50% of patients will localize the paresthesias within the distribution of the distal median nerve; often the paresthesias will involve all fingers

(ii) may be elicited by tapping on carpal tunnel {Tinel’s sign} or by prolonged wrist flexion {Phalen’s sign}, which are insensitive and nonspecific means of inducing paresthesias for any focal nerve injury

Box 9.3 Unlike carpal tunnel syndrome, C6 radiculopathy has radiating neck pain, loss of sensation in thenar eminence, and weakness in the forearm, wrist flexion, and pronation

(c) sensory loss, usually limited to part of the distal median nerve sensory territory; sensory loss should not involve the thenar eminence, which is supplied by a branch of the median nerve that leaves above the carpal tunnel (d) weakness of thumb abduction (abductor pollicis brevis) and opposition (opponens pollicis) causing grip weakness; weakness of flexor pollicis brevis (partly ulnar nerve innervated) and 1st–2nd lumbricals are generally asymptomatic (Fig. 9–9) (i)

thenar atrophy may develop rapidly in the elderly

(3) diagnostic testing

Traumatic and Compression Neuropathies

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(a) nerve conduction study: useful in prognostication because it identifies demyelination (mild injury) or axonal injury (severe injury) (i)

often detects abnormalities in asymptomatic individuals, therefore is overly sensitive

(b) EMG: may demonstrate the presence of denervation potentials in cases of severe injury (c) serology for comorbid conditions: routinely evaluate for hypothyroidism, diabetes, and pregnancy (4) treatment (a) medical treatment: attempt for 4–6 weeks in patients with mild symptoms; high likelihood of failure in patients who have continuous symptoms or with duration of symptoms  10 months (i)

Figure 9–9 The “preacher’s hand” posture of median nerve lesions above the wrist, i.e., involving the median-nerve supplied finger flexor muscles of the forearm. (From Mumenthaler M, Neurology. 3rd ed. Stuttgart, Germany: Georg Thieme; 1990:414, Fig. 10.8. Reprinted by permission.)

avoidance of repetitive wrist motions; immobilization with neutral wrist splint

(ii) NSAIDS; diuretics if swelling is involved; local glucocorticoid injection (b) surgical treatment: transverse carpal ligament release, either by open procedure or endoscopic approach, in patients with refractory symptoms or in cases with atrophy ii.

anterior interosseous syndrome (1) pathophysiology: compression of the anterior interosseous branch of the median nerve as it passes over the two heads of the pronator teres muscle, usually related to abnormal tendon or muscle insertions, repetitive elbow flexion, or local trauma (2) symptoms (a) pain in the forearm at the site of nerve injury, but no sensory loss (b) weakness of distal thumb flexion (flexor pollicis longus), flexion of the second and third digits (radial side of the flexor digitorum profundus), and pronation (pronator quadratus) (i)

a variant innervation of the whole flexor digitorum profundus may cause weakness of flexion in all digits

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9 Diseases of the Nerves

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Figure 9–10 The Martin-Gruber anastomosis, in which the median nerve carries part of the ulnar nerve. In such cases, stimulation (S) of the median nerve along the Martin-Gruber anastomosis causes an augmented motor response in the hand intrinsic muscles by involving ulnar-innervated muscles (B) in comparison with distal stimulation that involves only muscles typical for the median nerve (A). This activation of the ulnarinnervated muscles by median nerve stimulation (S1) can be blocked by retrograde action potentials from distal ulnar nerve stimulation (S2) (C).

(ii) weakness in the intrinsic muscles of the hand (normally ulnar nerve-innervated) as part of an anterior interosseous syndrome indicates the presence of a Martin-Gruber anastomosis between the median and ulnar nerves (Fig. 9–10), which occurs in 15% of people (3) diagnostic testing (a) EMG: can distinguish between anterior interosseous nerve injury and a more proximal median nerve injury (which should additionally have radial wrist flexion weakness from flexor carpi radialis involvement) (b) nerve conduction study: impractical because of the difficulty in isolating the anterior interosseous nerve (4) treatment (a) medical treatment: avoid provocative movements; NSAIDs; local glucocorticoid injection (b) surgical treatment: exploration for an anatomical abnormality in cases without obvious cause or in cases refractory to medical treatment for 6 months b.

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ulnar nerve compression syndromes (Fig. 9–11) i.

ulnar nerve entrapment at the elbow

Figure 9–11 Ulnar nerve anatomy. (From Rohkamm R. Color Atlas of Neurology. Stuttgart, Germany: Georg Thieme; 2004:35. Reprinted by permission.)

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(1) pathophysiology: compression of the ulnar nerve as it enters forearm through the cubital tunnel/humero-ulnar aponeurotic arcade, which lacks soft tissue protection

(2) symptoms (Fig. 9–12): pain and paresthesias are exacerbated by elbow flexion (a) pain at the elbow, or rarely in the hypothenar eminence (b) paresthesias of fourth and fifth digits (i)

patients may describe a splitting of the fourth digit with paresthesias

(ii) 20% will also have paresthesias in the third digit, whereas 20% will have paresthesias only of the fifth digit (c) weakness of the hand intrinsic muscles manifesting as grip weakness and repeatedly catching the fifth digit against objects due to adduction weakness (i)

weakness of the adductor pollicis (ulnar nerve-innervated) can be demonstrated by having the patient pinch a piece of paper between the tips of the thumb and the second digit, which normally requires the flexor pollicis longus (median nerve-innervated); weakness of this pinching position is associated with an inability to form a circle with the thumb and the second digit {Froment’s sign} (Fig. 9–13)

Traumatic and Compression Neuropathies

(a) anatomical variations (i.e., an accessory anconeus muscle, or olecranon hypertrophy causing nerve displacement) also can cause injury or predispose to trauma

(3) diagnostic testing (a) nerve conduction study: 70% of cases with weakness demonstrate conduction block with stimulation above the elbow; the study should be performed with the elbow in a partially flexed position (i)

in some patients, anastomosis between the ulnar nerve and the anterior interosseous branch of the median nerve {Martin-Gruber anastomosis} allows the median nerve to supply some of the hand intrinsic muscles; therefore it is better to examine CMAPs in the ulnarinnervated muscles of the forearm

(b) EMG: presence of abnormalities in the flexor digitorum profundus diagnoses injury at the elbow better than abnormalities in the flexor carpi ulnaris (4) treatment (a) medical treatment: 2–3-month trial of splints, NSAIDs; no benefit of local glucocorticoid injection (b) surgical treatment: the type of procedure is best determined by an intraoperative nerve conduction study, such that (i)

decompression is indicated with nerve injuries in the cubital tunnel

(ii) nerve transposition is indicated if injury occurs along medical epicondyle of the humerus ii.

ulnar nerve entrapment at the wrist (1) pathophysiology: caused by repetitive wrist trauma or occasionally a ganglion cyst of the ulnar nerve as it enters the hand through Guyon’s tunnel (Fig. 9–14), which is formed by the deep forearm fascia and the carpal bones and ligaments; once through Guyon’s tunnel, the ulnar nerve then travels across the palm from the hypothenar eminence to the thenar eminence; along this course it is also susceptible to injury (2) symptoms: may exhibit pure sensory or motor variants (a) pain in the wrist and hand

213

A

B

C

Figure 9–12 Differentiation between a C8 root lesion (A), lower brachial plexus lesion (B), and an ulnar nerve palsy (C). (From Mumenthaler M, Neurological Differential Diagnosis. 2nd ed. Stuttgart, Germany: Georg Thieme; 1992:38, Fig. 16. Reprinted by permission.)

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9 Diseases of the Nerves

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(c) weakness in hand intrinsic muscles: distal lesions of the ulnar nerve in the hand may occur past the innervation of the hypothenar muscles, producing weakness only in the thumb and clawing of the second digit

Figure 9–13 Froment’s sign: Paralysis of the adductor pollicis requires that the thumb be held in flexion for an effective pinching motion. (From Mumenthaler M, Neurology. 3rd ed. Stuttgart, Germany: Georg Thieme; 1990:419, Fig. 10.12. Reprinted by permission.)

(3) diagnostic testing (a) nerve conduction study (i)

for lesions in Guyon’s canal, identifies prolongation of distal CMAP latencies and reduced CMAP amplitudes in the abductor digiti minimi and 1st dorsal interosseous muscle

(ii) for lesions distal to Guyon’s canal, identify the lesion location by step-wise evaluation of distal motor latencies and CMAPs of interossei muscles

palmar arterial arches superficial deep

flexor digitorum superficial tendons

palmor digital nerves

opponens digiti minimi

flexor retinaculum

Traumatic and Compression Neuropathies

(b) paresthesias and sensory loss in the palm side of the fourth and fifth digits

abductor pollicis opponens pollicis

entrance to Guyon’s tunnel medial nerve

ulnar artery radial artery palmaris longus tendon

Hexor carpi radialis & flexor pollicis longus tendon

flexor digitorum superficialis tendon

Figure 9–14 Guyon’s tunnel.

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(b) treatment: wrist splinting, NSAIDs; surgical transection of Guyon’s canal, for cases caused by trauma or those refractory to medical care c.

radial nerve compression syndromes (Fig. 9–15) i.

radial nerve injury in the brachium (1) pathophysiology: caused by fractures of the proximal humerus where the radial nerve crosses posteriorly in the spiral groove, or prolonged compression at that site {Saturday night palsy} (2) symptoms

9 Diseases of the Nerves

(a) weakness in wrist extension, and thumb and finger extension; weakness in elbow extension occurs only with radial nerve injury in the axilla (i)

apparent weakness in grip strength is caused by an inability to extend the wrist; intrinsic hand strength must be checked with the palm of the hand placed on a flat surface

(b) sensory loss on the radial side of dorsal hand and thumb, and the dorsal brachium and antebrachium (c) pain over the dorsal brachium, which is generally mild (3) diagnostic testing (a) nerve conduction study: demonstrates focal CMAP conduction block and relative preservation of SNAPs (b) EMG: evidence of denervation in the radial nerve-innervated muscles of the forearm (4) treatment (a) medical treatment: wrist splints to prevent contractures and to provide wrist extension to assist with use of hand (b) surgical treatment: exploration of suspect injury site after failure of medical management for 4 months or in cases of severe trauma; in chronic cases with loss of wrist extension, tendon transfer from anterior forearm compartment to wrist and thumb extensors allows for wrist extension ii.

posterior interosseous nerve syndrome (1) pathophysiology: commonly caused by trauma or repetitive pronation-supination movements; nerve injury occurs in the arcade of Frohse (Fig. 9–16) formed by the fascia of the supinator muscle (2) symptoms (a) weakness in forearm supination, wrist extension, and thumb abduction (extensor pollicis longus and brevis) (i)

extensor carpi radialis is usually unaffected because it is innervated by branches arising from the radial nerve above the arcade of Frohse

(b) may have pain in elbow, but does not have sensory deficits (similar to the anterior interosseous syndrome) (3) diagnostic testing (a) nerve conduction study: demonstrates focal motor conduction block; the diagnosis requires preserved SNAPs in the superficial radial nerve (b) EMG: thorough testing of posterior forearm muscles can localize lesion site along the course of the nerve because the relative locations of the various branches of the posterior interosseous nerve are reliable

216

(4) treatment: wrist extension splint, which allows for better use of hand; local glucocorticoid injection; surgical exploration for cases caused by trauma or after failed medical management

Figure 9–15 Radial nerve anatomy. (From Rohkamm R. Color Atlas of Neurology. Stuttgart, Germany: Georg Thieme; 2004:35. Reprinted by permission.)

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brachial artery

radial recurrent artery

brachialis radial nerve

biceps tendon

deep branch (posterior interoseus) arcade of Frohse

superficial branch pronator teres

brachioradicialis

Traumatic and Compression Neuropathies

median nerve

bicipital aponeurosis flexor carpi radialis

palmaris longus

flexor carpi ulnaris

Figure 9–16 The arcade of Frohse.

3.

Specific compression neuropathies of the lower extremity a.

femoral nerve syndromes (Fig. 9–17) i.

pathophysiology: caused by (1) entrapment in the psoas muscle: from trauma or mass lesions, or as a complication of retroperitoneal surgery (2) entrapment under the inguinal ligament: from prolonged hip flexion or hip abduction and external rotation, or by compression from a fetus

ii.

symptoms (1) weakness in knee extension; weakness in hip flexion may occur with nerve entrapment in psoas muscle (i.e., a very proximal lesion), but this is not a reliable finding

Figure 9–17 Femoral nerve anatomy. (From Rohkamm R. Color Atlas of Neurology. Stuttgart, Germany: Georg Thieme; 2004:37. Reprinted by permission.)

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(2) paresthesias and sensory loss in the anterior thigh and medial calf (from the saphenous nerve branch) (3) pain in the groin, anterior thigh, and medial calf iii. diagnostic testing: neuroimaging is necessary because much of the femoral nerve is not accessible to electrophysiological testing (1) nerve conduction study: can demonstrate motor conduction block across the inguinal ligament (2) EMG: can identify a pattern of muscle denervation that is consistent with root lesions (i.e., involving paraspinal and gluteus muscles), but the root lesions may be hiding a lesion of the femoral nerve iv.

9 Diseases of the Nerves

b.

treatment: knee bracing; surgical removal of any causative mass lesions

lateral femoral cutaneous nerve syndrome/meralgia paresthetica (Fig. 9–18) i.

ii.

pathophysiology: caused by compression of the nerve as it emerges from underneath the inguinal ligament on the anterolateral thigh (e.g., by tight pants or belts, or by an abdominal pannus in the obese) symptoms: paresthesias and sensory loss over lateral thigh, exacerbated by prolonged standing; no weakness

Figure 9–18 Lateral femoral cutaneous nerve anatomy. (From Rohkamm R. Color Atlas of Neurology. Stuttgart, Germany: Georg Thieme; 2004:37. Reprinted by permission.)

iii. treatment: weight loss; avoidance of compressive clothing c.

syndromes of the common peroneal nerve and its superficial and deep branches (Fig. 9–19) i.

ii.

pathophysiology: generally caused by external compression (e.g., prolonged bed rest, surgical positioning, weight loss, prolonged crossing of the legs) symptoms (Box 9.4) (1) weakness in ankle eversion and dorsiflexion (Box 9.5), causing foot drop

Box 9.4 Unlike peroneal nerve injury, an L5 radiculopathy also has weakness in hip extension and abduction, and foot inversion, and sensory symptoms in the sole of the foot that extend above the knee into the lateral thigh.

(2) paresthesias and sensory loss in the lateral calf and lateral foot (a) superficial peroneal nerve sensory symptoms are limited to the distal calf and dorsum of the foot, and may not involve the proximal calf as does common peroneal injury

Box 9.5 The tibial nerve mediates ankle inversion and plantar flexion.

(b) deep peroneal nerve sensory symptoms are limited to the webspace between the first and second digits (3) may have pain in popliteal fossa d.

e.

diagnostic testing i.

nerve conduction studies: evaluation of superficial peroneal nerve SNAPs is necessary to differentiate between the common and deep peroneal nerves as the cause of foot drop

ii.

EMG: test the peroneus longus and brevis muscles to confirm involvement of the superficial peroneal nerve; should also test the short head of the biceps femoris, which is innervated by the common peroneal nerve above the popliteal fossa, to test for very proximal common peroneal nerve lesions

treatment: avoid posterior knee compression and pad the affected knee; use splints or casting only for superficial peroneal nerve compression

V. Hereditary Neuropathies A. Charcot-Marie-Tooth (CMT) Neuropathies/Hereditary Motor-Sensory Neuropathies 1.

218

General symptoms: distal weakness with atrophy; hypo- or areflexia; mild sensory loss; acquired or congenital lower extremity deformity (Fig. 9–20); kyphoscoliosis

2.

Subtypes (Table 9–2)

3.

Diagnostic testing: generally relies upon genetic testing

Figure 9–19 Peroneal nerve anatomy. (From Rohkamm R. Color Atlas of Neurology. Stuttgart, Germany: Georg Thieme; 2004:37. Reprinted by permission.)

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A

Hereditary Neuropathies

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B

Figure 9–20 Lower extremity deformities in CMT, including toe walking, foot eversion, and hammertoes (A), and distal atrophy (B). (From Mumenthaler M, Neurology. 3rd ed. Stuttgart, Germany: Georg Thieme; 1990:306, Fig. 7.1a, 7.1b. Reprinted by permission.)

Table 9–2 Subtypes of Charcot-Marie-Tooth Neuropathies Group & subtype

Pathophysiology and gene mutations

Distinguishing features

All AD; exhibit demyelination

Relatively normal NCS

A

Duplication or mutation of PMP-22, which has an unknown function

Nerve enlargement

B

Mutation of P0 protein, which opposes the external faces of myelin sheets {compaction}

Essential tremor

D

Mutation of early growth regulator (EGR)-2, a transcription factor

CMT-1

Have AD and AR subtypes; exhibit axonal loss

Relatively normal NCS

AD-A

Mutation of Kif-1b, which transports mitochondria along microtubules

? anticipation across generations

AD-B

Unknown

ulcers → amputations

AD-C

Unknown

Vocal cord paralysis; respiratory failure

AR-A

Mutation in lamin A/C intermediate filament that forms inner skeleton of the nucleus (Box 9.6)

Facial weakness

All are AD; exhibit demyelination

Severely abnormal NCS

CMT-2

CMT-3/ Dejerine-Sottas

Box 9.6

A

Mutation of PMP-22 (as with CMT-1A)

B

Mutation of P0 (as with CMT-1B)

CMT-4

All are AR; exhibit demyelination

Moderately abnormal NCS

A

Mutation in ganglioside-induced differentiation-associated protein (GDA-P1)

Facial synkinesis

B

Mutation in myotubularin-related protein-2 (MTMR-2), a protein phosphatase (Box 9.7)

Thick lips

F

Mutation in periaxin, which may regulate axon-Schwann cell interaction

CMT-X

X-linked mutations in connexin-32, which forms gap junctions; exhibits axonal loss

Lamin A/C is also mutated in Emery-Dreifuss muscular dystrophy type II.

Box 9.7 Myotubularin mutations also occur in myotubular myoypathy. Mildly abnormal NCS

Abbreviations: AD, autosomal dominant; AR; autosomal recessive; NCS, nerve conduction study.

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a.

4.

nerve biopsy: demonstrates radial layers of proliferative Schwann cells {myelin onion bulbs}, which is a nonspecific finding (Fig. 9–21)

Treatment: none specific

B. Hereditary Neuropathy with a Predilection to Pressure Palsies (HNPP)

9 Diseases of the Nerves

1.

2.

3.

4.

5.

Subtypes a.

HNPP-A: caused by monosomy of the PMP-22 gene due to chromosomal deletion

b.

HNPP-B: not linked to any genetic deficit

Histology (Fig. 9–22): telescoping of adjacent Schwann cells {tomaculae} with paranodal demyelination on teased single nerve fibers; invagination of myelin sheath into the axon demonstrated on transverse sections of the axons

Figure 9–21 Myelin onion bulbs. (From Hirano A. Color Atlas of Pathology of the Nervous System, 2nd Ed. Tokyo/New York: Igaku-Shoin Press; 1988:138, Fig. 339. Reprinted by permission.)

Symptoms: onset 30–40 years of age a.

recurrent focal neuropathies that are caused by minor trauma

b.

mild sensorimotor neuropathy, often with hyporeflexia (40%)

c.

may have pes cavus or scoliosis

d.

rarely has pain

Diagnostic testing a.

nerve conduction study: demonstrates focal conduction block at sites of injury, but also generalized mild slowing consistent with diffuse demyelinating disease

b.

genetic testing for the PMP-22 monosomy

Treatment: avoidance of trauma

A

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Figure 9–22 (A) Thickening of the myelin sheaths with onion bulb formation on nerve cross-section (arrows). (B) Thickened myelin sheaths folding into the axon. (C) Tomacula on teased fiber preparation (arrow). (From Adlkofer K et al. Heterozygous peripheral myelin protein 22-deficient mice are affected by progressive demyelinating tomaculous neuropathy. J Neurosci 1997, 17(12): 4662–71, Fig, 9.22A; 4664, Fig. 1F; 4668, Fig. 6D. Copyright 1997 by the Society of Neuroscience. Reprinted by permission.)

B

C

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6.

Prognosis: 50% exhibit complete recovery after focal neuropathy; 10% exhibit long-term neurological dysfunction

C. Giant Axonal Neuropathy

2.

Pathophysiology: caused by mutations in the gene for gigaxonin, the protein of which likely acts in microtubule organization and stabilization; mutations may lead to the breakdown of cytoskeletal organization a.

the majority of cases are sporadic mutations, although some familial cases with an autosomal recessive inheritance have been reported

b.

histology: focal regions of axonal swelling that exhibit decreased myelination occurring in both the peripheral and central nervous systems, which are pronounced in the long tracts of spinal cord (particularly in the cervical region) (Fig. 9–23)

Figure 9–23 Giant axonal neuropathy, peripheral nerve biopsy. Courtesy of Dr. C. Yamada.

i.

swollen astrocyte processes {Rosenthal fibers} are present in the subependymal region

ii.

neurons and other cell types (e.g., fibroblasts, melanocytes, endothelial cells) exhibit accumulations of neuronal intermediate filaments, likely because they cannot be transplanted around the cell due to microtubule disruption

Acquired Neuropathies

1.

Symptoms: onset  7 years of age a.

General symptoms: Tightly curled hair; skeletal abnormalities (short stature, pes cavus, kyphoscoliosis)

b.

peripheral nervous system symptoms i.

distal weakness, particularly in the lower extremities

ii.

distal large-fiber sensory loss causing gait ataxia

iii. cranial neuropathies (CN VII  III, XII) c.

3.

central nervous system symptoms i.

cerebellar dysfunction: nystagmus, ataxia, dysarthria

ii.

mental retardation; seizures (rare)

Diagnostic testing a.

nerve conduction study: SNAPs are reduced to much greater extent than are CMAPs

b.

evoked potential studies are generally abnormal

c.

EEG demonstrates areas of focal slowing

d.

neuroimaging: diffusely increased T2 signal in the subcortical white matter with atrophy that is particularly pronounced in parietal and occipital lobes and in the cerebellum

4.

Treatment: none specific

5.

Prognosis: progressive loss of motor function invariably leads to use of wheelchair; death by 30 years of age

VI. Acquired Neuropathies A. Guillain-Barre Syndrome (GBS) 1.

General pathophysiology a.

caused by IgG and complement deposits in various parts of the nerve that recruit local macrophage infiltration; these deposits can be located on i.

the Schwann cells leading to demyelination, as in the acute inflammatory demyelinating polyneuropathy (AIDP) subtype

ii.

the nodes of Ranvier so that macrophages directly attack the axon causing Wallerian degeneration, as in the acute motor axonal neuropathy (AMAN) and acute motor-sensory axonal neuropathy (AMSAN) subtypes

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b.

GBS is often preceded by . . . i.

infection: 65% of cases have history of recent infection, particularly an upper respiratory tract infection or gastroenteritis (1) viral causes include Epstein-Barr virus, cytomegalovirus, human immunodeficiency virus (HIV), influenza, Coxsackie, and hepatitis viruses (2) bacterial causes include Campylobacter jejuni (30% of all cases), Mycoplasma pneumoniae, and Escherichia coli (a) preceding gastroenteritis is a risk factor for poor outcome from GBS (3) parasitic causes include malaria and toxoplasma

9 Diseases of the Nerves

ii.

a systemic disorder: hyperthyroidism, cancer (Hodgkin’s lymphoma, chronic lymphocytic leukemia)

iii. pregnancy, immunizations, or recent surgery c. 2.

epidemiology: sporadic occurrence except for AMAN, which can occur in epidemics in China

Subtypes of GBS with pronounced weakness a.

acute inflammatory demyelinating polyneuropathy (AIDP): accounts for 90% of all GBS cases i.

symptoms: develop over a period of a few hours to days (1) pain in the back (often between the shoulders), buttocks, or lower extremities (in 50% at the onset, and 90% ultimately) with paresthesias and dysesthesias; the pain is exacerbated by the straight-leg raise (2) weakness beginning in lower extremities that advances into the upper extremities; the weakness is usually symmetric and may occasionally be mild (a) weakness involves the face in 60% of cases (b) weakness may rarely begins in oropharynx, neck, and upper extremities {cervico-pharyngeo-brachial variant of AIDP} (3) hypo- or areflexia (4) mild distal panmodal sensory loss (5) ophthalmoplegia (20%) (6) autonomic dysfunction (65%): arrhythmia, fluctuant blood pressure, gastroparesis, urinary retention

ii.

diagnostic testing (1) early cerebrospinal fluid analysis ( 1 week) may exhibit a pleocytosis that is typically  10 cells/cc; protein increases after 1 week, which can be used to confirm the diagnosis (2) nerve conduction study: abnormalities develop within 2–3 weeks, and include (a) reduced conduction velocities and temporal dispersion (b) conduction block (35%) (c) prolonged or lost F waves in the presence of preserved distal CMAPs, which is fairly specific for inflammatory demyelinating neuropathies (3) EMG: no evidence of denervation (i.e., fibrillation potentials) (4) serology: poorly associated with increased titers of anti-ganglioside antibodies

iii. prognosis: worsening of symptoms over  4 weeks, during which 30% require mechanical ventilation; 5% mortality with treatment, and 80% exhibit complete recovery in 6 months b.

acute motor axonal neuropathy (AMAN) i.

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symptoms: indistinguishable from AIDP, except for a shorter symptomatic course ( 1 week) because some of the weakness may be due to reversible axonal block

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ii.

diagnostic testing (1) cerebrospinal fluid studies as per AIDP (2) nerve conduction study: in comparison with AIDP, AMAN exhibits reduced CMAP amplitudes with preserved velocities and normal sensory nerve conduction velocities (3) EMG: fibrillation potentials develop by 2–3 weeks

iii. prognosis:  5% mortality acute motor-sensory axonal neuropathy (AMSAN) i.

symptoms: same as AIDP and AMAN, but more rapid onset and progression of weakness

ii.

diagnostic testing (1) cerebrospinal fluid: increased protein after 1 week, but not a pleocytosis (2) nerve conduction study: in comparison with AIDP and AMAN, AMSAN exhibits reduced CMAP amplitudes and reduced sensory nerve conduction velocities (3) EMG: fibrillation potentials develop within 2–3 weeks

iii. prognosis: slower recovery, more residual deficits; 10% mortality rate d.

subtypes of GBS without pronounced weakness i.

Miller-Fisher syndrome—accounts for 5% of GBS (1) symptoms

Acquired Neuropathies

c.

(a) ophthalmoplegia: usually begins as a partial ophthalmoplegia (not necessarily in a cranial nerve distribution), but progresses to complete ophthalmoplegia within a few days that always spares the pupillary light reflex (b) hypo- or areflexia (c) limb and gait ataxia, likely due to large fiber neuropathy rather than cerebellar dysfunction (i.e., no nystagmus or dysarthria) (d) mild large fiber sensory loss in the distal extremities (2) diagnostic testing (a) cerebrospinal fluid: similar to other types of GBS (b) nerve conduction study: reduced SNAP velocities; motor studies and EMG are normal (c) serology: anti-GQ1b and anti-GT1a ganglioside antibodies are present in 95% of cases, but are nonspecific for other subtypes of GBS (3) prognosis: self-limited course ii.

acute panautonomic neuropathy (rare) (1) symptoms: orthostatic hypotension and syncope; gastroparesis or diarrhea, abdominal pain; abnormal diaphoresis; blurred vision and pupil dysfunction; cold or heat intolerance; sexual dysfunction (a) minimal somatic motor and sensory dysfunction (2) diagnostic testing (a) cerebrospinal fluid: increased protein without pleocytosis occurs in 60% of cases and then only after 4 weeks (b) normal nerve conduction study and EMG

iii. pure sensory neuropathy (rare) (1) symptoms: tremor; limb and gait ataxia; hypo- or areflexia (2) diagnostic testing: reduced SNAP velocities on nerve conduction study e.

general treatment: intravenous immunoglobulin (IVIg; 0.4 g/kg/d for 5 days) or plasmapheresis (250 mL/kg total exchange volume divided over 5–6 q.o.d. sessions) administered within first 2 weeks increases the rate of recovery but does not ultimately improve functional recovery

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i.

IVIg is preferred for acute panautonomic neuropathy subtype

ii.

no benefit of combining both IVIg and plasmapheresis

iii. glucocorticoids are proven ineffective

B. Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) 1.

Pathophysiology: unknown, but may be related to hyperactivity of CD8 T lymphocytes a.

often occurs in conjunction with monoclonal gammopathy of unknown significance (MGUS), cancer, connective tissue diseases, HIV infection, or hyperthyroidism

9 Diseases of the Nerves

i.

2.

b.

associated with human leukocyte antigen (HLA)-B8 and –DR2, and -antitrypsin polymorphisms; no association with anti-ganglioside antibodies like some subtypes of GBS

c.

histology: evidence of demyelination and remyelination that is often excessive, resulting in myelin onion bulb formation (like the Charcot-Marie-Tooth neuropathies)

d.

epidemiology: most common in patients 40–60 years of age, but can occur at any age

Symptoms: course may be progressive or relapsing–remitting, but must have lasted at least a 2-month symptomatic period (Box 9.8) a.

3.

weakness in multiple limbs that usually begins in the lower extremities but that involves both proximal and distal muscles simultaneously (which may best distinguish CIDP from other neuropathies); weakness is generally symmetric, but it may start focally before progressing to other limbs {Lewis-Sumner syndrome} i.

neck flexor weakness is common and occasionally may spare upper extremities; rarely involves respiratory muscles

ii.

mild facial weakness occurs in 10%

b.

large fiber sensory loss with paresthesias, generally in the distal lower extremities, that may cause a gait ataxia

c.

hyporeflexia

d.

Adie’s tonic pupil, from injury to the ciliary ganglion and short ciliary nerves

e.

central nervous system dysfunction (5%): usually is mild and most commonly limited to spasticity, but it may have a multiple sclerosis-like course

Diagnostic testing a.

nerve conduction study: must demonstrate at least three demyelinating abnormalities (see p. 205) i.

4.

prolonged or lost F waves in presence of preserved distal CMAPs is fairly specific for inflammatory demyelinating neuropathies

b.

cerebrospinal fluid demonstrates mild pleocytosis (usually  10 white blood cells (WBCs) in immunocompetent patients, or  50 WBCs in HIV patients) and increased protein

c.

peripheral nerve biopsy may demonstrate demyelination and remyelination, but this is only observed in 60% of cases due to the multifocal nature of the disease

d.

neuroimaging: 20% of cases demonstrate focal subcortical white matter lesions that are similar to multiple sclerosis plaques

Treatment: may use multiple treatments simultaneously in severe cases a.

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some MGUS and cancer (lymphoma, leukemia) patients have antibodies against myelin associate glycoprotein (MAG), and 25% develop a hematological malignancy shortly after they develop neuropathy

glucocorticoids: high-dose prednisone PO or methylprednisolone IV to achieve a clinical response, followed by maintenance dosing that should continue until no further clinical improvement is obtained (generally 6 months) and then tapered

Box 9.8 Diagnostic Requirements for Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) Probable CIDP—2-month duration; weakness in multiple limbs; large fiber sensory loss; hyporeflexia; NCS with three demyelinating-type abnormalities (see p. 205); cerebrospinal fluid with minimal pleocytosis Definite CIDP—Also requires consistent nerve biopsy abnormalities

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b.

IVIg and plasmapheresis are equally efficacious, and either is probably superior to glucocorticoids; generally require periodic treatments that are scheduled according to the patient’s clinical responsiveness

c.

cyclophosphamide, azathioprine, interferon

Prognosis: 50% achieve maximal improvement within 6 months, 95% by 12 months a.

50% relapse rate, more commonly in patients with long-standing and treatment-resistant symptoms

C. Multifocal Motor Neuropathy Pathophysiology: thought to be an autoimmune neuropathy because 50% of cases are associated with anti-GM1 antibodies, but there is no histological evidence of inflammation in nerve biopsies; antibody deposits develop at the nodes of Ranvier, as in the AMAN subtype of GBS a. 2.

3.

Acquired Neuropathies

1.

epidemiology: 3:1 male preference; no age preference

Symptoms: may be progressive or relapsing a.

asymmetric distal weakness developing over a period of years that often has a focal appearance (e.g., foot or wrist drop) suggestive of a mononeuropathy; rarely has facial weakness or respiratory muscle involvement

b.

fasciculations are common, but there is disproportionately little atrophy

c.

myokymia

d.

hyporeflexia

e.

minimal sensory abnormalities, if any

Diagnostic testing a.

nerve conduction study: demonstrates demyelinating abnormalities specifically affecting select motor nerves; no abnormalities in sensory nerve function are demonstrable

b.

EMG: no evidence of denervation

c.

serology: high anti-GM1 ganglioside IgM titers in 50% of cases

4.

Treatment: IVIg, cyclophosphamide; glucocorticoids are rarely effective, and often worsens symptoms after initiation of treatment

5.

Prognosis: Often requires chronic treatment, and has frequent relapses

D. Paraproteinemic Neuropathies 1.

Monoclonal gammopathies: caused by an overproduction of a single monoclonal antibody {M protein} from a clone of B lymphocytes/plasma cells a.

the antibody is IgG  IgM or IgA  a partial immunoglobulin protein (e.g., light chain) i.

b.

 5% have multiple monoclonal immunoglobulins, that is, they are biclonal or oligoclonal gammopathies

causes include i.

monoclonal gammopathy of undetermined significance (MGUS): accounts for 60% of monoclonal gammopathies; 20% will develop a hematologic malignancy (1) in 40% of cases, the monoclonal antibody is an IgM specific for the myelin-associated glycoprotein (MAG) that acts to space the layers of myelin (Box 9.9) (2) symptoms: often just neuropathy; does not even have nonspecific constitutional symptoms (a) neuropathy is typically distal symmetric sensorimotor in patients with anti-MAG antibodies, or CIDP-like in patients without anti-MAG antibodies

Box 9.9 Anti-MAG antibodies also bind P0 protein

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(3) specific diagnostic testing: increased IgM or IgG levels, but still  3 g/dL total globulins ii.

multiple myeloma: accounts for 10% of monoclonal gammopathies (1) symptoms: bone pain, weight loss, fatigue, neuropathy (only 5%) (2) specific diagnostic testing:  10% plasmacytes on bone marrow aspirates; lytic bone lesions on skeletal survey

iii. amyloidosis: accounts for 10% of monoclonal gammopathies iv.

leukemia or lymphoma: account for 10% of monoclonal gammopathies; may exhibit anti-MAG antibodies, like MGUS and Waldenstrom’s macroglobulinemia

v.

plasmacytomas: accounts for 5% of monoclonal gammopathies

9 Diseases of the Nerves

(1) symptoms: bone pain from lytic bone lesions; neuropathy (50%) (a) POEMS syndrome—only common with osteosclerotic myeloma (a type of plasmacytoma); specific symptoms include (i)

polyneuropathy

(ii) organomegaly (iii) endocrinopathy: diabetes mellitus, hypothyroidism, gonadal dysfunction (iv) M protein (only 90%) (v) skin changes: hyperpigmentation, digit clubbing vi. Waldenstrom’s macroglobulinemia: accounts for  5% of monoclonal gammopathies (1) exhibits anti-MAG antibodies, like MGUS, lymphoma, and leukemia (2) symptoms: fatigue, anemia, bleeding tendency, organomegaly; neuropathy (5%); no bone lesions (3) specific diagnostic testing:  3 g/dL total globulin; malignant lymphoplasmacytoid cells on bone marrow biopsy c.

general diagnostic testing i.

serum protein electrophoresis (SPEP): may detect only 70% of monoclonal gammopathies by itself, therefore SPEP must be done with immunofixation (IPEP)

ii.

urine protein electrophoresis (UPEP) with urine concentrated from a 24-hour sample, which is particularly useful in detecting  and  light chains or heavy chains

iii. blood cell differential iv.

radiological skeletal survey for malignancy

v.

bone marrow biopsy for hematological malignancies

vi. soft tissue biopsy (e.g., fat, cutaneous nerves, kidney) for amyloidosis 2.

Cryoglobulinemias a.

subtypes i.

type I cryoglobulinemia: caused by monoclonal immunoglobulins that precipitate at reduced temperatures; often occurs with other monoclonal gammopathies

ii.

types II and III cryoglobulinemias: caused by mixed immunoglobulins that precipitate at reduced temperatures, often occurs in autoimmune diseases or infection (1) type II: monoclonal rheumatoid factor (anti-IgG IgM) and polyclonal IgG (2) type III cryoglobulinemia: polyclonal IgG and IgM; strongly associated with hepatitis C infection

b.

226

symptoms: organomegaly, renal failure, purpura, arthralgia; neuropathy is usually a painful distal sensorimotor polyneuropathy, rarely mononeuritis multiplex (Box 9.10)

Box 9.10 Mononeuritis multiplex is much more commonly caused by polyarteritis nodosa.

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Supraclavicular N.

Axillary N.

Radial N. Medial Cutaneous N. of Arm

Iliohypogastric N.

Acquired Neuropathies

Medial Cutaneous N. of Forearm Musculocutaneous N. Genitofemoral N. Dorsal Digital N. (Radial N. Median N. Ulnar N. llionguinal N. Pudendal N. Lat. Cutaneous N. of Thigh Obturator N.

Femoral N.

Lateral Cutaneous N. of the Calf

Superficial Peroneal N.

Calcaneal N.

Saphenous N.

Sural N. Deep Peroneal N. Plantar Digital N.

Lat. and Med. Plantar Nn. Sural N.

Figure 9–24 Peripheral sensory dermatomes (right side of body) and radicular sensory dermatomes (left side of body). Shading indicates the important branches. (From Mumenthaler M, Neurological Differential

Diagnosis. 2nd ed. Stuttgart, Germany: Georg Thieme; 1992:141, Fig. 53a, Fig. 53b. Reprinted by permission.)

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Supraclavicular N.

Axillary N.

Radial N.

Medial Cutaneous N. of Arm

Superior Gluteal N.

Musculocutaneous N.

Medial Gluteal N.

9 Diseases of the Nerves

Medial Cutaneous N. of Forearm Iliohypogastric N. Dorsal Branch of Ulnar N. Inferior Gluteal N. Superficial Branch of Radial N.

Lateral Cutaneous N. of Thigh

Posterior Cutaneous N.

Lateral Cutaneous N. of the Calf

Saphenous N.

Sural N.

Medial Plantar N.

Figure 9–24 (Continued)

c.

diagnostic testing i.

serology: demonstration of immunoglobulin precipitates in the blood

ii.

nerve conduction study demonstrates axonal loss; EMG demonstrates denervation

iii. nerve biopsy: often shows a necrotizing vasculitis from ischemia, even in cases of type I cryoglobulinemia that involve monoclonal immunoglobulins against myelin components (1) leukocyte infiltration and precipitates of immunoglobulin in vasa nervorum can be demonstrated (2) hepatitis C virus particles may be demonstrable in vascular endothelial cells d.

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treatment i.

glucocorticoids, plasmapheresis, immunosuppressants

ii.

interferon therapy for cryoglobulinemia patients with hepatitis C infection

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Appendix 9–1

Key Movements, Muscles, Nerves, and Roots (Figure 9–24)

Upper Extremity Movement

Muscle

Nerve

Root

Proximal thumb flexion

Flexor pollicis brevis

Ulnar nerve

T1  C8

Distal thumb flexion

Flexor pollicis longus

Anterior interosseous branch, median nerve

C8  T1

Thumb adduction

Adductor pollicis

Ulnar nerve

T1

Thumb abduction

Abductor pollicis brevis

Median nerve

T1

Abductor pollicis longus

Radial nerve

Thumb opposition

Opponens pollicis

Median nerve

T1

Distal finger flexion

Flexor digitorum profundus

Anterior interosseous branch, median nerve (digits 2–3)

C8

Supination

Supinator

Radial nerve

C6,7

Pronation

Pronator teres

Median nerve

C6,7

Pronator quadratus

Anterior interosseous branch, median nerve

C8

Radial wrist flexion

Flexor carpi radialis

Median nerve

C6,7

Ulnar wrist flexion

Flexor carpi ulnaris

Ulnar nerve

C8

Shoulder abduction

Medial deltoid ( 15°)

Axillary nerve

C5

Supraspinatus

Suprascapular nerve

Teres major

Subscapular nerve

C5,6

Latissimus dorsi

Thoracodorsal nerve

C7

Biceps brachialis

Musculocutaneous nerve

C5,6

Brachioradialis

Radial nerve

C6

Triceps

Radial nerve

C7

Movement

Muscle

Nerve

Root

Foot dorsiflexion

Tibialis anterior

Deep branch of the common peroneal nerve

L4

Foot plantar flexion

Gastrocnemius

Tibial nerve

S1,2

Ulnar nerve (digits 3–4)

Shoulder adduction Elbow flexion Elbow extension

Last HeadNeuropathies Acquired 1

Median nerve

Lower Extremity

Soleus Foot inversion

Tibialis posterior

Tibial nerve

L4,5

Foot eversion

Peroneus longus and brevis

Superficial branch of the common peroneal nerve

L5

Knee extension

Quadriceps

Femoral nerve

L3,4

Knee flexion

Hamstrings

Sciatic nerve

L5, S1

Hip flexion

Iliopsoas

Femoral nerve and direct radicular branches

L1,2

Hip extension

Gluteus maximus

Inferior gluteal nerve

L5,S1

Hip abduction

Gluteus medius and minimus

Superior gluteal nerve

L4,5

Hip adduction

Adductor muscles

Obturator nerve

L2,3

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10 10 Diseases of the Muscles

Diseases of the Muscles

230

Note: Significant diseases are indicated in bold and syndromes in italics.

I. Muscle Physiology 1.

Muscle contraction (Fig. 10–1) and neuromuscular transmission (Fig. 10–2)

2.

Muscle fibers: distinguished biochemical by the expression of different isozymes of myosin

Figure 10–1 Muscle contraction. (From Koolman J, Rohm KH. Color Atlas of Biochemistry. Stuttgart, Germany: Georg Thieme; 1996:307. Reprinted by permission.)

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Muscle Physiology

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Figure 10–2 Neuromuscular transmission. SR  smooth endoplasmic reticulum. (From Koolman J, Rohm KH. Color Atlas of Biochemistry. Stuttgart, Germany: Georg Thieme; 1996:309. Reprinted by permission.)

3.

a.

slow twitch/type I muscle fibers: characterized by a small diameter, a high myoglobin content, and numerous mitochondria; relies on aerobic metabolism, which is better for tonic contraction

b.

fast twitch/type II muscle fibers: characterized by a large diameter, a low myoglobin content, and few mitochondria; relies on anaerobic metabolism, which is better for phasic contraction (Fig. 10–3)

c.

super-fast muscle fibers: found in extraocular muscles

d.

tonic muscle fibers: found in extraocular muscles, tensor tympani

The motor unit: composed of the motoneuron and the muscle fibers it innervates; the muscle fibers for a particular motoneuron are always of the same type, but are not necessarily located near to each other in the muscle a.

motoneurons innervate a greater number of muscle fibers in larger muscles; conversely, motoneurons for the small muscles of face and hands may innervate less than 10 muscle fibers, allowing for fine motor control

Figure 10–3 Normal gastrocnemius muscle. ATPase stain demonstrates fast-twitch (f) and slow-twitch (s) muscle fibers. (From Beltri K et al. Contribution of the distal nerve sheath to nerve and muscle preservation following denervation and sensory protection. J Reconstruct Microsurg 2005, 21:67, Fig. 8e. Reprinted by permission.)

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types of motor units listed in order of recruitment i.

fatigue-resistant slow-twitch motor units: respond to low levels of activation of the motoneuron pool

ii.

fatigue-resistant fast-twitch motor units: respond to intermediate levels of activation of the motoneuron pool; produce only half the contraction force of fatigue-resistant slow-twitch motor units

iii. fatigable fast-twitch motor units: respond to the highest levels of activation of the motoneuron pool; generates the largest force during twitch or tetanic contraction

10 Diseases of the Muscles

4.

Recruitment principle: the force of a muscle contraction is produced by activating an increasingly larger number of motor units in a fixed order beginning with the weakest and progressing to the strongest; this simplifies the modulation of force, because only the magnitude of the response has to be determined, not the identity of the responding motor units a.

the recruitment principle also keeps fatigable fast-twitch motor units quiescent until they are absolutely needed, which is metabolically advantageous

b.

the order of activation can be reversed under certain physiological conditions, for example, activation of cutaneous pain receptors that inhibit fatigueresistant slow-twitch motor units while promoting the fast-twitch motor units, thereby allowing rapid force modulation

II. Diagnostic Testing 1.

EMG: normal motor unit potentials (MUPs) (Fig. 10–4) a.

pathological MUPs i.

myopathic changes on EMG (1) MUPs tend to exhibit a decreased, not increased, amplitude after myopathic changes, because the muscle fibers are atrophying (2) contractions of a diseased muscle results in an increased number of MUPs that are firing at normal or slower-than-normal rates

ii.

neuropathic changes on EMG: involve a lesser degree of denervation and reinnervation than do myopathic changes (1) denervation: acutely denervated muscle fibers are electrically inactive unless they are irritated (e.g., at the time of needle insertion), until the development of fibrillation potentials 3 weeks after injury (a) fibrillation potentials: spontaneous, regular potentials of chronically denervated muscle fibers (i)

the most accurate indicator of axonal loss in a neuropathic disorder, but fibrillation potentials last only  2 years after denervation before they spontaneously resolve

(ii) presence of fibrillation potentials in the proximal musculature (e.g., paraspinal muscles) indicates a motor root injury (versus peripheral nerve disease), but it is not always present (2) reinnervation: can be accomplished by regeneration of an injured axon or by collateral sprouting of nearby intact motoneuron terminals (a) MUPs from collateral sprouts are different from those of normally innervated motor units in that they (i)

have an increased duration

(ii) have an increased amplitude (iii) have a polyphasic waveform

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(iv) are of reduced number and are firing at faster than normal rates ( 15 Hz) during muscle contraction (i.e., abnormal recruitment pattern) iii. abnormalities of insertional activity and irritability on EMG (Fig. 10–4) (1) reduced insertional activity and irritability are caused by replacement of the muscle by other soft tissues or by physiological contracture (e.g., as in McArdle’s disease, phosphofructokinase deficiency, paramyotonia congenita, or during episodes of the periodic paralysis disorders)

A

(2) increased insertional activity and irritability exists in several forms including (a) fibrillation potentials: bi- or triphasic waveforms with an initial negative potential originating in the muscle; occurs at 1–30 Hz at a regular rhythm (i)

caused by lower motoneuron disease, muscular dystrophies, and inflammatory myopathies

Diagnostic Testing

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B

(ii) insertional sharp waves: essentially a fibrillation potential caused by the initial irritation of a muscle fiber during insertion of the EMG needle (b) fasciculation potentials: less than 6 Hz potentials with an irregular rhythm and variably shaped waveforms caused by pathological processes that irritate the lower motoneuron anywhere along its course (even within the spinal cord, as with amyotrophic lateral sclerosis) (Box 10.1) (c) myokymic discharges: short bursts of sharp waves occurring at regular intervals and that produce a rhythmic, undulating muscle contraction; occurs at 5–150 Hz (i)

can be caused by most diseases of the muscle

(d) myotonic discharges: sustained runs of positive- or negative-sharp waves (depending upon the site of electrode placement) with fluctuant amplitudes, producing a tonic muscle contraction; occurs at 50–100 Hz (Box 10.2) (i)

C

D Figure 10–4 Normal (A) and abnormal EMG activity. Reinnervation (B) demonstrates broad, high-amplitude waveforms. Complete denervation (C) demonstrates fibrillation potentials (left and middle potentials) and positive sharp waves (right potential). Myopathy (D) exhibits low-amplitude, polyphasic waves that are often split. (From Mumenthaler M, Neurology. 3rd ed. Stuttgart, Germany: Georg Thieme; 1990:389, Fig. 10. 2a–d. Reprinted by permission.)

neuromyotonic discharges: similar to myotonic discharges, except they occur at 150–300 Hz, are continuous even during sleep, and are induced by physical stimulation; caused by diseases of the nerve that involve aberrant activity of the most distal portion of the nerve branches (e.g., Isaac’s disease)

(e) complex repetitive discharges: a coordinated burst involving several MUPs induced by a “pacemaker” muscle fiber that drives nearby muscle fibers, producing a stable but abnormal waveform; occurs at 5–100 Hz b.

Box 10.1 Differential diagnosis of fasciculation potentials—Motoneuron diseases; chronic radiculopathy or neuropathies; cholinesterase use

technical considerations for EMG i. ii.

limb temperature variations: cold prolongs the MUP and increases its amplitude patient age (1) neonates: MUPs amplitudes are proportionately small due to immature size of the muscle fibers

Box 10.2 Differential diagnosis of acquired myotonia— Chronic radiculopathy or neuropathy; severe myopathies; drug exposure

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(2) elderly: MUP amplitudes are larger than in young adulthood due to compensatory reinnervation caused by age-appropriate loss of motoneurons

10 Diseases of the Muscles

2.

Muscle biopsy a.

open biopsy allows for multiple sampling sites that may be necessary for muscle diseases that do not involve the whole muscle body (i.e., are patchy, as in the inflammatory myopathies)

b.

evaluate both frozen and glutaraldehyde-fixed sections; fixed sections should be prepared by embedding in plastic (for electron microscopy, if necessary) and paraffin

c.

technical limitations i.

in cases of chronic muscle diseases, avoid biopsies of severely affected muscles; in cases of relative acute muscle diseases, select severely affected muscles

ii.

do not perform within 1 month of an episode of rhabdomyolysis, and avoid muscles that have suffered recent trauma (e.g., EMG testing)

III. Myasthenic Syndromes 1.

Myasthenia gravis a.

pathophysiology: caused by antibodies that disrupt the function of postsynaptic nicotinic acetylcholine receptors on striated muscle; these antibodies may be derived from i.

a paraneoplastic syndrome: anti-acetylcholine receptor antibodies block acetylcholine receptor binding and crosslink the receptor proteins causing their internalization and destruction; antibodies target the gamma subunit of the receptors, which are most concentrated in the extraocular muscles (1) antibodies on the myocytes induce (Box 10.3) (a) complement membrane attack complexes: damage to the postsynaptic membrane initially causes loss of infoldings of the muscle fiber membranes {T tubules} and disorganization of the muscle end plate with widening of the synaptic cleft, and may ultimately cause muscle fiber death (b) mild lymphocyte invasion of the muscle, in severe cases (2) associated with thymoma (15% of cases) or thymic hyperplasia (80% of cases) (a) B lymphocytes produce the anti-acetylcholine receptor antibodies but require T lymphocytes to make them in the form of IgG, therefore thymectomy changes the antibody expression from IgG to the less damaging IgM form

ii.

an autoimmune reaction: antibodies against the muscle specific tyrosine kinase (MuSK) may disrupt acetylcholine receptor aggregation in the muscle end plate by deregulating the function of the intracellular protein agrin (1) this form of myasthenia gravis is associated with HLA-B8 and –DR3 in young patients, and with other autoimmune disorders (rheumatoid arthritis, lupus, polymyositis, pernicious anemia) or immunosuppression

b.

epidemiology: a bimodal prevalence with peaks at 20–30 years of age (female predominance) and 60–80 years of age (male predominance) (1) myasthenia gravis patients greater than 40 years of age commonly have a thymoma; patients less than 40 years of age are more likely to have thymic hyperplasia

234

c.

symptoms

Box 10.3 Thymoma paraneoplastic syndromes— Myasthenia gravis; Isaac’s syndrome; cerebellar degeneration (CV-2 paraneoplastic autoantibody); pure red cell aplasia

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weakness of the extraocular and facial muscles  neck (particularly flexion), bulbar, and oropharyngeal muscles  proximal upper extremity muscles  lower extremity muscles (1) weakness is typically asymmetric and becomes evident after prolonged use of a muscle (i.e., it is not present with immediate movements) (a) weakness is often evident as a loss of postural tone, or as tremulousness during prolonged muscle use (2) the weakness may be specifically limited to the extraocular muscles; the pupils are spared in myasthenia gravis, unlike botulism

ii.

muscle soreness

iii. muscle atrophy occurs in only 15% of chronic cases and reflexes are always normal

Myasthenic Syndromes

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(1) the tongue often exhibits longitudinal furrows in patients with MuSK antibodies, but this is a poorly understood abnormality that is not true atrophy d.

diagnostic testing i.

edrophonium (Tensilon) test: double-blinded injection of edrophonium (10 mg total in divided doses) produces improvement in a preexisting weakness within 1 minute of injection (1) best to measure the degree of ptosis, which can be easily quantified (2) requires a 2-mg test dose to assess tolerability; monitoring for bradycardia (3) not as accurate as serological tests and EMG, because the response to edrophonium is not specific for myasthenia gravis

ii.

serum antibodies (1) acetylcholine receptor: present in 95% of myasthenia gravis cases (2) striated muscle: present in 30% of myasthenia gravis cases; more common in older patients (3) MuSK: present in 65% of acetylcholine receptor-negative patients; patients usually exhibit mild symptoms limited to the extraocular muscles

Figure 10–5 Myasthenia gravis. Significant decrement at rest and postexercise potentiation followed by exhaustion. (From McKhann GM et al. Q&A Color Review of Clinical Neurology and Neurosurgery. Stuttgart, Germany: Georg Thieme; 2003: 131, Fig. 130. Reprinted by permission.)

(4) titan: more common in patients with normal thymus glands (5) ryanodine-sensitive voltage-gated calcium channels (Box 10.4) iii. EMG demonstrates increased jitter, at least in facial muscles if not diffusely iv.

nerve conduction studies: repetitive nerve stimulation produces decremental responses

v.

muscle biopsy can be used to demonstrate immune deposits in seronegative cases

Box 10.4 The ryanodine-sensitive voltage-gated calcium channel is also mutated in central core myopathy; not the same as the L-type dihydropyridine calcium channel that is mutated in hypokalemic periodic paralysis.

vi. thymoma screening with CT chest, which always should be performed irrespective of the likelihood of its occurrence e.

treatment (Fig. 10–5) i.

ii.

pyridostigmine (Mestinon): better for paraneoplastic myasthenia (i.e., anti-acetylcholine receptor antibody), and is minimally effective in autoimmune myasthenia (i.e., anti-MuSK antibody)

Box 10.5

(1) the results of edrophonium testing should not be used to adjust medication doses

✧ Occurs in patients with a baseline respi-

immunosuppressants: better for autoimmune myasthenia (Box 10.5) (1) chronic prednisone, which may cause transient worsening of the weakness at the time of initiation of the therapy (2) chronic cyclosporine, azathioprine, or mycophenolate in patients who are poorly responsive to glucocorticoids (3) plasma exchange or intravenous immunoglobulin (IVIg) for severe bulbar and oropharyngeal dysfunction

Myasthenia crisis ratory impairment who develop a second respiratory disorder (usually infection); typically defined as a forced vital capacity (FVC)  15 cc/kg ✧ Distinguish from respiratory failure due to acetylcholinesterase inhibitor overdose by challenging the patient with edrophonium after the patient is intubated

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iii. thymus removal for thymoma or thymic hyperplasia: thymus removal is useful only for paraneoplastic myasthenia and is not usually effective acutely, in severe disease, or in patients with anti-MuSK antibodies (1) thymomas are generally encapsulated, but 35% may be invasive; thymoma invasion of surrounding tissues may require irradiation and/or chemotherapy (2) in postthymectomy patients, rising antibody titers may indicate thymoma recurrence

10 Diseases of the Muscles

f.

2.

prognosis: slow progression of symptoms over months with periods of exacerbation i.

no clear association exists between exacerbations and pregnancy

ii.

no association between antibody titers and severity of disease

Pediatric myasthenia syndromes a.

transitory neonatal myasthenia—caused by transplacental passive transfer of antibodies from a myasthenic mother to the fetus; occurs in 20% of children of myasthenic mothers i.

symptoms are present at birth, and include hypotonia and poor feeding

ii.

treatment: may require plasmapheresis if severe

iii. prognosis: self-limited course usually lasting  2 weeks b.

c.

congenital myasthenia—caused by abnormalities in acetylcholine release, neuromuscular junction acetylcholinesterase function, or postsynaptic acetylcholine receptors; usually exhibits autosomal recessive inheritance i.

symptoms develop at birth, and include ptosis, ocular motor weakness, and facial weakness; limb weakness is mild

ii.

treatment: as per adult myasthenia gravis

familial infantile myasthenia—associated with polymorphisms on chromosome 17 i.

symptoms are present at birth, and include poor feeding and respiratory failure often leading to sudden death

ii.

treatment: as per adult myasthenia

iii. prognosis: symptoms generally improve with age 3.

Lambert-Eaton myasthenia a.

pathophysiology: a paraneoplastic syndrome caused by antibodies to the P/Q calcium channel on presynaptic motoneuron terminals, thereby reducing acetylcholine release; rarely involves antibodies against the N-type calcium channels

b.

subtypes: both occur with approximately equal frequencies i.

Lambert-Eaton myasthenia without associated cancer: average age of onset  50 years of age; often associated with other autoimmune conditions (i.e., myasthenia gravis, pernicious anemia, vitiligo, diabetes, lupus)

ii.

Lambert-Eaton myasthenia with associated cancer: average age of onset  60 years of age; classically associated with small-cell lung cancer or rarely associated with leukemia or lymphoma (1) 3% of small-cell lung cancer patients with develop Lambert-Eaton myasthenia (2) symptomatic onset of myasthenia precedes the diagnosis of cancer in  80%

c.

symptoms: usually is subacute at onset, but may be acutely precipitated by exposure to calcium channel blockers, iodinated contrast agents, and muscle paralytic agents i.

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weakness in the proximal lower extremities  upper extremities  oropharyngeal muscles  respiratory muscles (1) weakness improves with brief exercise but then worsens with sustained exercise; similarly, patients are initially hyporeflexic but the reflexes improve with repetition

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(2) ocular and facial muscles are generally spared, although  40% will complain of diplopia ii. d.

e.

autonomic dysfunction (Box 10.6): dry mouth, constipation, impotency

diagnostic testing: EMG exhibits transient, incremental compound muscle action potential (CMAP) response to rapid nerve stimulation (20–50 Hz) and a decremental response to slow nerve stimulation (1–5 Hz), similar to botulism; also exhibits small CMAP amplitudes (Box 10.7) treatment: inconsistently responsive to acetylcholinesterase inhibitors i.

Box 10.6 Autonomic dysfunction does not occur with myasthenia gravis.

Box 10.7 CMAP is a summation of multiple MUPs

Lambert-Eaton myasthenia without associated cancer: chronic immunosuppression

ii.

Lambert-Eaton myasthenia with associated cancer (1) treatment of neoplasm (2) 3, 4-diaminopyridine; immunosuppression; plasma exchange, IVIg

IV. Congenital Myopathies 1.

X-linked myopathies: Mostly symptomatic in males; however, female carriers may develop mild symptoms at later ages due to random inactivation of the X chromosome a.

Congenital Myopathies

(1) requires careful and frequent evaluation for development of a neoplasm

Duchenne’s muscular dystrophy i.

pathophysiology: caused by mutation of the dystrophin gene, which encodes a protein that anchors the cytoskeleton to actin in the myocontractile apparatus (1) the majority of mutations are frameshift; 30% of cases are novel mutations, and 15% of novel mutations are gonadal mosaics

ii.

symptoms (1) progressive symmetric weakness beginning at 3–5 years of age as cramping and fatigue of the proximal muscles that progresses to the inability to walk by 13 years of age (a) the waddling gait with toe walking is due to weakness of the gluteus muscles and shortness of the ankle tendon (b) proximal muscle weakness necessitates that the patient stands up with the hands pushing on the knees {Gower’s sign}, which is nonspecific for Duchenne’s muscular dystrophy (2) progressive generalized muscle hypertrophy that is most pronounced in calf muscles (3) joint contractures, particularly in lower extremities (4) dilated cardiomyopathy: 60% of cases are symptomatic by 18 years of age (5) mild mental retardation

iii. diagnostic testing (1) elevated CK (100-times normal levels) that declines with muscle loss over time (2) genetic testing for dystrophin mutations (3) muscle biopsy demonstrates endomysial fibrosis and clumps of variable-sized, irregular muscle fibers in a contracted state but with normal internal muscle architecture (Fig. 10–6) (a) immunohistochemical analysis demonstrates absent staining for dystrophin iv.

treatment: avoid exercise, which likely worsens muscle injury

Figure 10–6 Duchenne’s muscular dystrophy. Endomysial fibrosis is noted in the region at the top of the figure. Courtesy of Dr. C. Yamada.

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(1) weekly glucocorticoid treatment delays loss of ability to walk by 2–3 years (2) androgenic steroids to increase muscle bulk (3) splints and release surgery for contractures v.

10 Diseases of the Muscles

b.

prognosis: death by 25 years of age from respiratory or cardiac failure

Becker’s muscular dystrophy i.

pathophysiology: caused by mutations of dystrophin gene that do not completely eliminate its functional activity; 70% of mutations are point mutations, and novel mutations are rare (unlike Duchenne’s muscular dystrophy)

ii.

symptoms: as for Duchenne’s muscular dystrophy; the severity of symptoms correlates with the residual level of dystrophin activity (1) onset of symptoms  7 years of age, progressing slowly to the loss of the ability to walk in late adolescent or even adulthood (2) cardiomyopathy and mental retardation are not as common as they are in Duchenne’s muscular dystrophy

iii. diagnostic testing (1) elevated CK ( 10-fold normal levels) (2) muscle biopsy exhibits high levels of muscle regeneration and reduced (but present) dystrophin staining (a) must rule out reduced levels of sarcoglycans as a cause for decreased dystrophin levels, as occurs in limb-girdle muscular dystrophies (3) cannot rely on genetic testing to establish the diagnosis because decreased expression of an otherwise normal dystrophin protein may cause the disease iv. c.

treatment: as for Duchenne’s muscular dystrophy

Emery-Dreifuss muscular dystrophy i.

subtypes (1) Emery-Dreifuss muscular dystrophy type 1: caused by an X-linked mutation of the emerin gene, which encodes a protein located on the inner surface of the nuclear membrane that (in association with lamin A/C and nuclear actin) forms the nucleoskeleton

ii.

(2) Emery-Dreifuss muscular dystrophy type 2: caused by an autosomal mutation of the gene for lamin A/C (Box 10.8)

Box 10.8

symptoms: onset in childhood or adolescence

Lamin A/C

(1) weakness of the shoulders, brachium, and calf muscles (a distinctive pattern for Emery-Dreifuss muscular dystrophy)

Other mutations cause autosomal-recessive Charcot-Marie-Tooth disease type 2A and autosomal-dominant limb-girdle dystrophy.

(2) contractures, which develop earlier than would be expected given the weakness (3) cardiomyopathy with conduction block iii. diagnostic testing: elevated CK ( 10-fold normal levels) iv. 2.

treatment: cardiac pacing; contracture release

Autosomal-dominant congenital myopathies a.

myotonic dystrophy i.

subtypes (1) myotonic dystrophy type I (98% of cases): caused by an expanded trinucleotide repeat in the 3 untranslated region of the myotonin protein kinase gene, which encodes a protein that regulates actinmyosin interaction and voltage-gated ion channel activity (a) disease usually develops with  100 trinucleotide repeats (2) myotonic dystrophy type II: mutation on chromosome 3

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symptoms: an earlier age of onset is associated with increased number of trinucleotide repeats {anticipation} (1) congenital-onset myotonic dystrophy (a) severe hypotonia, dysphagia, and facial diplegia; no myotonia is present (b) multiple joint contractures {arthrogryposis} (c) mental retardation, which is often associated with hydrocephalus ex vacuo, hypoplasia of the corpus callosum, and abnormal myelination (2) adult-onset myotonic dystrophy (a) weakness of face and neck muscles, wrist and finger extensors, and foot extensors (a distinctive pattern for myotonic dystrophy) (i)

facial weakness involves the levator palpebrae, masseters, and temporalis muscles, causing a characteristic sleepy, slack-jawed facial appearance with a narrow forehead (“hatchet head” appearance [Fig. 10–7])

(ii) palate weakness produces a nasal voice (b) delayed relaxation of a muscle after contraction (e.g., grasping a doorknob) or after tapping on a muscle {myotonia} (c) muscle flaccidity after cold exposure (d) frontal balding (e) hypersomnia

Figure 10–7 Myotonic muscular dystrophy. (From McKhann GM et al. Q&A Color Review of Clinical Neurology and Neurosurgery. Stuttgart, Germany: Georg Thieme; 2003:89, Fig. 82. Reprinted by permission.)

Congenital Myopathies

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(f) cardiac conduction defects with an increased risk of tachyarrhythmias (g) gonadal atrophy leading to infertility in males (h) cataracts (i)

insulin resistance or type II diabetes mellitus

iii. diagnostic testing (1) normal to mildly elevated CK (2) EMG displays spontaneous bursts of high-amplitude discharges {myotonic discharges} that are usually of longer duration than those of myotonia congenita (3) genetic testing (4) muscle biopsy demonstrates myocytes with numerous internal nuclei, and rarely a reduced size of the type I (fast twitch) muscle fibers (Fig. 10–8) iv.

treatment: patients are generally not bothered by the myotonia, and the weakness has no effective treatment (1) prophylactic antiarrhythmic medications or cardiac pacemaker implantation (2) acetazolamide or mexiletine for myotonia

v.

b.

prognosis: average lifespan with adult onset  60 years of age, but 50% are wheelchair bound before their death

myotubular/centronuclear myopathy i.

subtypes (1) autosomal dominant form: caused by mutation of the MYF6 gene protein, a myogenic factor (2) autosomal recessive form: caused by an unknown mutation

Figure 10–8 Myotonic dystrophy. Courtesy of Dr. C. Yamada.

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(3) X-linked form: caused by mutation of the myotubularin gene, the protein of which may function in myocyte maturation (Box 10.9)

Box 10.9

symptoms: onset in infancy (X-linked form), childhood (autosomal recessive form), or adulthood (autosomal dominant form)

Mutations of myotubularin-related protein occur in Charcot-Marie-Tooth type 4B.

(1) diffuse weakness lacking the typical proximal-distal gradient of a myopathy (2) generalized atrophy, or rarely muscle hypertrophy (e.g., calf pseudohypertrophy) (3) mild ophthalmoplegia, usually ptosis  limitation of upgaze

10 Diseases of the Muscles

iii. diagnostic testing: muscle biopsy demonstrates myocytes with centrally located nuclei associated with radial extensions of the sarcoplasmic reticulum from the nuclei that are observable on NADH staining; these abnormal myocytes resembles neonatal myocytes {myotubules} (Fig. 10–9) (1) nonspecific findings include type I fiber predominance and hypotrophy iv.

treatment: none specific

v.

prognosis: severity is dependent upon the age of onset (1) onset in infancy leads to death within 1 year (2) childhood onset progresses to wheelchair dependency by adulthood (3) adult onset generally progresses only to mild gait impairment in old age

c.

Figure 10–9 Centronuclear myopathy. Note the central location of the nuclei, radial distribution of the sarcoplasmic reticulum, and the predominance of hypertrophic (type 1) fibers. (From Jeannet PY et al. Clinical and histologic findings in autosomal centronuclear myopathy. Neurology 2004, 62:1488. Reprinted by permission.)

nemaline rod myopathy i.

pathophysiology: caused by mutations in -actin; rarely by mutations of troponin

ii.

symptoms: symptoms are apparent at birth (1) weakness leading to feeding difficulties and respiratory failure; hypotonia (2) arthrogryposis (3) mental retardation

iii. diagnostic testing: muscle biopsy demonstrates red-blue-stained structures on Gomori trichrome stain in type I muscle fibers {nemaline rods} (Fig. 10–10) (1) electron microscopy demonstrates nemaline rods as electron densities radiating from the Z-lines along the lengths of the thin filaments iv. d.

prognosis: death from respiratory failure

facioscapulohumeral muscular dystrophy i.

pathophysiology: caused by partial deletion of a repeat sequence near a telomere of chromosome 4 that controls expression of the nearby gene for polyA-binding protein 2, the protein of which participates in mRNA turnover and initiation of translation (1) large deletions produce more severe symptoms and an earlier age of onset (2) 40% of cases involve novel mutations that often present with mild symptoms because of mosaic expression (i.e., every cell does not contain the mutation)

ii.

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A

symptoms (1) weakness of facial (particularly orbicularis oris and oculi muscles), scapular, and brachial muscles that is typically

B Figure 10–10 Nemaline rods under light microscopy (A) and electron microscopy (B), which shows the rods to be aligned in parallel with the myofibers. (From Lamont PJ et al. Nemaline rods and complex I deficiency in three infants with hypotonia, motor delay, and failure to thrive. Neuropediatrics 2004, 35:303, Fig. 1; 304, Fig. 2. Reprinted by permission.)

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asymmetric; the weakness progresses to involve the distal extremities (a) facial weakness produces a characteristic transverse smile and pouting lips as well as an inability to close the eyes while sleeping; patients are dysarthric for labial consonants and have difficulty using straws (b) drooping shoulders from trapezius weakness gives a triangular appearance to the neck

(2) mental retardation (90%); seizures (40%) (3) pectus excavatum (4) retinal telangiectasias {Coat’s syndrome}

and

detachment

Figure 10–11 Facioscapulohumeral muscular dystrophy. Courtesy of Dr. C. Yamada.

(5) cardiac arrhythmia (5%) iii. diagnostic testing (1) normal or mildly elevated CK (2) muscle biopsy demonstrates endomysial and perivascular inflammation, and hypertrophied muscle fibers with pale centers that are mixed together with atrophied muscle fibers (Fig. 10–11)

e.

iv.

treatment: scheduled albuterol increases muscle mass but not strength

v.

prognosis: progression of the weakness may arrest around 50 years of age, leaving 20% of patients wheelchair bound; normal lifespan

Congenital Myopathies

(c) deltoids, oropharyngeal, and respiratory muscles are typically spared

limb-girdle dystrophies (LGMD) types 1A–E (autosomal dominant forms) i.

general symptoms: symmetric proximal weakness

ii.

common subtypes (Table 10–1) (1) myotilin: an actin-binding protein located in the I-band of the sarcomere (2) lamin A/C: located on the inner nuclear membrane and forms the nucleoskeleton (Box 10.10)

Box 10.10

(3) caveolin-3: forms invaginations of the sarcolemma {caveolae} that act as aggregation sites for transmembrane signaling proteins

Other mutations of lamin A/C cause EmeryDreifuss muscular dystrophy type 2 and Charcot-Marie-Tooth disease type 2A

Table 10–1 Subtypes of Limb-Girdle Muscular Dystrophy Subtype

Gene product

LGMD 1A

Myotilin

Notes

LGMD 1B

Lamin A/C

Cardiomyopathy; onset  10 years of age

LGMD 1C

Caveolin-3

Onset  5 years of age; slowly progressive

LGMD 2A*

Calpain-3

Pronounced gluteus muscle involvement sparing the quadriceps

LGMD 2B

Dysferlin

LGMD 2C

-sarcoglycan

LGMD 2D*

-sarcoglycan

LGMD 2E

-sarcoglycan

LGMD 2F

-sarcoglycan

LGMD 2G

Telethonin

Pronounced quadriceps involvement

*common subtypes of the autosomal recessive form. Note: Light background  autosomal dominant forms; dark background  autosomal recessive forms.

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iii. diagnostic testing (1) mildly increased CK, in comparison with autosomal recessive LGMDs (2) muscle biopsy (3) genetic testing 3.

Autosomal-recessive congenital myopathies

10 Diseases of the Muscles

a.

limb-girdle dystrophies (LGMD) types 2A–H i.

general symptoms: symmetric proximal weakness

ii.

subtypes (Table 10–1) (Fig. 10–12) (1) calpain-3: a cytosolic calciumactivated protease that may regulate expression of transcription factors for myocyte differentiation; interacts with the myoskeletal protein titan

Figure 10–12 The dystrophin–sarcoglycan complex. (From Gilchrist JM. Overview of neuromuscular disorders affecting respiratory function. Semin Respir Crit Care Med 2002, 23:197, Fig. 2. Reprinted by permission.)

(2) dysferlin: located on the cytoskeletal membrane and may be involved in membrane resealing caused by the trauma of muscle contraction (3) sarcoglycans: may function to translate mechanical stresses into biochemical signaling reactions, particularly with nitric oxide synthase (4) telethonin: involved in sarcomere formation; interacts with myoskeletal protein titan iii. diagnostic testing (1) greatly increased CK, unlike autosomal dominant LGMDs (2) muscle biopsy with specific immunohistochemistry (3) genetic testing b.

central core disease i.

ii.

pathophysiology: caused by mutations of the ryanodine-sensitive calcium channel (Box 10.11), which normally releases calcium from the sarcoplasmic reticulum by means of a physically connection between the L-type/dihydropyridine calcium channels in the t-tubule symptoms (1) congenital form: reduced fetal movements, hypotonia; congenital hip dislocation, scoliosis, arthrogryposis

Box 10.11 Other mutations of the ryanodininesensitive calcium channel cause malignant hyperthermia; antibodies to ryanodine calcium channel are implicated in myasthenia gravis.

(2) childhood form: mild proximal weakness sparing the face, usually resulting in delayed acquisition of motor milestones and clumsiness; weakness is associated with muscle cramps (a) may develop episodes of malignant hyperthermia (see p. 202) by 20 years of age iii. diagnostic testing (1) increased CK (2) muscle biopsy demonstrates (a) variable-sized muscle fibers with internalized nuclei (like myotonic dystrophy) (b) lucent central core on NADH staining particularly in type I muscle fibers (like facioscapulohumeral muscular dystrophy) (Fig. 10–13) iv. v.

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c.

treatment: avoid anesthetics and paralytic agents that can cause malignant hyperthermia prognosis: weakness is not progressive

Fukuyama congenital myopathy

Figure 10–13 Central core disease. (From Neudecker S. Klassifikation und benennung von myopathien. Psychoneuro 200, 29:86. Reprinted by permission.)

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pathophysiology: caused by a transpositional insertion into the fukutin gene, the protein of which may be necessary for proper extracellular glycosylation of the protein dystroglycan that is necessary for cell–cell adhesions (1) fukutin protein is highly expressed in the developing brain but is not apparently expressed in muscle (a) abnormal function of fukutin protein in the brain likely explains the frequently associated developmental abnormalities (polymicrogyria, lissencephaly, disruption of gray matter lamination, hypomyelination)

ii.

symptoms: onset  1 year of age (2) mental retardation, seizures, hydrocephalus (3) retinal hypoplasia

iii. diagnostic testing (1) neuroimaging of the brain exhibits multiple developmental abnormalities (2) muscle biopsy demonstrates internal nuclei, and disrupted and increased connective tissue

4.

iv.

treatment: none specific

v.

prognosis: death by 10 years of age

Congenital Myopathies

(1) hypotonia and weakness

Inherited metabolic diseases of the muscle a.

carnitine palmitoyl transferase deficiency i.

pathophysiology: autosomal recessive mutations of carnitine palmitoyl transferase that links fatty acids to carnitine for transportation into the mitochondria where they are oxidized

ii.

symptoms: fatigue and muscle pain developing well after the onset of exercise; episodes may present in childhood or adulthood

iii. diagnostic testing: significant myoglobinuria; increased respiratory exchange ratio ( expired [CO2]/inspired [O2]) at rest, reflecting the use of glucose for resting metabolism rather than fatty acids iv. b.

treatment: glucose intake during periods of exercise

McArdle’s disease i.

pathophysiology: autosomal recessive mutations in myophosphorylase, which cleaves glycogen into free glucose for glycolysis

ii.

symptoms: rapid-onset fatigue that can be overcome with continuing activity; muscle pain with forced muscle contraction or exercise; normal acute muscle strength and bulk

iii. diagnostic testing (1) mild myoglobinuria (2) EMG during ischemic contraction demonstrates no electrical activity (3) increased CK occur only with significant muscle contractions (4) minimal rise in serum lactate levels with anaerobic exercise iv. c.

treatment: none specific

phosphofructokinase deficiency i.

pathophysiology: caused by autosomal recessive mutations of phosphofructokinase, which phosphorylates fructose-6-phosphate prior to its cleavage into glyceraldehyde that then enters the Krebs cycle (1) the rate-limiting enzyme for metabolism of glucose for the Krebs cycle

ii.

symptoms: as per McArdle’s disease, although more severe; also hemolytic anemia

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V. Acquired Muscle Diseases 1.

Inclusion body myositis a.

b.

pathophysiology: likely an autoimmune reaction since CD8 T lymphocytes are found in affected muscles (Box 10.12) i.

associated with HLA-DR and –DQ

ii.

20% of cases occur in the setting of a monoclonal gammopathy (i.e., paraproteinemia)

symptoms: typically develops in patients  50 years of age

10 Diseases of the Muscles

i.

weakness of the lower extremities  upper extremities; the weakness spares the face, deltoids, and interossei muscles, but frequently involves the oropharyngeal muscles producing dysphagia (a characteristic pattern for this disease)

Box 10.12 Autoimmune diseases with myopathy— Mixed connective tissue disorders; scleroderma; lupus Myopathies with autoimmune diseases— Polymyositis (40%); inclusion body myopathy (15%)

(1) the weakness is atypical for a disease of the muscle because it (a) is asymmetric, to the degree that it appears to be focal (b) may be distal  proximal in 20% of cases c.

diagnostic testing i.

mildly increased CK

ii.

muscle biopsy demonstrates endomysial inflammation, rimmed vacuoles on Congo Red stain, and muscle fiber hypertrophy; myocytes demonstrates accumulations of -amyloid, transglutaminases, and ubiquitin as inclusion bodies (similar to the inclusions of Alzheimer’s disease) (Fig. 10–14)

iii. nerve conduction studies often demonstrate a subclinical sensorimotor neuropathy iv.

2.

elevated M protein levels (20%)

d.

treatment: none specific; IVIg has been proven ineffective, and glucocorticoids are likely ineffective

e.

prognosis: progressive weakness

Box 10.13

Dermatomyositis (Box 10.13) a.

pathophysiology: an inflammatory myopathy with multiple causes

b.

subtypes i.

childhood dermatomyositis (1) often exhibits a viral prodrome (Coxsackie B, parvovirus, echovirus); also associated with hepatitis B vaccination, growth hormone treatment, and excessive sun exposure (2) associated with HLA-DQ (90% of cases)

ii.

CKs in Diseases of the Muscle Really high CKs—Duchenne’s muscular dystrophy; autosomal recessive LGMDs; central core disease; glycogen storage diseases; acid maltase deficiency; hypothyroidism Surprisingly low CKs—childhood dermatomyositis; hyperthyroidism; rheumatologic diseases; glucocorticoid myopathy

adult dermatomyositis: may or may not have antibodies against the Mi-2 protein, which is a transcription regulatory factor (1) Mi-2 antibody-positive cases are highly associated with underlying malignancy, particularly advanced ovarian cancers (2) Mi-2 antibody-negative cases are associated with rheumatoid arthritis, scleroderma, and the CREST syndrome, also with an increased risk of underlying malignancy

c.

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symptoms i.

proximal muscle weakness and pain; dysphagia is common

ii.

erythematous, edematous rash predominantly on the face and eyelids, extensor joint surfaces, and neck {shawl sign}; the rash occurs in sunexposed areas {heliotrope rash} and is exacerbated by sun exposure

Figure 10–14 Inclusion body myositis. Rimmed inclusion bodies are demonstrated at the arrow. Courtesy of Dr. C. Yamada.

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iii. keratotic thickening of the skin on the extensor surfaces of the joints {Gottron’s papules} iv. d.

serositis and arrhythmias, in the adult Mi-2 antibody-negative subtype

diagnostic testing i.

increased CK ( 30-fold normal levels)

ii.

muscle biopsy demonstrates perivascular inflammation, atrophy around the perimysium, microvascular IgM and complement deposits, and necrosis and regeneration (Fig. 10–15) (1) adult Mi-2 antibody-positive subtype uniformly is antinuclear antibody (ANA-) positive (2) adult Mi-2 antibody-negative subtype often exhibit Jo-1 antibodies that target a t-RNA synthetase; these antibodies are fairly specific for inflammatory myopathies (polymyositis  dermatomyositis)

e.

Figure 10–15 Dermatomyositis. Note atrophy around the perimysium (arrow) and perivascular inflammation (double arrow). Courtesy of Dr. C. Yamada.

treatment i.

solumedrol acutely followed by prednisone tapered over several months or maintained chronically if needed

ii.

immunosuppressants: azathioprine, methotrexate

Acquired Muscle Diseases

iii. serology for the Mi-2 antibody

(1) all immunosuppressants typically have a 2–3-month delay before symptomatic improvement becomes evident iii. IVIg 3.

Polymyositis a.

pathophysiology: an inflammatory myopathy associated with autoimmune disorders (lupus, Sjögren’s syndrome, antiphospholipid antibody syndrome), hyperthyroidism, or underlying malignancy (10%)

b.

symptoms i.

symmetric proximal weakness, particularly of the oropharyngeal, posterior neck, and quadriceps muscles; involvement of the proximal third of the esophagus and the respiratory muscles is common

ii.

pain in affected muscles (20%)

iii. inflammatory cardiomyopathy producing arrhythmias c.

diagnostic testing i.

increased CK

ii.

antimyosin antibodies (90%)

iii. Jo-1 antibodies against the histidine t-RNA synthetase (95%)

d.

iv.

EMG demonstrates small-amplitude, shortduration MUPs; fibrillation potentials and sharp waves

v.

muscle biopsy demonstrates endomysial and perivascular monocytic inflammation, and necrosis with regeneration (Fig. 10–16)

treatment i.

glucocorticoids as per dermatomyositis

ii.

immunosuppressants: azathioprine, methotrexate, cyclosporine

iii. plasmapheresis, IVIg e. 4.

prognosis: progressive course over a period of several months

Isaac’s syndrome/neuromyotonia

Figure 10–16 Polymyositis. Note the intense perivascular and endomysial leukocyte infiltration. (From Gonzalez PP, Richter HW. Akute polymyositis under glatiramerazetat (copaxone). Aktuelle Neurologie 2001, 28: 392, Fig. 1. Reprinted by permission.)

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subtypes i.

paraneoplastic neuromyotonia: exhibits antibodies against voltagegated potassium (Box 10.14) channels and the nicotinic acetylcholine receptor that are located on peripheral nerves (Box 10.15)

Box 10.14 Antibodies against voltage-gated potassium channels are also seen in limbic encephalitis paraneoplastic syndrome

(1) associated with small cell lung cancer and lymphoma as well as myasthenia gravis ii.

10 Diseases of the Muscles

b.

neuromyotonia associated with human immunodeficiency virus (HIV) infection and penicillamine use

symptoms: onset typically  60 years of age; the severity of symptoms fluctuates with the patient’s level of physical activity i.

neuromyotonia: prolonged muscle contraction induced by physical stimulation

ii.

myokymia: rhythmic rippling of the muscles that is not sensitive to physical stimulation (e.g., percussion) as is myotonia

Box 10.15 Other diseases of potassium channels— Paraneoplastic limbic encephalitis; Hashimoto’s encephalopathy; Morvan syndrome ( Isaac’s syndrome  encephalopathy)

iii. stimulation-independent muscle cramping that may involve the face and oropharynx iv.

stiffness but little weakness (if any); normal reflexes

v.

abnormal limb posturing similar to dystonias

vi. hyperhidrosis vii. insomnia c.

diagnostic testing i.

EMG: shows spontaneous motor unit potentials, fasciculations, and myokymia and neuromyotonia potentials

ii.

nerve conduction studies demonstrates axonal motor neuropathy

iii. CK is not reliably elevated iv. d.

muscle biopsy: demonstrates type I fiber predominance and hypertrophy

treatment: antiepileptics (phenytoin, carbamazepine); plasmapheresis

VI. Channelopathies of Muscle 1.

Diseases of sodium channels a.

hyperkalemic periodic paralysis i.

pathophysiology: caused by mutations in a voltage-gated sodium channel (Box 10.16) that increase its open time and slow its inactivation once it is open, thereby allowing prolonged membrane depolarization (1) an increased extracellular potassium concentration depolarizes the cell and activates the abnormal channels, which then causes efflux of potassium from the cell that further depolarizes the cell and maintains the sodium channel in an open state (2) exhibits autosomal dominant inheritance with complete penetrance

ii.

symptoms: provoked by cold exposure, by resting after exercise, or by potassium-rich foods (e.g., fruit juices); attacks develop before 10 years of age (1) acute onset of symmetric proximal weakness that is generally less severe and of shorter duration than in hypokalemic periodic paralysis, but that occur more frequently than in hypokalemic periodic paralysis (2) myotonia (an uncommon feature)

iii. diagnostic testing: provoke an attack with oral potassium supplements or exercise (1) genetic testing (2) increased serum and urinary potassium during attacks

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(3) muscle biopsy demonstrates internalized nuclei and fibrosis

Box 10.16 Other mutations in the voltage-gated sodium channel cause paramyotonia congenita.

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treatment (1) avoid provocative stimuli, but during an attack (a) consume glucose, which drives cellular potassium uptake to be absorbed (b) administer intravenous calcium gluconate or sodium chloride (2) chronic prophylaxis with acetazolamide or thiazide diuretics

paramyotonia congenita i.

pathophysiology: caused by mutations in a voltage-gated sodium channel (the same one as in hyperkalemic periodic paralysis)

ii.

symptoms: stiffness provoked by cold exposure, exercise, or hypokalemia; severe cold exposure or strenuous exercise can also evoke weakness that outlasts the stiffness

Channelopathies of Muscle

b.

iii. diagnostic testing (1) EMG demonstrates fibrillation potentials or repetitive MUPs induced by cooling or exercise that disappears with further cooling or exercise (2) muscle biopsy demonstrates only variable-sized muscle fibers iv.

treatment (1) avoid provocative stimuli, but during attacks treat as hyperkalemic periodic paralysis (2) prophylaxis with mexiletine in severe cases

2.

Diseases of calcium channels a.

hypokalemic periodic paralysis i.

caused by (1) mutations in the L-type (dihydropyridine) voltage-gated calcium channel (Box 10.17) that excessively depolarizes the myocyte (a) voltage-gated calcium channel mutations are associated with reduced expression of voltage-gated sodium channels for unknown reasons

Box 10.17 Not the same as the ryanodine calcium channel, which is mutated in central core disease and malignant hyperthermia.

(b) exhibits autosomal dominant inheritance with incomplete penetrance particularly in women; onset of symptoms in early childhood (2) hyperthyroidism, which increases expression of the sodiumpotassium ATPase in muscle that would excessively hyperpolarize the myocyte; exhibits an autosomal dominant pattern of inheritance (3) hypokalemia from metabolic acidosis, hyperaldosteronism, or urine alkalinization ii.

symptoms: provoked by resting after exercise, carbohydrate consumption, or the use of aminergic agents or steroids (1) acute attacks involve soreness in back and thighs that progresses to the extremities; muscle swelling, firmness, and weakness then develop (a) episodes may last several hours, but have an acute onset and resolution (2) chronic symptoms: residual weakness following an acute attack accumulates to symptomatic level by 40 years of age

iii. diagnostic testing: potassium levels during an attack are not reliable for the diagnosis (1) muscle biopsy demonstrates vacuolation and tubular aggregates in the myocytes iv.

treatment (1) correct underlying hypokalemia-inducing disorders, if any (2) oral potassium supplementation

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Table 10–2 Comparison of Myotonic Conditions Myotonic dystrophy

Paramyotonia congenita

Myotonia congenita

Distribution of myotonia

Distal  proximal

Diffuse

Diffuse

Effect of repetitive stimulation

Mild decrement

No effect

Significant decrement

MUAP morphology

Myopathic changes

Normal

Normal

10 Diseases of the Muscles

(3) low sodium, low carbohydrate diet (4) spironolactone for prophylaxis; avoid acetazolamide unless a calcium channel mutation is known to be the cause 3.

Diseases of chloride channels a.

myotonia congenita/Thomsen’s disease (Table 10–2) i.

pathophysiology: caused by mutations in a chloride channel that decrease chloride conductance; the reduced chloride efflux during membrane depolarization allows accumulation of potassium in the T tubules, which induces repetitive membrane depolarizations by activation of the voltage-gated sodium channels (1) exhibits autosomal dominant inheritance

ii.

symptoms (1) muscle stiffness and myotonia that is pronounced after inactivity but that improves after exercise (2) normal strength and tone that temporarily decreases with exercise before returning to normal (3) muscle hypertrophy, in the autosomal recessive form

iii. diagnostic testing: EMG demonstrates myotonic discharges iv.

treatment: mexiletine; quinine; phenytoin

VII. Diseases of Absent Muscles (Table 10–3) Table 10–3 Diseases of Absent Muscles

248

Disease

Pathology

Mutation

Inheritance

Congenital fibrosis of extraocular muscles

Developmental absence of the superior division of CN III, causing bilateral atrophy of the levator palpebrae and superior rectus muscles; anomalous origins and insertions of the remaining muscles are common

Kinesin

Autosomal dominant

Duane’s syndrome

Absent or hypoplastic CN VI causes atrophy of lateral rectus muscle; may be bilateral

Chromosome 2, 8

Sporadic or autosomal dominant

Mobius syndrome

Absence or hypoplasia of the facial and/or abducens nuclei, usually bilateral; also may have hypoglossal palsy, dysarthria, dysphagia, irregular respiration, and/or hypoplasia of the lower extremities

Chromosome 1, 3, 10, 13

Autosomal dominant

Poland syndrome

Absence of the sternal head of the pectoralis muscle, possibly with absence of rotator cuff muscles; hand and spine deformations; dextrocardia

?

Sporadic

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11 Infections of the Nervous System Note: Significant diseases are indicated in bold and syndromes in italics.

I. Bacteria Bacterial meningitis a.

General symptoms: Only subtle behavioral changes may be apparent early in the disease course, but progression of the disease typically involves i.

fever, headache, meningismus, photophobia, somnolence

ii.

focal neurological dysfunction (15%), particularly hearing loss

Bacteria

1.

iii. seizures (20%) b.

general diagnostic testing i.

blood cultures identify causative pathogens in 50% of cases

ii.

cerebrospinal fluid analysis (1) increased intracranial pressure, protein, and lactate (2) decreased glucose (3) pleocytosis is typically  100 cells/L, and  60% neutrophils; may be lower early in disease course (4) Gram stain is positive in 60% (Box 11.1) (5) cultures identify causative pathogen in 75%

iii. neuroimaging: usually is normal, but it may demonstrate hydrocephalus, parenchymal edema, and/or meningeal enhancement; in complicated cases, venous thrombosis or collections of pus between the dura and arachnoid layers of the meninges {empyema} may develop c.

pathophysiology (Table 11–1)

d.

general treatment i.

Box 11.1 Yield of CSF Gram stain in bacterial meningitis is reduced only with  2 hour of antibiotic administration.

antibiotics, as in Table 11–1; adjust as the causative bacteria are identified (1) always use bactericidal agents, not bacteriostatic agents (2) meningeal inflammation makes the brain permeable to essentially all antibiotics

ii.

dexamethasone: reduces morbidity and mortality by 40% when used in children or adults with meningitis; give first dose prior to initiation of antibiotic therapy

iii. surgical drainage of any empyema, otitis media, or sinusitis iv.

e. 2.

prophylaxis with the Haemophilus influenza vaccine routinely in children, and with the Neisseria meningitidis vaccine in persons at high-risk for exposure

prognosis: 20% mortality; 40% of survivors will develop seizures

Brain abscess a.

pathophysiology: causes include i.

contiguous spread: the most common route for brain abscess formation; always results in a single abscess (Box 11.2)

Box 11.2 Metastic tumors more commonly spread to the brain by a hematogenous route

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Table 11–1 Common Causes of Bacterial Meningitis Patient group

Causative bacteria (in order)

Empiric treatment

Neonates

Group B Streptococcus

Ampicillin  third-generation cephalosporin

Escherichia coli

11 Infections of the Nervous System

Listeria monocytogenes Children, adolescents, young adults

Neissera meningitidis Streptoccus pneumoniae

Third-generation cephalosporin  vancomycin/rifampin

(H. influenza is rare due to vaccination) Older adults ( 50 years of age)

Neissera meningitidis

Immunosuppressed

Listeria monocytogenes

Listeria monocytogenes

Gram-negative bacilli Klebsiella Shunt infection

Staphylococcus epidermidis Staphylococcus aureus

Ampicillin  third-generation cephalosporin  vancomycin/ rifampin Ampicillin  third-generation cephalosporin  vancomycin/ rifampin Vancomycin  third-generation cephalosporin

(methacillin resistant) Head trauma

Staphylococcus epidermidis Staphylococcus aureus

Vancomycin  third-generation cephalosporin  metronidazole

Gram-negative bacilli anaerobic bacteria Note: Local flora and sensitivity patterns require consultation with an infectious diseases expert.

(1) the initial infection is located in a parameningeal site, such as (a) purulent sinusitis, which produces frontal lobe abscesses (b) otitis media or mastoiditis, which produce temporal lobe or cerebellar abscesses ii.

hematogenous spread: abscesses preferentially target areas of old brain injury (e.g., infarction), and are multiple in 15% of cases (Box 11.3) (1) in adults, hematogenous spread of bacteria is usually from a pulmonary infection or (less commonly) endocarditis (2) in children, hematogenous spread of bacteria is usually from some type of cyanotic congenital heart disease that provides a hypoxic environment and a right–left shunt thereby bypassing normal lung filtration

iii. head injury: closed head trauma is a rare cause of abscesses except in cases that involve unrepaired cerebrospinal fluid leaks

b.

c.

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d.

iv.

neurosurgery, usually in cases where an air sinus has been opened

v.

idiopathic (20%)

common pathogens: abscesses include multiple organisms in 90%, usually Streptococcus species (50%), Bacteroides, and Enterobacteriaceae and other anaerobic bacteria i.

abscesses from trauma also include multiple Staphylococcal species

ii.

abscesses in infants often include Gram-negative bacteria

symptoms: headache, nausea, and somnolence caused by increased intracranial pressure  focal neurological injury i.

increased intracranial pressure may enlarge the head circumference in infants

ii.

fever occurs in only 50% because the infection is isolated

diagnostic testing: ultimately requires tissue therapy

Box 11.3 Osler-Weber-Rendu syndrome/hereditary hemorrhagic telangiectasia—pulmonary arteriovenous fistulas bypass normal lung filtration; 5% of cases develop cerebral abscesses

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neuroimaging staging (1) early cerebritis (stage I): exhibits poorly demarcated ring enhancement that does not wash out and parenchymal edema (2) late cerebritis (stage II): exhibits a developing necrotic center (3) early encapsulation (stage III): exhibits a vascularized, necrotic center (4) late encapsulation (stage IV): exhibits a thin collagen capsule that enhances but then washes out; gliosis develops around capsule

ii.

diagnosis requires tissue biopsy

iii. blood cultures are rarely helpful; avoid lumbar puncture due to herniation risk treatment i.

medical treatment: most effective in neuroimaging stages I–II, before the development of an abscess capsule (1) empiric therapy: vancomycin  third-generation cephalosporin  metronidazole or chloramphenicol (2) glucocorticoids prevent fibrous encapsulation but also reduce penetration of antibiotics, therefore use only in patients who are clinically deteriorating

ii.

3.

surgical drainage in cases with mass effect, elevated intracranial pressure, poor neurological condition, or proximity of the abscess to a ventricle (i.e., to prevent ventriculitis)

Mycobacteria

e.

Bacterial encephalitis: an uncommon form of bacterial infection in the brain a.

Bartonella henselae/cat scratch disease i.

pathophysiology: a Gram-negative bacillus transmitted by scratches from a colonized cat and possibly by cat fleas

ii.

symptoms: fever; lymphadenopathy proximal to the scratch; encephalitis with seizures develops in only 1% of infected patients (1) may also cause myelitis and/or radiculitis in conjunction with angiomatous skin lesions that are similar to Kaposi’s sarcoma in the immunosuppressed

iii. diagnostic testing: B. henselae enzyme linked immunosorbent assay (ELISA) or polymerase chain reaction (PCR); cerebrospinal fluid is normal in 70% and otherwise shows only a mild lymphocytosis; cultures are unrevealing

4.

iv.

treatment: gentamicin or trimethoprim-sulfamethoxazole (TMP-SMX)

v.

prognosis: complete recovery in the immunocompetent

Bacterial vasculitis (see p. 77)

II. Mycobacteria 1.

Mycobacterium tuberculosis/tuberculosis a.

pathophysiology: transmitted from person to person by infected respiratory droplets; infection of the central nervous system may develop during the initial infection (usually pulmonary) or after reactivation of a dormant infection (as in the newly immunosuppressed) i.

Mycobacterium usually spread from a peripheral site of infection to the brain by a hematogenous route or rarely by rupture of a mass of infected granulation tissue {tubercles} into the cerebrospinal fluid; may form abscesses {tuberculomas} directly in brain parenchyma as well

ii.

target organs (1) pulmonary, lymphatic, genitourinary (2) bones and joints, including the vertebral bodies and intervertebral disks causing spondylosis {Pott’s disease} (3) meninges  brain parenchyma

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b.

epidemiology: neurological complications are most common in children  5 years of age and in the immunosuppressed HIV infection, glucocorticoid use, diabetics

c.

symptoms (neurological): neurological symptom from i.

11 Infections of the Nervous System

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meningitis, which has a relatively high rate of cranial neuropathy (25%, particularly CN VI  III, IV, VII) and the syndrome of inappropriate antidiuretic hormone secretion (SIADH) due to its preference for the basal meninges (1) seizures, focal deficits (15%), and hydrocephalus may also occur (2) can infect the spinal meninges, producing radicular and local back pain and an ascending paralysis {Foix-Alajouanine syndrome} (Box 11.4)

ii.

tuberculoma development (rare), which causes focal neurological injury

iii. vasculitis (see p. 77) d.

diagnostic testing: the diagnosis of tuberculosis infection in the brain is supported by identifying tuberculosis elsewhere in the body i.

for meningitis: cerebrospinal fluid demonstrates increased protein, low glucose, and a lymphocytic pleocytosis; immunosuppressed patients may not exhibit the pleocytosis (1) elevated total protein levels ( 100 mg/dL, often  1000) may form a web-like coagulant that is very characteristic of tuberculosis meningitis {Froin’s syndrome}; removal of the coagulant leaves a supernatant with a very low protein level (2) cerebrospinal fluid smear is positive in only 30%; acid-fast bacilli cultures are positive in 70%, but take 8 weeks to complete (3) M. tuberculosis PCR is positive in 75% (4) neuroimaging may demonstrate skull base meningeal enhancement

ii.

for tuberculoma (1) neuroimaging demonstrates one or more ring-enhancing lesion(s), either high or low density (2) tissue biopsy is required if the diagnosis of systemic tuberculosis cannot be made

e.

treatment i.

medical treatment: isoniazid  rifampin  pyrazinamide  ethambutol or streptomycin, typically continued for 6–9 months; optimal drug regimen depends upon local resistance patterns (1) may consolidate into a two-drug regimen if the patient is clinically improved after 2 months on the four-drug regimen; continue the two-drug regimen for 10 more months (2) vitamin B6 supplementation is necessary to prevent isoniazid neuropathy (3) glucocorticoids can be used to control tissue edema or Froin’s syndrome that can obstruct the arachnoid granulations and cause communicating hydrocephalus

ii.

surgical treatment (1) cerebrospinal fluid shunting for any signs of hydrocephalus (2) excision for tuberculomas that are causing symptomatic mass effect despite glucocorticoid therapy

f. 2.

Mycobacterium leprae/leprosy a.

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prognosis: uniformly fatal within 6 weeks if untreated; 20% mortality in the immunocompetent, 30% mortality in immunosuppressed pathophysiology: M. leprae is spread between persons by infected droplets, and it grows best at temperatures a few degrees below human body temperature; preferentially infects in the epineurium and perineurium of nerves of the extremities

Box 11.4 The Foix-Alajouanine syndrome is more commonly seen with spinal arteriovenous malformation (AVM) growth.

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symptoms: exhibits tuberculoid, intermediate, and lepromatous forms, that can occur in the same patient at different times depending upon the level of cellular immunity i.

tuberculous leprosy (in patients with strong cell-mediated immunity): a few skin nodules develop that are associated regions of sensory loss; palpable nerve hypertrophy

ii.

indeterminate leprosy: a single hypopigmented patch that has sensory loss (1) progresses to either tuberculous or lepromatous forms depending upon the effectiveness of the patient’s cell-mediated immunity

iii. lepromatous leprosy (in patients with poor cell-mediated immunity): multiple skin nodules with cartilage erosion in the nose and ears {leonine face deformity}; distal small-fiber sensory loss in the extremities, nose, and ears with palpable nerve hypertrophy (1) skin nodules are not initially associated with sensory loss, as they are in the tuberculous form of leprosy (2) weakness and arthropathy develop late in the disease course

d.

diagnostic testing i.

identifying bacterial particles in macrophages in skin biopsies, nasal mucosa, or nerve biopsies

ii.

lepromin skin test is useful for distinguishing between lepromatous and tuberculous forms of the disease, but is not useful in diagnosis because it is commonly negative in the lepromatous form

Spirochetes

c.

treatment: dapsone  clofazimine  rifampin; treat for 1 year in patients with indeterminate or tuberculous forms, or for 2 years in patients with lepromatous form i.

treatment often induces an erythema nodosum-like reaction upon initiation

III. Spirochetes 1.

Lyme disease a.

pathophysiology: caused by Borrelia burgdorferi in North American; ticks of Ixodes (Box 11.5) genus serve as the vectors and deer serve as the reservoir i.

the host reaction is largely directed against Borrelia outer-surface proteins (Osp), which are membrane lipoproteins encoded by 21 plasmids that have high antigenic variability, which may account for the organism’s prolonged infectious course

ii.

Borrelia preferentially invades meninges, nerve roots, and peripheral nerves, but only rarely brain parenchyma

b.

epidemiology: common in New England, Minnesota–Wisconsin, and the Pacific Northwest

c.

symptoms: 50% of infections are asymptomatic i.

stage 1 (acute infection): localized erythema migrans

ii.

stage 2 (within weeks): nonspecific flu-like symptoms or meningitis; heart block and myocarditis; arthritis

Box 11.5 Some Ixodes ticks also produce holocyclotoxin, causing tick paralysis.

iii. stage 3 (within months): mild sensory polyneuropathy; subtle cognitive disturbances occur in 5% of cases {Lyme encephalitis} (1) radiculoneuritis is prominent only with B. afzelii or B. garinii infection, which cause Lyme disease in Europe iv.

d.

“chronic” Lyme disease: similar to chronic fatigue syndrome and fibromyalgia, however, there is no clear evidence for its existence as a distinct disease entity

diagnostic testing: cerebrospinal fluid B. burgdorferi ELISA and Western blotting, or else positive blood serology in the presence of a consistent clinical syndrome i.

serum or cerebrospinal fluid Borrelia PCR is not sufficiently reliable

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treatment i.

prior to development of neurological symptoms: doxycycline for 14–21 days

ii.

with neurological symptoms: third-generation cephalosporin IV for 2–4 weeks

11 Infections of the Nervous System

iii. prophylaxis with the Lyme disease vaccine, an OspA adjuvant (1) single-dose doxycycline may prevent infection it administered within 72 hours of a tick bite 2.

Syphilis: Caused by Treponema pallidum a.

primary syphilis: the only symptom is a painless chancre that is acquired by contact with an actively infected site on another person (i.e., another chancre, mucous membrane or skin rash, condyloma lata) i.

b.

may exhibit asymptomatic central nervous system infection as documented by pleocytosis of the presence of spirochetes on dark field microscopy

secondary syphilis (Fig. 11–1) i.

symptoms (1) flu-like syndrome (2) rash with hyperkeratosis involving the palms and soles (3) condyloma lata, particularly during relapses

Figure 11–1 Stages of syphilis.

(4) meningitis in only 2% of cases, although 30% of secondary syphilis patients have an asymptomatic central nervous system infection ii.

diagnostic testing: cerebrospinal fluid evaluation by a Venereal Disease Research Laboratory (VDRL) test is specific but not sensitive, and cerebrospinal fluid fluorescent treponemal antibody (FTA) testing is sensitive but not specific; therefore, evaluate with a VDRL, but treat even if these tests are negative so long as there is pleocytosis or the presence of oligoclonal bands in a patient with a compatible clinical syndrome (1) baseline cerebrospinal fluid cell count, protein level, and VDRL titer should be obtained to compare with follow-up tests to assess the adequacy of treatment

iii. treatment: penicillin G 4  106 U IV q.4.h. for 14 days (1) to determine the adequacy of treatment, reexamine cerebrospinal fluid every 6 months for 3 years whereas successful treatment is defined as (a) reduction in the lymphocyte pleocytosis and protein level, which are the most sensitive and rapidly changing indicators of treatment efficacy (b) fourfold reduction in VDRL titer, which may take 1 year to achieve (2) repeated treatment is indicated if the cerebrospinal fluid studies fail to normalize or if symptoms persist (3) in penicillin-allergic patients, attempt penicillin desensitization or else use doxycycline for 4 weeks c.

latent syphilis: an asymptomatic central nervous system infection that can be demonstrated in 40% of cases i.

diagnostic testing: as above; obtain baseline cerebrospinal fluid studies to assess adequacy of treatment, as per secondary syphilis

ii.

treatment: penicillin G as described above (1) reexamine the cerebrospinal fluid every 6 months for 3 years to determine adequacy of treatment, as per secondary syphilis

d.

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tertiary syphilis: aortitis, iritis, and painless granulomatous nodules {gummas} that may develop in numerous organ systems; neurological symptoms include i.

meningitis

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meningovascular neurosyphilis, involving arteries of all sizes and causing strokes typically in the MCA distribution (see p. 77) (1) diagnosis and treatment as per secondary syphilis

iii. parenchymatous neurosyphilis: develop years to decades after primary syphilis (1) tabes dorsalis: inflammatory destruction of the lumbosacral dorsal root ganglia with subsequent loss of spinal sensory pathways (a) symptoms: begin after a period of meningitis (i)

episodic pain in the lower extremities, or in the abdomen and thorax {visceral crises}

(ii) vision loss from optic atrophy (iii) ataxia, areflexia, Charcot joints, and trophic ulcers from large-fiber sensory loss (iv) insensitivity to pain, overflow incontinence, constipation, and sexual dysfunction from small-fiber sensory loss

Rickettsia

(v) small, irregular pupils that accommodate but do not react to light {Argyll-Robertson pupil}; involves an unknown injury in the light reflex circuit (b) diagnosis and treatment as per secondary syphilis (2) general paresis: an encephalitic infection (a) symptoms (i)

personality changes

(ii)

affect abnormalities

(iii) reflex abnormalities (generally hyperreflexic) (iv) eye: Argyll-Robertson pupils (v)

sensorium: illusions, delusions, hallucinations

(vi) intellectual dysfunction  progressive dementia (vii) speech  dysarthria (b) diagnosis and treatment as per secondary syphilis

IV. Rickettsia 1.

Rocky Mountain spotted fever a.

pathophysiology: caused by Rickettsia rickettsii; Dermacentor (Box 11.6) ticks serve as the vector, and rodents and dogs serve as the reservoir i.

b.

symptoms: rash beginning on the ankles (Box 11.7); meningitis with focal neurological signs (15%) and seizures (5%)

c.

diagnostic testing: immunofluorescence or immunoperoxidase staining of skin biopsy from the rash site; R. rickettsii serology i.

2.

epidemiology: predominant in the north and east United States, Canada, and Mexico

Box 11.6 Dermacentor also carries Colorado tick fever virus.

Box 11.7 Other types of meningitis with petechial rash: N. meningitidis, S. pneumoniae, S. aureus

cerebrospinal fluid analysis is nondiagnostic

d.

treatment: tetracycline or doxycycline continued until 2 days after the fever ends

e.

prognosis: 20% mortality if treatment is delayed

Typhus a.

pathophysiology: caused by Rickettsia prowazekii, which is transmitted from human to human by lice; epidemic typhus occurs in overcrowded and unsanitary conditions during cold weather

b.

symptoms: rash beginning in the axilla; meningitis  focal neurological injury

c.

diagnostic testing: R. prowazekii ELISA, PCR, or agglutination tests

d.

treatment: tetracycline or doxycycline; vaccination for persons at exposure risk

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V. Viruses 1.

Herpes viruses a.

herpes simplex (HSV) type I and II

11 Infections of the Nervous System

i.

pathophysiology: causes hemorrhagic necrosis of the temporal lobes that is histologically characterized by large, solitary nuclear inclusions surrounded by a halo in neurons, astrocytes, and oligodendroglia {Cowdry type A inclusions} (Fig. 11–2) and by Alzheimer’s disease-like neurofibrillary tangles (1) acquired by person-toperson transmission of contaminated body fluids, but most herpes encephalitis is likely caused by a reactivation of latent infection of the trigeminal nerve (not by primary infection)

Figure 11–2 Cowdry type A inclusions (arrows). (From Hirano A. Color Atlas of Pathology of the Nervous System, 2nd Ed. Tokyo/New York: Igaku-Shoin Press; 1988:219, Fig. 550. Reprinted by permission.)

(2) viral subtypes (a) HSV-1: causes oral herpes and encephalitis (b) HSV-2: causes genital herpes and neonatal encephalitis occurring within a week of birth ii.

symptoms: encephalitis that is often, but not always, acute in onset; slowly progressive cases may present only with personality changes (1) seizure and focal neurological injury occur in 50% of cases

iii. diagnostic testing: cerebrospinal fluid may be frankly hemorrhagic, and the inflammatory leukocytosis is often not proportionate to the clinical severity (1) diagnosis requires HSV PCR, which can be serially evaluated to determine the effectiveness of treatment

b.

iv.

treatment: acyclovir 10 mg/kg IV q.8.hr. for 14 days; side effects include reversible renal failure

v.

prognosis: 70% mortality untreated; 20% mortality treated

varicella zoster virus: types of infections include i.

chickenpox:  1% develop a self-limited encephalitis at the time of the rash; a transient meningitis-like syndrome with ataxia may develop  3 weeks after the rash

ii.

herpes zoster/shingles: local reactivation of varicella infection in an infected dorsal root ganglia causes lymphocytic infiltration and local hemorrhage in the dorsal root ganglia and spinal roots; reactivation has been related to spinal trauma and immunosuppression, but often it just occurs spontaneously (1) symptoms: pain and paresthesias in spinal or cranial dermatomes followed by a pruritic vesicular rash that develops within 3–4 days and crusts by 10 days; usually resolves within 2 weeks (Box 11.8) (a) location: usually limited to 1–2 adjacent dermatomes in the thoracic  cervical  lumbosacral region (i)

256

20% of cases have a cranial nerve distribution (1) herpes zoster ophthalmicus: viral reactivation in the ophthalmic division of CN V causes conjunctivitis, keratitis, and uveitis, but rarely causes vision loss

Box 11.8 Post-Herpetic Neuralgia ✧ Common in shingles patients  50 years

of age who had sensory symptoms prior to rash ✧ Symptoms include various pains, dysesthesia, and allodynia in the previously affected region ✧ Develops 1–6 months after resolution of the rash and lasting several months ✧ Treat with gabapentin, topical lidocaine or capsaicin, or amitriptyline

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(2) Ramsay-Hunt syndrome/otic zoster: viral reactivation in the geniculate ganglion of CN VII causes facial paresis and rash on the tympanic membrane and external auditory canal (a) associated with a large-vessel vasculitis (b) flaccid weakness develops in 5%, likely because the infection has involved the ventral root and spinal cord (c) zoster sine herpete: radicular pain without rash; requires demonstration of varicella in the cerebrospinal fluid by PCR analysis or an increased ratio of cerebrospinal fluid-to-serum varicellazoster virus (VZV) titres (2) treatment: acyclovir, famciclovir, valacyclovir for 7 days, started within 3 days of symptom onset; glucocorticoids for 3 weeks

c.

cytomegalovirus (CMV) i.

histology: Cowdry type A inclusions are found in ependymal cells  neurons, glia

ii.

types of infection (1) in utero infection: symptoms include retinitis and encephalitis, leading to vision loss, deafness, and mental retardation; cerebral calcifications, microcephaly, and migrational defects (lissencephaly/ pachygyria, polymicrogyria, cerebellar agenesis) can occur even without signs of systemic infection

Box 11.9 Reye’s Syndrome ✧ A pediatric encephalopathy from cere-

bral edema and elevated ammonia levels caused by rapid liver failure with fatty infiltration of the liver ✧ Induced by aspirin use during several types of viral infections, including varicella and influenza

Viruses

iii. varicella encephalitis: dissemination to the brain occurs in 2% of immunocompetent patients and 50% of immunosuppressed patients who develop shingles; treat with acyclovir (Box 11.9)

(2) infection in the immunosuppressed (e.g., HIV, following bone marrow transplantation): usually spreads to the brain by a hematogenous route (causing encephalitis) or by direct spread through the cerebrospinal fluid (causing ventriculoencephalitis); often occurs with CMV retinitis, esophagitis, or colitis, and CMV viremia is invariably present (a) symptoms: confusional state developing over weeks (encephalitis) or days (ventriculoencephalitis); cranial nerve palsies, nystagmus, hydrocephalus (b) prognosis: usually fatal within a few months iii. diagnostic testing: demonstration of CMV by PCR in the cerebrospinal fluid iv. 2.

treatment: ganciclovir, foscarnet, cidofovir

Rabies virus a.

pathophysiology: viral inoculation occurs after a bite from an infected animal (dog, cat, fox, raccoon, bat); retrograde and transsynaptic transport carries the virus up the peripheral nerves and into the central nervous system (i.e., to the brain producing an encephalitic disease, or to the spinal cord producing a paralytic disease) i.

b.

histology: characterized by microglial nodules {Babes nodes}, perivascular inflammation, and viral inclusions in the cytoplasm of Purkinje cells and hippocampal pyramidal cells {negri bodies} that appear as bullet-shaped particles on electron microscopy (Fig. 11–3)

symptoms: begins several days to weeks after the inoculating bite as a flulike syndrome that progresses to either i.

an encephalitic form, involving behavioral changes (agitation, hyperactivity), severe dysphagia producing frothing, and eventually seizures and psychosis before death (1) hydrophobia is likely due to the inability to swallow

ii.

a paralytic form, which develops over a period of days leading to death

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11 Infections of the Nervous System

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A

B

Figure 11–3 Pathological findings of rabies. (A) Negri body (arrows). (B) Babes nodules (arrows). Courtesy of Dr. C. Yamada and the Centers for Disease Control.

3.

c.

diagnostic testing: histological evaluation of the brains of the infected animal for viral particles; observe apparently healthy animals for 10 days after the bite to ensure they are not infected

d.

treatment i.

wound cleansing specifically with benzyl ammonium chloride

ii.

postexposure treatment and prophylaxis with the human diploid cell vaccine and local injection of rabies immunoglobulin

Arboviruses (Table 11–2) a.

general pathophysiology: carried by arthropods (ticks, mosquitoes); all exhibit an epidemic pattern in the summer

b.

general symptoms: a flu-like syndrome followed in some cases by meningitis or encephalitis

c.

treatment: none proven; may treat West Nile virus (WNV) with ribavirin, interferon, or WNV immunoglobulin, although these are of unproven value

Table 11–2 Arboviruses

258

Arbovirus

Region

Vector/reservoir

Notes

West Nile

Entire US and Canada

Mosquito/birds

10% mortality; 20% incidence of focal neurological injury (e.g., poliomyelitis)

St. Louis encephalitis

North and South America

Mosquito/birds

Slow development, occasionally fatal; rarely causes focal neurological injury

California-LaCross encephalitis

Midwest US

Mosquito/many mammals

Frequently causes seizures that develop into epilepsy (10% of cases) but rarely causes focal neurological injury

Eastern equine encephalitis

Eastern US

Mosquito/birds

60% mortality; neuroimaging may show focal lesions in the basal ganglia and thalamus; exhibits simultaneous epidemics in horses

Western equine encephalitis

Northern US and Canada

Mosquito/birds

10% mortality

Box 11.10

Colorado tick fever

Western US

TIck (Dermacentor)/ Box 11.10) rodents (B

Infected ticks live only at high altitudes

Dermacentor also carries Rickettsia rickettsii, which causes Rocky Mountain spotted fever.

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Polio viruses and polio-related syndromes a.

polio: commonly caused by one major (i.e., poliovirus) and several minor enteroviruses that directly infect the anterior horn lower motoneurons, causing their death; polio has been largely eradicated by vaccination i.

symptoms: developed 2–5 days after viral gastroenteritis with asymmetric and focal myalgias, fasciculations, and weakness in the lower extremity  upper extremity  bulbar muscles

ii.

epidemiology: risk increased with age into young adulthood

iii. diagnostic testing: stool cultures for poliovirus

5.

treatment: prophylaxis with inactivated polio vaccine, which is routine in children

v.

prognosis: significant improvement occurred in 80% after the acute illness

polio-related syndromes i.

postvaccination polio: caused by oral polio vaccine use, which was a live-attenuated virus that is no longer in use in the US; occurred in 0.04 per 100,000 vaccinations

ii.

postpolio syndrome: progressive weakness beginning at least 10 years after polio that occurs in the previously affected musculature; a dubious disease entity that may reflect normal age-related loss of lower motoneurons

JC virus/progressive multifocal leukoencephalopathy (PML) a.

pathophysiology: a polyoma virus infection of oligodendroglia and astrocytes that causes cell death and demyelination; usually occurs in immunosuppressed patients after reactivation of a latent infection

b.

histology: “ground glass” intranuclear inclusions in oligodendroglia; spheres and elongated rods (“spaghetti and meatballs”) on electron microscopy

c.

symptoms: focal neurological injury with dementia progressing over months

d.

diagnostic testing: identification of JC virus in cerebrospinal fluid by PCR i.

6.

Viruses

b.

iv.

neuroimaging demonstrates multiple nonenhancing areas of decreased T1 and increased T2 signal without mass effect or edema; begin as small lesions that eventually form large confluent lesions

e.

treatment: none specific against the JC virus, but reversing an immunosuppressed state (e.g., highly active antiretroviral therapy (HAART) therapy in HIV patients) may improve the symptoms

f.

prognosis: 4-month survival, but 10% exhibit spontaneous remission

Measles virus a.

general pathophysiology: histologically characterized by Cowdry type A inclusion bodies in neurons and glia, and multinucleated giant cells

b.

types of infection i.

acute self-limited encephalitis, associated with the rash

ii.

measles inclusion body encephalitis: occurs in immunosuppressed patients several months after measles infection (1) symptoms: rapidly-progressive dementia, seizures, and myoclonus progressing to coma (2) treatment: reverse immunosuppressed state, if possible

iii. subacute sclerosing panencephalitis: a post-infection complication caused by abnormal assembly of the measles virus particles in the infected cells, leading to viral particle accumulation and transmission only at sites of cell–cell contact; develops in children several years after the viral rash

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(1) symptoms: behavioral changes progressing slowly to dementia and ultimately to coma; myoclonus; seizures; chorea; ataxia (2) specific diagnostic testing: EEG demonstrates reduced background activity with generalized slow wave complexes occurring regularly every 5–10 seconds (Fig. 11–4) (3) treatment: intrathecal  systemic interferon may be helpful (4) prognosis: death within a few years

7.

c.

general diagnosis: high measles antibody titres in the cerebrospinal fluid; neurological infections do not involve pleocytosis

d.

general treatment: prophylaxis with the measles vaccine given routinely to infants

Human immunodeficiency virus (HIV) (Table 11–3) a.

pathophysiology: infects monocytes, T lymphocytes, and microglia by binding to CD4 and a chemokine receptor with the viral gp120 glycoprotein; direct infection of neurons and oligodendroglia does not appear to occur, despite neuron apoptosis and myelin loss that is likely due to the actions of proinflammatory cytokines i.

b.

asymptomatic cerebrospinal fluid abnormalities occur throughout the course of HIV infection, typically protein  45 but  100, lymphocytic pleocytosis  25, and presence of anti-HIV IgG

treatment of HIV infection: HAART, which is a combination of three or more antiretroviral medications i.

d.

histology: reactive gliosis diffusely distributed throughout the brain parenchyma

general diagnostic testing: blood HIV ELISA with confirmatory Western blot, which may take 4–8 weeks from the time of infection to turn positive i.

c.

Figure 11–4 Subacute sclerosing panencephalitis. (From McKhann GM et al. Q&A Color Review of Clinical Neurology and Neurosurgery. Stuttgart, Germany: Georg Thieme; 2003:19, Fig. 9. Reprinted by permission.)

side effects of antiretroviral medications include neuropathy (didanosine, zalcitabine, stavudine), myopathy (zidovudine), and oral paresthesias (ritonavir)

direct effects of HIV infection i.

HIV encephalitis/AIDS dementia complex—occurs in  1% with CD4  500, 7% with CD4  100 (1) pathophysiology: perivascular inflammation with multinucleated giant cells and reactive gliosis that may ultimately produce diffuse cerebral atrophy (2) symptoms: develop over months

Table 11–3 Manifestations of Human Immunodeficiency Virus (HIV) Infection Related to CD4 Count

260

CD4

Direct effects of HIV

Opportunistic

500

Distal sensory polyneuropathy

200–500

Dementia

VZV radiculitis (shingles)

100–200

Myelopathy

Progressive multifocal leukoencephalopathy

 100

Toxoplasma, Cryptococcus

 50

Lymphoma, CMV

Abbreviations: CMV, cytomegalovirus, VZV, varicella-zoster virus.

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(a) subcortical dementia: impaired concentration, memory loss, apathy (b) psychosis (10%) (c) bradykinesia; hyperreflexia and spasticity (3) diagnostic testing (a) neuroimaging: MRI demonstrates diffuse high white matter signal on T2; late in the disease diffuse atrophy becomes apparent (b) cerebrospinal fluid demonstrates increased protein, lymphocytosis, and elevated markers of lymphocyte and macrophage activation (e.g., 2 microglobulin, quinolinic acid) (4) treatment: high-dose zidovudine, which can be a component of HAART ii.

vacuolar myelopathy: symptoms include spastic weakness, loss of large-fiber sensation (particularly proprioception), and incontinence developing over a period of months, caused by degeneration of posterior and lateral spinal cord columns (1) unlikely caused directly by HIV infection, instead may be related to impairment of vitamin B12 utilization

iii. distal sensory polyneuropathy: symmetric sensory  motor, rarely painful (Box 11.11) (1) epidemiology: develops in 30% of AIDS patients iv.

HIV myopathy: can develop at any CD4 count; histologically is a poorly defined condition because of coincident myopathy from antiretroviral medications (particularly zidovudine) and from cachexia

Box 11.11

Viruses

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(1) symptoms: proximal  distal weakness, muscle soreness (2) diagnostic testing: normal or increased baseline CK that is greatly increased by exercise v.

stroke: may be caused by HIV vasculitis, induced protein C and S deficiency, antithrombin III deficiency, or antiphospholipid antibody syndrome (1) vasculitis can also be caused by cytomegalovirus, varicella, tuberculosis, or syphilis coinfection

e.

opportunistic diseases with focal findings (Box 11.12) i.

toxoplasmosis: caused by Toxoplasma carinii (see p. 264) (1) epidemiology: develops in 10% of AIDS patients (2) symptoms: focal symptoms and encephalopathy  fever  headache developing over days to weeks (3) diagnostic testing (a) neuroimaging: usually exhibits multiple ring-enhancing lesions with mass effect, most commonly at the gray–white junction or basal ganglia (i)

70% of cases have multiple lesions

(ii) negative Toxoplasma IgG titers suggests the lesions are lymphoma (iii) repeat neuroimaging after antibiotic treatment for 10 days to determine if the lesions have been reduced in size; avoid glucocorticoids unless the mass is inducing herniation as they will reduce both infectious and cancerous lesions

Box 11.12 Brain Lesion Management in AIDS 1. Acute empiric treatment for toxoplasmosis except in cases of negative serologic studies ✧ Evaluate for radiographic shrinkage within 10 days ✧ Continue toxoplasmosis treatment indefinitely if the lesions are shrinking 2. Lesions with negative toxoplasmosis serology are an indication for brain biopsy 3. SPECT or PET suggests primary CNS lymphoma, which still requires brain biopsy confirmation 4. Immediately brain biopsy in children with AIDS and lesions

(4) treatment (a) acute: pyrimethamine  sulfadiazine or clindamycin  folate (b) prophylactic: TMP-SMX or dapsone (5) prognosis: 90% of patients respond to treatment

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primary CNS lymphoma (1) epidemiology: develops in 5% of AIDS patients (2) histology: lymphoma is of the non-Hodgkin B-cell type and it always is related to transformation by the Epstein-Barr virus

11 Infections of the Nervous System

(3) symptoms: focal neurological injury (usually multiple), encephalopathy, and headache developing over weeks; symptoms are less severe than those of toxoplasmosis (4) diagnostic testing (a) neuroimaging: usually one or a few ring-enhancing lesions with mass effect, most commonly in the periventricular region or corpus callosum; lesions do not shrink after 10 days of antibiotics (b) thallium201 SPECT or fluoro-2-deoxyglucose (FDG)- PET scanning shows label uptake (c) cerebrospinal fluid cytology is usually negative, but markers of lymphocyte activity (2-microglobulin, lactate dehydrogenase) are usually increased (d) tissue biopsy is ultimately required for diagnosis (5) treatment: irradiation, particularly with the gamma knife; chemotherapy cannot usually be tolerated (6) prognosis: 1-month survival untreated; 6-month survival with conformal radiation therapy (XRT) iii. progressive multifocal leukoencephalopathy (see p. 259) caused by the JC virus, occurring in 5% of AIDS patients f.

opportunistic diseases with minimal focal findings i.

cytomegalovirus (see p. 257)

ii.

meningitis, caused by (1) Cryptococcus (see p. 263) occurs in 10% of AIDS patients, usually with CD4  200; 30% acute mortality; outcome is proportionate to Cryptococcus antigen titer and low level of CSF pleocytosis (2) syphilis (see p. 254): rate of neurosyphilis is not affected by HIV infection, although it generally develops faster; cerebrospinal fluid examination for syphilis is required even without clinical evidence of neurosyphilis (3) tuberculosis (see p. 252): in HIV infected patients, there is an increased risk of developing tuberculous meningitis (10% overall incidence) but there does not appear to be a worse outcome from the disease (4) bacteria: Listeria monocytogenes, Gram-negative bacilli (5) cancer (carcinomatous meningitis, see p. 131), particularly from systemic lymphoma

VI. Fungus

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1.

General fungal pathophysiology: most are initially respiratory infectious processes that enter the CNS via hematogenous spread

2.

General symptoms: all can present as acute, subacute, or chronic meningitis; focal neurological

Figure 11–5 Aspergillus centered about a small parenchymal vessel. Courtesy of Dr. C. Yamada.

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signs can be indicative of abscess formation, but may also be part of subacute-chronic meningitis (e.g., cranial nerve palsies) vision loss may occur from an elevated intracranial pressure

3.

General diagnosis: fungal stain is positive in 50% or less of cases, depending upon the fungus

4.

Types of fungi a.

b.

Aspergillus—invades blood vessels in the brain (Fig. 11–5), leading to a necrotizing vasculitis, thrombosis, and/or granulomatous inflammation; forms abscesses more commonly than meningitis, particularly around the ependymal region (Fig. 11–6) i.

epidemiology: common in postsurgical/post-head trauma patients

ii.

specific diagnostic testing: Aspergillus PCR

Cryptococcus—found in bird droppings and soil, which is subsequently inhaled; can also directly colonize human skin i.

epidemiology: can infect the immunocompetent, but more commonly infects HIV patients and chronic glucocorticoid users

ii.

causes meningitic that form involves granulomas with multinucleated giant cells  5-mm diameter, similar to tubercular meningitis (1) 50% of cases develop small groups of intraparenchymal cysts that represent cryptococcal abscesses {cryptococcoma}

Figure 11–6 Cerebral aspergilliosis with cerebral and ependymal lesions on MRI. (From McKhann GM et al. Q&A Color Review of Clinical Neurology and Neurosurgery. Stuttgart, Germany: Georg Thieme; 2003:115, Fig. 112. Reprinted by permission.)

Fungus

a.

iii. specific diagnostic testing (1) Cryptococcus antigen latex agglutination test is positive in the cerebrospinal fluid of  90% of meningitis cases; in HIV patients, a negative serum cryptococcal antigen testing is sufficient to rule out the diagnosis of Cryptococcus meningitis (2) India ink stain may demonstrate encapsulated organisms (Fig. 11–7) c.

Coccidioides sp., Histoplasma sp.: cause chronic meningitis

Figure 11–7 Encapsulated Cryptococcus. (From Citow JS et al. Neuropathology and neuroradiology: a review. Stuttgart, Germany: Georg Thieme; 2001:28, Fig. 29. Reprinted by permission.)

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VII. Parasites 1.

Protozoans a.

amebiasis: cause hemorrhagic encephalitis i.

Acanthamoeba/Balamuthia—infects the lower respiratory tract and skin

ii.

Naegleria—initially infects the nasal cavity, then spreads to the brain via the cribriform plate

11 Infections of the Nervous System

iii. Entamoeba—transmission is human to human via reservoirs of food or water; commonly infects the GI tract or liver b.

toxoplasmosis (Toxoplasma carinii)—ingested cysts develop into larva in the intestines and disseminate hematogenously to the brain (causing encephalitis and focal mass lesions), eye (causing chorioretinitis), heart and muscle; can be transmitted from reservoir animals (birds, cats) directly or across the placenta i.

diagnostic testing: Toxoplasma antibodies or PCR on cerebrospinal fluid

ii.

treatment: pyrimethamine  sulfadiazine or clindamycin (1) prevent fetal infection by avoiding risk factors (e.g., cleaning cat boxes) in seronegative pregnant women, particularly during the first trimester when the complications of infection to the neonate are most severe (2) treat acutely infected pregnant women with sulfadiazine; may also use pyrimethamine after the first trimester

c.

malaria (Plasmodium falciparum)—parasite-infected erythrocytes aggregate and cause capillary and small vein obstruction and vascular congestion, producing the characteristicly swollen “slate gray” brain on autopsy i.

symptoms: develop after a 12-day period of a flu-like syndrome that involves periodic (approximately q.3.day) attacks of shaking chills, high fever, and diaphoresis, as well as hepatosplenomegaly (1) cerebral malaria: develops in 1% of cases, usually within 2 weeks of the initial infection in adults but may develop as rapidly as 1 day in children (a) symptoms include encephalopathy, seizures, and meningismus; focal neurological injury is common

ii.

diagnostic testing (1) ring-shaped trophozoites in erythrocytes on blood smear (2) cerebrospinal fluid demonstrates increased intracranial pressure, elevated protein, and a lymphocytosis  50

A

(3) neuroimaging demonstrates diffuse cerebral edema iii. treatment: quinine; artemether for multidrug resistant Plasmodium falciparum; transfusion for severe anemia (1) do not use glucocorticoids as they worsen outcome iv.

prognosis: cerebral malaria is lethal within 3 days if untreated (1) postmalaria syndromes (a) delayed-onset coma, which develops within 2 days of recovery from cerebral malaria; recovery is variable (b) delayed-onset psychosis

2.

Metazoans: Cause cystic mass lesions in the brain parenchyma, ventricles, or subarachnoid spaces; the death of the organism leads to an intense local inflammatory response that can exacerbate symptoms up to 30 years after the initial infection a.

cysticercosis (Taenia solium; pig tapeworm)—acquired by eating poorly cooked pork or by fecal-oral transmission; ingested eggs hatch in GI tract, migrate to brain, eye, and muscle i.

diagnostic testing: Taenia ELISA; neuroimaging demonstrates multiple cystic mass lesions with a visible scolex (Fig. 11–8)

ii.

treatment: albendazole or praziquantel

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B Figure 11–8 Neurocysticercosis. (A) T1 posgadolinium. (B) FLAIR demonstrating the scolex (arrow). (From McKhann GM et al. Q&A Color Review of Clinical Neurology and Neurosurgery. Stuttgart, Germany: Georg Thieme; 2003:79, Fig. 70b, Fig, 70c. Reprinted by permission.)

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echinococcosis/hydatid disease (Echinococcus)—acquired by eating poorly cooked meat from several types of animals or by fecal-oral transmission; ingested eggs hatch in GI tract, migrate to brain, spinal cord {hydatid Pott’s disease}, liver, and lung i.

diagnostic testing: neuroimaging demonstrates parasite cysts

ii.

treatment: surgery after cyst reduction with albendazole; if unresectable, use prolonged albendazole treatment

A

1.

General pathophysiology: caused by a toxic gain-of-function that is associated with a conformational change in the prion protein (PrP), which is a membrane-bound glycoprotein that may be involved in copper metabolism a.

abnormal PrP is resistant to denaturation and proteases, and can induce the toxic conformational change in native PrP

b.

general histology: prion diseases involve spongiform degeneration of the gray matter that is caused by the loss of neurons (Fig. 11–9); affected brain parenchyma does not have inflammatory changes but may have a reactive gliosis, depending upon the specific prion disease i.

2.

B

Prion Diseases

VIII. Prion Diseases

spongiform changes are not unique to prion diseases, and can be observed in Alzheimer’s, Pick’s, and Lewy body dementias, and in certain aminoacidopathies

Types of prion diseases a.

idiopathic prion diseases i.

sporadic Creutzfeldt-Jakob (sCJD) disease—accounts for 80% of CJD; typically occurs in older patients (average age of onset  65 years of age) (1) symptoms: rapidly progressive myoclonus and dementia; average 4-month duration of symptoms at time of diagnosis (2) diagnostic testing: EEG demonstrates periodic sharp waves (Fig. 11–10)

C Figure 11–9 (A) Spongiform vacuolation. (B) Multicentric plaques of Gerstmann-Straussler-Scheinker disease. (C) florid plaques of vCJD. (From Mastrianni JA, Roos RP. The prion diseases. Semin Neurol 2000,20:343, Fig. 3a, Fig, 3c, Fig, 3d. Reprinted by permission.)

Figure 11–10 Development of EEG abnormalities in Creutzfeldt-Jakob disease. Within 2 months of symptomatic onset, periodic activity is evident and it becomes dominant within 1 month. Gradual attenuation develops thereafter. (From Mumenthaler M, Neurology. 3rd ed. Stuttgart, Germany: Georg Thieme; 1990:170, Fig. 1.23. Reprinted by permission.)

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familial/inherited prion diseases i.

inherited Creutzfeldt-Jakob disease—accounts for 15% of all CJD; symptomatic onset is typically less than 60 years of age, but there is still an increasing incidence with advanced age (1) pathophysiology: caused by mutation of the PrP gene on chromosome 20; exhibits autosomal dominant inheritance (2) symptoms: as per sCJD

11 Infections of the Nervous System

(3) diagnostic testing: as per sCJD ii.

fatal familial insomnia (1) pathophysiology: degeneration occurs predominantly in the anterior and mediodorsal thalamus with pronounced gliosis and minimal spongiform degeneration (2) symptoms: onset between 30–40 years of age (a) insomnia, fatigue (b) anorexia (c) hallucinations; stupor progressing to coma (d) ataxia, dysarthria (e) sympathetic hyperactivity (3) diagnostic testing: cerebrospinal fluid is reliably negative for 14-3-3 protein, and neuroimaging is normal (a) polysomnography demonstrates absent rapid eye movement (REM) and slow-wave sleep stages (b) PET scan shows reduced blood flow in thalamus

iii. Gerstmann-Straussler-Scheinker disease (1) histology: Alzheimer-like amyloid plaques and kuru-type plaques in cerebellum  cerebrum, brainstem; relatively little spongiform degeneration (2) symptoms: onset between 50–60 years of age; symptoms are progressive over a period of years (a) limb and trunk ataxia (b) dementia, delirium c.

infectious prion diseases (Box 11.13) i.

variant Creutzfeldt-Jakob (vCJD) disease/transmissible spongiform encephalopathy/mad cow disease (1) specific histology: spongiform changes occur in the basal ganglia and thalamus; PrP aggregates into dense cores with halos in the cerebrum and cerebellum that are surrounded by spongiform change {florid plaques} (Fig. 11–9C) (2) symptoms: onset between 20–30 years of age, with a relatively slow course compared with other CJD subtypes (a) psychiatric disorders: anxiety, insomnia (b) dysesthesias (c) gait ataxia, dysarthria, tremor; chorea; myoclonus (d) dementia (3) diagnostic testing (a) EEG does not demonstrate periodic complexes as it does in sporadic or inherited CJD (b) cerebrospinal fluid demonstrates 14–3-3 protein in 50% of cases (c) neuroimaging: increased T2 signal in posterior thalamus (75%)

d.

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iatrogenic prion diseases: rarely causes of CJD include contaminated dural grafts, cadaveric human growth hormone therapy, or surgical instruments

Box 11.13 Kuru Pathophysiology: Transmissible only by cannibalism, occurs only in New Guinea Histology: Kuru-type plaques in cerebellum Symptoms: limb and truncal ataxia; dementia

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Toxin Syndromes Toxin pathophysiology

Route

Key symptoms

Treatment

Botulism (Clostridium botulinum)

Cleaves SNAP-25, syntaxin, or synaptobrevin; inhibits presynaptic acetylcholine release from motoneurons

Contaminated food, wound, GI colonization (infants), inhalation (bioweapons)

Flaccid paralysis & hyporeflexia; ophthalmoparesis & unreactive pupils

Emetics, antiserum, wound debridement, penicillin

Tetanus (Clostridium tetani)

Inhibits GABA & glycine release from premotoneuron inhibitory interneuron

Wound, including umbilical stump

Painful muscle spasms that are inducible by startle; hyperreflexia; sympathetic hyperactivity

Anti-tetanus IgG, wound debridement, metronidazole, penicillin

Diphtheria (Corynebacterium diphtheriae)

Inhibits protein synthesis

Skin infection; pharyngitis, tonsillitis, sinusitis

Local sensory loss and weakness (skin infection); sensorimotor polyneuropathy involving vagus and phrenic nerves

Diphtheria antitoxin, erythromycin, penicillin

Tick paralysis (holocyclotoxin of Ixodes ticks)

Inhibits presynaptic acetylcholine release

Tick bite

Ataxia, flaccid paralysis (like GBS), diffuse paresthesias

Remove tick

Abbreviations: GI, gastrointestinal; IgG, immunoglobulin G; GBS, Guillain-Barre syndrome; SNAP, sensory nerve action potential.

IX. Toxin Syndromes 1.

Major neurotoxins (Table 11–4)

2.

Other neurotoxins (Table 11–5)

X. Idiopathic Infection-Like Conditions 1.

Idiopathic hypertrophic pachymeningitis (Box 11.14) a.

histology: infiltration of meninges by mature lymphocytes and histiocytes, rarely with granuloma formation

b.

symptoms: severe headache (90%); vision loss (60%), papilledema; ataxia; seizures

c.

diagnostic testing i.

Table 11–5

neuroimaging demonstrates dural enhancement involving nodularity and cerebral edema in the proximal brain parenchyma

Idiopathic Infection-Like Conditions

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Box 11.14 Unexpected Causes of Dural Enhancement Infections: Spirochetes, mycobacteria, fungi, parasites Autoimmune disorders: Wegener’s granulomatosis, sarcoidosis, Behçet’s syndrome, Sjögren’s syndrome, rheumatoid arthritis Carcinomatous meningitis Spontaneous intracranial hypotension En plague: Meningioma

Other Neurotoxins

Toxin

Source

Action

Symptoms

Bungarotoxin

Snakes

Nicotinic ACh receptor antagonist;

Paralysis, including respiratory muscles

Alpha

inhibits presynaptic ACh release

Beta Latrotoxin

Black Widow spider

Binds presynaptic neurexin, causing increased neurotransmitter release

Local pain, muscle fibrillation; generalized muscle cramping; hypertension

Domoate*

Shellfish

Kainate NMDA receptor agonist

Nausea, diarrhea, abdominal pain; somnolence, amnesia, mutism, seizures, myoclonus

Saxitoxin,*

Shellfish

Voltage-gated sodium channel antagonists

tetrototoxin*

Pufferfish, newts

Nausea, diarrhea, abdominal pain; paresthesias; progressive weakness with oropharyngeal involvement; hypotension

Brevitoxin

“Red tide” shellfish

Voltage-gated sodium channel agonists

Nausea, diarrhea; paresthesias

Ciguatoxin,* scaritoxin*

Large fish

*Produced by single-cell microorganisms eaten by the larger animal. Abbreviations: NMDA, nicotimide adenine dinucleotide.

Diffuse myalgias, paresthesias; inverted temperature sensation (e.g., cold feels hot)

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2.

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3.

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cerebrospinal fluid demonstrates a lymphocyte pleocytosis and increased protein

treatment: glucocorticoids

Mollaret’s meningitis a.

pathophysiology: possibly related to recurrent bouts of limited herpes virus reactivation, but generally no pathogen can be identified

b.

symptoms: several days of meningitis-like symptoms that spontaneously resolve

c.

diagnostic testing: cerebrospinal fluid contains various types of leukocytes and large endothelium-like cells {Mollaret’s cells}; Mollaret’s cells usually are observable only at the very beginning of an attack

d.

treatment: none specific

Vogt-Koyanagi-Harada syndrome a.

pathophysiology: possibly an autoimmune reaction against retinal photoreceptor antigens; associated with (HLA)-DR

b.

symptoms: a self-limited episode of meningitis and iritis followed weeks later by hair loss, focal loss of hair pigmentation {poliosis}, and vitiligo; meningitis episode can involve focal neurological injury, and vision loss can occur from iritis

c.

diagnostic testing: cerebrospinal fluid has melanin-containing macrophages

d.

treatment: glucocorticoids

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12 Disorders of Embryogenesis

Developmental and Metabolic Diseases of the Nervous System Note: Significant diseases are indicated in bold and syndromes in italics.

I. Disorders of Embryogenesis A. Malformations 1.

Cortical malformations—general symptoms include medication-refractory seizures, mental retardation, and focal neurological abnormalities a.

heterotopia—formed by either the abnormal proliferation or migration of neurons; neurons are generally misshapen and incorrectly organized i.

subtypes (1) focal cortical dysplasia—a gray matter connection between the cortex and the periventricular zone formed by neuroblasts that have incompletely migrated toward the cortex (2) periventricular heterotopia—clumps of neurons that failed to migrate to the cortex (or move at all) and instead reside in the periventricular white matter (Fig. 12–1) (a) some cases are related to X-linked mutations in the filamin A gene, the protein of which regulates cytoskeletal actin filament formation (3) laminar heterotopia: waves of neurons fail to migrate the entire distance to the cortex and instead form a band underneath the cortex in the white matter (Box 12.1)

b.

lissencephaly—diffuse neuronal migration failure that produces only a few enlarged gyri {pachygyria}

c.

polymicrogyria—small cortical gyri with fusion and/or loss of the underlying neuronal layers, often occurring in a regional distribution (e.g., peri-Sylvian)

d.

schizencephaly—clefts in the cortex that penetrate to the ventricular system occurring in areas of polymicrogyria; the clefts are lined by cortical neurons, unlike porencephaly (Fig. 12–2) i.

e.

f.

Box 12.1 Laminar heterotopia and lissencephaly are both associated with mutations of the doublecortin gene (X-linked) or LIS-1 gene (autosomal dominant).

the severity of symptoms is related to size of the cleft and a patent cleft opening

porencephaly—cortical clefts that can penetrate to the ventricular system, and that have openings that are surrounded by abnormal gyri (often polymicrogyria); unlike schizencephaly, clefts are usually bilateral and symmetric, and gray matter does not extend into the cleft i.

clefts likely represent tissue loss from in utero injuries

ii.

growth of the clefts due to fluid retention may compress ventricular flow, causing hydrocephalus

holoprosencephaly—failure of prosencephalon development, producing a smooth cortical surface without gyri or sulci i.

related to (1) maternal diabetes

Figure 12–1 Bilateral periventricular nodular heterotopias located on the lateral surface of the ventricles. (From McKhann GM et al. Q&A Color Review of Clinical Neurology and Neurosurgery. Stuttgart, Germany: Georg Thieme; 2003:73, Fig. 64. Reprinted by permission.)

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12 Developmental and Metabolic Diseases of the Nervous System

(2) mutation in the sonic hedgehog gene (10% of cases) (Box 12.2), which encodes a secreted intracellular signaling molecule; under expression of sonic hedgehog at the rostral end of the neural tube leads to incomplete development

Box 12.2 Other mutations of the sonic hedgehog gene cause cerebellar hypoplasia and/or pituitary gland abnormalities and VACTERL syndrome.

(3) mutations in Zic-2, a transcription regulatory protein ii.

subtypes (1) alobar holoprosencephaly: no divisions develop between the hemispheres or lobes; associated with a single underlying ventricle, agenesis of the septum and corpus callosum, and olfactory and optic nerve hypoplasia (2) semilobar prosencephaly: failure of the anterior interhemispheric division allows for fusion of the anterior cortices with significant hypoplasia of the corpus callosum and olfactory nerves; a posterior interhemispheric division exists and the basic lobar structure is otherwise preserved (a) septo-optic dysplasia—a variant of semilobar prosencephaly; specific features include hypothalamic hamartomas causing panhypopituitarism, agenesis of the cerebellar vermis and fusion of the dentate nuclei causing ataxia (Fig. 12–3). (3) lobar prosencephaly: interhemispheric connections occurring between frontal poles and the cingulate cortices through an oversized indusium griseum (a vestigial gray matter band normally located on top of the corpus callosum); limited hypoplasia of the corpus callosum

g.

hydranencephaly—reduction of the cerebral cortex to a flat, thin layer, often sparing the basal cortex and hippocampus but severely disrupting the thalamus and basal ganglia; caused by destructive processes (which produce microcephaly at birth) or by hydrocephalus (which produces macrocephaly at birth)

Figure 12–2 Schizencephaly. (From Citow JS et al. Neuropathology and Neuroradiology: A Review. Thieme; Stuttgart, Germany: Georg Thieme; 2001:11, Fig. 9. Reprinted by permission.)

A Figure 12–3 Septo-optic dysplasia with absent septum pellucidum between the two frontal horns (A) and thin optic nerves (B). (From Citow JS et al. Neuropathology and Neuroradiology: A Review. Thieme; Stuttgart, Germany: Georg Thieme; 2001:10, Fig. 7A. Reprinted by permission.)

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B

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generally fatal within a few days due to hypothalamic dysfunction

Subcortical malformations a.

agenesis of the corpus callosum—caused by complete or partial failure of the extension of the developing corpus callosum posteriorly from the lamina terminalis; fibers that cannot cross in the corpus callosum run ipsilaterally in a rostrocaudal direction {bundle of Probst} (Box 12.3)

Box 12.3

i.

other commissures are enlarged

Aicardi’s syndrome

ii.

occurs in isolation in 2% of population

Pathophysiology—X-linked inherited agenesis of corpus callosum and anterior commissure, and polymicrogyria Symptoms—Mental retardation; myoclonic epilepsy; chorioretinal abnormalities; vertebral abnormalities

iii. symptoms: generally asymptomatic without other malformations, but may exhibit (1) learning disabilities or mental retardation (2) abnormally wide-spaced eyes {hypertelorism} (3) exotropia with inability to converge 3.

Abnormalities of cerebrospinal fluid and the ventricular system a.

symptoms of hydrocephalus include irritability, bulging fontanelles, prominent scalp veins, false-localizing CN VI palsies, Parinaud’s syndrome, hyperreflexivity, and irregular respiration

b.

diagnosis requires a head circumference  2 standard deviations for gestational age or an increase in head circumference  2 standard deviations during first year of life; diagnosis does not require elevated intracranial pressure, which only occurs after fusion of the cranial sutures

c.

pathophysiology: acquired pediatric hydrocephalus conditions

d.

i.

noncommunicating: aqueduct stenosis caused by intrauterine infection, hemorrhage, trauma, or tumor

ii.

communicating: following subarachnoid hemorrhage or meningitis

Disorders of Embryogenesis

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pathophysiology: syndromal hydrocephalus conditions i.

trisomy 9, 13, 18

ii.

VACTERL syndrome with hydrocephalus (Box 12.4)

iii. Hunter’s and Hurler’s syndromes iv.

Walker-Warburg syndrome (also has congenital muscular dystrophy, lissencephaly, Dandy-Walker malformation, and eye malformations)

v.

craniosynostosis syndromes: all involve premature closure of skull sutures leading to skull deformation, and have autosomal dominant and sporadic forms

Box 12.4 VACTERL syndrome Vertebral anomalies; anal atresia; cardiac defects; tracheoesophageal fistula; renal abnormalities; l imb abnormalities. Some cases can be caused by mutation in the sonic hedgehog gene, like holoprosencephaly.

(1) simple craniosynostosis: early closure of one or a few sutures that does not cause hydrocephalus or other symptoms (2) complex craniosynostosis (a) Crouzon’s syndrome—other symptoms include multiple cranial nerve palsies caused by jugular foramen narrowing; no mental retardation (b) Apert’s syndrome—other symptoms include facial deformity, syndactyly, short upper extremities, and mental retardation vi. X-linked hydrocephalus syndromes: both are caused by mutations in L1CAM, a cell adhesion molecule (Box 12.5) (1) mental retardation, aphasia, shuffling gait, adducted thumbs (MASA) disorder

Box 12.5 L1CAM is also mutated in X-linked hereditary spastic paraparesis.

(2) X-linked aqueduct stenosis—also exhibits adducted thumbs, agenesis of the corpus callosum, brainstem malformations, and hypoplastic corticospinal tracts 4.

Cerebellar and brainstem malformations a.

Chiari malformations

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12 Developmental and Metabolic Diseases of the Nervous System

Table 12–1 Chiari Malformations Chiari I malformation

Chiari II malformation

Onset in young adulthood

Onset in infancy

Head, neck, or upper back pain; extremity spastic weakness  distal atrophy; extremity sensory loss; gait ataxia; diplopia; downbeat nystagmus

Dysphagia: cyanosis during feeding, regurgitation, aspiration; apnea, stridor; upper extremity weakness; opisthotonos; nystagmus, particularly downbeat

Cerebellum

Downward herniation of cerebellar tonsils; elongated, peg-like tonsils

Downward herniation of cerebellar vermis; dysplastic, hypomyelinated cerebellar folia

Brainstem

Normal

Herniation of medulla into the spinal canal; buckling of medulla {Z deformity}, tectal beaking; stretched and atrophic lower cranial nerves

Spine and spinal cord

Syringomyelia, scoliosis

Myelomeningocele; syringomyelia, scoliosis

Ventricular system

Hydrocephalus due to adhesions occluding 4th ventricle foramen ( 5%)

Hydrocephalus from cerebral aqueduct stenosis; big occipital horns of lateral ventricles. {colpocephaly}

Skull

Minor abnormalities of basilar skull

Enlarged foramen magnum; multifocal skull defects {luckenschadel} (See figure at right.); platybasia/basilar impression

Supratentorial structures

Normal

Hypoplastic and irregular tentorium and falx {Chinese lettering sign}; enlarged thalamic massa intermedia, absent septum; agenesis of corpus callosum

Diagnostic testing

Neuroimaging: Descent of one tonsil  5 mm below foramen magnum, or both tonsils 3–5 mm below foramen magnum

Neuroimaging: For aforementioned abnormalities; skull films demonstrate luckenschadel

Treatment and prognosis

Craniocervical decompression

May need ventricular shunting

Good outcome with pain or cerebellar injury; poor outcome with central cord injury

Older patients (i.e., children) tend to improve after surgery; unclear if decompression alters course in infants

Symptoms

Luckenschadel. (From Citow JS et al. Neuropathology and Neuroradiology: A Review. Thieme; Stuttgart, Germany: Georg Thieme; 2001:14, Fig. 11, Fig. 13A. Reprinted by permission.)

Craniocervical decompression

i.

Chiari I and II malformations (Table 12–1) (Fig. 12–4)

ii.

other Chiari malformations (1) Chiari III malformation: a very rare malformation characterized by herniation of an abnormal brain stem and cerebellum into a low occipital/high cervical encephalocele; associated with hydrocephalus (2) Chiari IV malformation: aplasia or hypoplasia of the cerebellum, therefore not a true Chiari malformation due to the lack of any hindbrain herniation (3) Chiari 0 malformation: syringohydromyelia not associated with hindbrain herniation or other apparent etiology, likely due to functional disturbances of cerebrospinal fluid flow at the foramen magnum

b.

Dandy-Walker malformation (Box 12.6) i.

pathophysiology: atresia of the foramen of Luschka and Magendie together with agenesis of the cerebellar vermis creates a fluid space that communicates with the subarachnoid space (Fig. 12–5) (1) associated abnormalities include agenesis of the corpus callosum (20%) and occipital encephalocele (10%); rarely associated with true hydrocephalus

272

(a) may be associated with cleft palate, ocular abnormalities (iris defects {coloboma}, microphthalmia), and cardiac structural defects

Box 12.6 Dandy-Walker malformations look similar to posterior fossa subarachnoid cysts, which do not communicate with the subarachnoid space as does the Dandy-Walker malformation.

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Disorders of Embryogenesis

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A Figure 12–4 Chiari I malformation with syrinx (A), Chiari II malformation with mesencephalic malformation (“tectal beaking”), low-lying torcula (arrow), medullary/cervical spinal cord buckling, and descent of the

B cerebellar vermis. (From Citow JS et al. Neuropathology and Neuroradiology: A Review. Thieme; Stuttgart, Germany: Georg Thieme; 2001:13, Fig. 11, Fig. 12. Reprinted by permission.)

Figure 12–5 Dandy-Walker malformation demonstrating a hypoplastic cerebellar vermis, laterally displaced cerebellar hemispheres, retrocerebellar cyst, and hydrocephalus. (From Mori K. Anomalies of the Central Nervous System. Thieme; Stuttgart, Germany: Georg Thieme; 1985:92, Fig. 6–12A. Reprinted by permission.)

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symptoms: mental retardation; ataxia; spasticity; seizures (15%)

iii. treatment: if symptomatic, shunt the posterior fossa fluid space; ventricular shunts in absence of posterior fossa shunt may cause upward herniation 5.

Spinal malformations a.

spina bifida: a neurulation abnormality i.

subtypes: all are most common in lumbosacral region and may be associated with an overlying tuft of hair (1) spina bifida occulta: incidental defect in the dorsal bony vertebra; occurs in 20% of the general population (2) meningocele: a meningeal outpouching that does not contain neural tissues and is well-covered by skin; has minimal association with brain malformations (a) treatment: early surgical closure (3) myelomeningocele: failure of the posterior neuropore closure; meningeal outpouching includes neural tissues and is covered by minimal skin elements (Box 12.7) (a) always associated with a type II Chiari malformation, and may have hydrocephalus from aqueduct stenosis (80%) (b) treatment: early surgical closure, although this is unlikely to improve the patient’s quality of life

ii.

diagnostic testing: prenatal diagnosis with elevated amniotic fluid -fetoprotein and ultrasound

Box 12.7 Other Neurulation Abnormalities Anencephaly—Failure of anterior neuropore closure; extends caudally as failure of spinal cord neurulation {rachischisis} Encephalocele—Unilateral cortical protrusion through a midline skull defect (occipital  frontal)

iii. treatment: prenatal folate supplementation reduces the incidence of spina bifida b.

tethered spinal cord i.

pathophysiology: stretching of the spinal cord by an unusually strong filum terminalis or lipoma, causing ischemia; associated with spina bifida occulta in 90% of cases, and the tethered cord usually accounts for deterioration in such patients who have back pain (deterioration without back pain is usually due to syringomyelia) (1) can be associated with chromosomal abnormalities (trisomy 13, 18; DiGeorge syndrome)

ii.

symptoms: back pain; lower extremity weakness and sensory loss; lower extremity atrophy and/or foot deformities; bowel/bladder dysfunction; progressive kyphoscoliosis; delayed walking; constipation (most common presenting sign in children); imperforate anus and other anal anomalies

iii. treatment: surgical transection of the filum; removal of any lipoma c.

caudal regression syndrome/sacral agenesis i.

pathophysiology: degeneration of the coccyx and sacral vertebrae, and of the sacral spinal cord that causes atrophy of the lower extremities and malformations of the rectum and genitourinary system; caused by decreased expression of the sonic hedgehog protein at the caudal end of neural tube (1) also associated with maternal diabetes mellitus

6.

Vein of Galen malformations: Caused by direct arterial connections into the vein of Galen a.

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subtypes i.

neonatal onset: the shunt involves a significant proportion of the cardiac output, therefore it presents as high-output congestive heart failure

ii.

infantile onset: presents with hydrocephalus, likely due to obstruction of the aqueduct of Sylvius by the enlarged vein of Galen

Figure 12–6 Lisch nodules. (From McKhann GM et al. Q&A Color Review of Clinical Neurology and Neurosurgery. Stuttgart, Germany: Georg Thieme; 2003:93, Fig. 87a. Reprinted by permission.)

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iii. childhood onset: presents as mental retardation, seizures, and/or focal neurological injury caused by arterial steal iv.

adult onset: presents as hemorrhagic infarction

treatment: endovascular occlusion of the arterial connections

II. Neurocutaneous Syndromes/Phakomatoses A. Neurofibromatosis Type 1/von Recklinghausen’s Disease 1.

Pathophysiology: caused by mutation of NF-1 gene on chromosome 17, which encodes neurofibromin protein that is likely a GTPase-activating protein; somatic mosaicism may cause localization of abnormalities to one part of the body a.

histology i.

subcutaneous neurofibromas develop along peripheral nerves; neurofibromas and/or schwannomas can develop on cranial nerves, but not as frequently as in neurofibromatosis type 2

ii.

gliomas (usually juvenile pilocytic astrocytomas) develop on the optic nerve (25%) of in the brain parenchyma (5%)

Figure 12–7 Café-au-lait spots. (From Panteliadis CP, Darras BT. Encyclopaedia of Paediatric Neurology: Theory and Practice, 2nd ed. Stuttgart, Germany: Georg Thieme; 1999:491, Fig. 25–1. Reprinted by permission.)

iii. pigmented hamartomas or the iris {Lisch nodules (Fig. 12–6)} or retina 2.

Symptoms: onset by 5 years of age (Box 12.8) a.

b.

3.

neurological symptoms i.

mental retardation (40%), seizures (10%)

ii.

painful peripheral neuropathies or radiculopathies from subcutaneous neurofibromas

eye: abnormalities are asymptomatic

c.

skin: café-au-lait spots (Fig. 12–7); axillary freckling

d.

hypertension from pheochromocytoma and/or renal artery stenosis

Diagnostic testing a.

neuroimaging: MRI demonstrates areas of non-enhancing increased T2 and diffusion-weighted signal {unidentified bright objects (UBOs)} that are located commonly in the basal ganglia, brainstem, and cerebellum (Fig. 12–8) i.

b. 4.

Requires two or more of the following: ✧ At least six café-au-lait spots that are  5 mm before puberty or  15 mm after puberty ✧ Multiple neurofibromas or one plexiform neurofibroma ✧ Multiple Lisch nodules ✧ Axillary freckling ✧ Optic glioma ✧ Bony lesions: thinning of long bones, pseudoarthrosis ✧ A family history of NF type 1

genetic abnormalities of NF-1 gene are detected in only 70%

Treatment: None specific

Pathophysiology: mutation of NF-2 gene on chromosome 22, encodes merlin/ schwannomin protein, which acts as a tumor suppressor (Box 12.9) a.

2.

Diagnostic Criteria for Neurofibromatosis (NF) Type 1

UBOs likely represent areas of glial proliferation, and they are frequently sites for glioma development; 40% will spontaneous resolve, but persistence of UBOs into adulthood is associated with mental retardation

B. Neurofibromatosis Type 2 1.

Box 12.8

Neurocutaneous Syndromes/Phakomatoses

b.

histology: multiple schwannomas, classically bilateral on CN/VIII but also on peripheral nerves; frequently associated with ependymomas  meningiomas and astrocytomas

Symptoms: typically develop around 20 years of age (Box 12.10) a.

neurological symptoms: vertigo, hearing loss, tinnitus from CN/VIII schwannomas (usually develop on the vestibular portion); schwannomas  neurofibromas on peripheral nerves may cause painful peripheral neuropathies i.

may develop facial weakness from compression of CN/VII in the internal acoustic meatus

b.

skin: as per neurofibromatosis type 1 but less prominent; café-au-lait spots and subcutaneous neurofibromas are rare

c.

eye: rare Lisch nodule

Box 12.9 Other mutations of merlin/schwannomin produce sporadic low-grade meningiomas

Box 12.10 Diagnostic Criteria for Neurofibromatosis Type 2: Requires All Three of the Following ✧ Bilateral CN VIII tumors ✧ Family history of neurofibromatosis

type 2 ✧ One family member with a CN VIII tumor

or two other nervous system tumors (neurofibroma, schwannoma, meningioma, glioma)

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3.

Diagnostic testing: neuroimaging with MRI; genetic testing

4.

Treatment: none specific

C. Tuberous Sclerosis 1.

Pathophysiology a.

b.

2.

3.

caused by autosomal dominant mutations in the i.

TSC-1 gene (chromosome 9): encodes the hamartin protein, which functions in linking the cell membrane to the cytoskeleton

ii.

TSC-2 gene (chromosome 16): encodes the tuberin protein, which is similar to GTPase-activating proteins and interacts with hamartin

TCS1 mutations may be more likely to cause familial disease and have a milder course, but otherwise there is no obvious phenotype difference between the two genetic subtypes

Histology a.

nervous system: cortical hamartomas {tubers}; focal cortical hypoplasia; subependymal heterotopias that are generally calcified; subependymal giant cell astrocytomas

b.

eye: hamartomas, retinal depigmentation

c.

cardiac, pulmonary, and renal hamartomas

d.

vasculature: degeneration of the tunica media promotes aneurysm formation

Symptoms a.

neurological symptoms i.

mental retardation ( 50%)

ii.

seizures (90%): may occur in the absence of mental retardation (Box 12.11)

iii. autism and behavioral disorders (psychosis, attention deficit– hyperactivity disorder) b.

Box 12.11 Tuberous sclerosis is the most common cause of infantile spasms with a known etiology.

skin i.

ash-leaf patches (Fig. 12–9): nonspecific for the phakomatoses

A Figure 12–9 An ash-leaf patch (A). In a fair-skinned child (B), ash-leaf patches may be difficult to observe directly (left) and may require a Wood’s lamp (right). (Panel A, from Panteliadis CP, Darras BT. Encyclopaedia of Paediatric Neurology: Theory and Practice, 2nd ed. Stuttgart,

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Figure 12–8 Unidentified bright objects (arrow) of neurofibromatosis type 1. (From Raininko R et al. Non-neoplastic brain abnormalities on MRI in children and adolescents with neurofibromatosis type 1. Neuropediatrics, 2001, 32: 226, Fig. 1b. Reprinted by permission.)

B Germany: Georg Thieme; 1999:497, Fig. 25–4. Reprinted by permission. Panel B, from Kurlemann G, Schuierer G. Ash-leaf spots in tuberous sclerosis. New Eng J Med, 1998, 338:1887. Copyright 1998 Massachusetts Medical Society. All rights reserved.)

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Figure 12–10 Ungual fibromas. (From McKhann GM et al. Q&A Color Review of Clinical Neurology and Neurosurgery. Stuttgart, Germany: Georg Thieme; 2003: 177, Fig. 177a. Reprinted by permission.)

ii.

Figure 12–11 Shagreen patch. (From Thappa DM et al. Giant shagreen patch associated with spina bifida occulta in tuberous sclerosis. Pediatric Dermatol 2003, 453–454. Reprinted by permission.)

ungual fibromas (Fig. 12–10): nodular fibromas that develop under the nails, particularly after trauma

iii. shagreen patch (Fig. 12–11): raised, leather-like skin usually on the back; usually develops in childhood, late in the disease

4.

5.

iv.

adenoma sebaceum/facial angiofibromas (Fig. 12–12): specific for tuberous sclerosis

v.

poliosis: white patches of hair on the forehead or eyebrows

c.

eye: abnormalities are asymptomatic

d.

cardiac: occasionally rhabdomyomas cause congestive heart failure, rarely arrhythmias

Diagnostic testing: neuroimaging

Neurocutaneous Syndromes/Phakomatoses

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Figure 12–12 Adenoma sebaceum. (From McKhann GM et al. Q&A Color Review of Clinical Neurology and Neurosurgery. Stuttgart, Germany: Georg Thieme; 2003:177, Fig. 177b. Reprinted by permission.)

a.

MRI demonstrates cortical tubers (in neonates, ↑ T1 and ↓ T2; in children, ↓ T1 and ↑ T2) and poorly defined underlying white matter abnormalities (Fig. 12–13)

b.

computed tomography (CT) demonstrates intracranial calcifications, particularly of the subependymal nodules

c.

angiography can demonstrate intracranial and peripheral aneurysms

Treatment: None specific

D. Sturge-Weber Syndrome 1.

Pathophysiology: no known genetic cause; occurs sporadically

2.

Histology: angiomas of the face and the underlying meninges and brain that cause atrophy and dystrophic calcification of the brain

3.

a.

intracranial angiomas drain into a dilated subependymal venous plexus; cortical veins are often thrombosed, leading to poor filling of the superior sagittal sinus

b.

angioma distribution is variable, and isolated face or intracranial angiomas can occur

Figure 12–13 Subependymal nodules in tuberous sclerosis. (From McKhann GM et al. Q&A Color Review of Clinical Neurology and Neurosurgery. Stuttgart, Germany: Georg Thieme; 2003:75, Fig. 66b. Reprinted by permission.)

Symptoms a.

neurological symptoms i.

mental retardation (70%), particularly in patients with bilateral intracranial angiomas

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seizures (90%), generally focal motor or generalized tonic-clonic; early onset of seizures increases the risk for mental retardation

iii. focal neurological deficits: typically develop acutely after the onset of seizures and suggest ischemic stroke iv.

4.

5.

megacephaly with hydrocephalus

b.

skin: angioma {port-wine stain} typically is in the CN V1 distribution but it may extend downwards on neck, trunk, and upper extremity; may occur bilaterally (Fig. 12–14)

c.

eye: glaucoma when the angioma involves the choroid

Diagnostic testing a.

contrast MRI and MR angiography (MRA) demonstrate intracranial angiomas; confirm with angiography

b.

CT: demonstrates dystrophic calcification

c.

skull plain films: classic “tram-track” calcifications develop over decades, and are rarely present at the time of symptomatic onset (Fig. 12–15)

Figure 12–14 Port-wine stain. (From Panteliadis CP, Darras BT. Encyclopaedia of Paediatric Neurology: Theory and Practice, 2nd ed. Stuttgart, Germany: Georg Thieme; 1999: 501, Fig. 25–8. Reprinted by permission.)

Treatment: Complete seizure control with antiepileptic medications in 50%; may require resection of seizure foci or hemispherectomy

E. von Hippel-Lindau Syndrome 1.

Pathophysiology: autosomal dominant mutations in the VHL gene, the protein of which acts as tumor suppressor by inhibiting endothelial-derived growth factor

2.

Histology: multiple hemangioblastomas of the eye and brain a.

in the brain, hemangioblastomas are found in the cerebellum  spinal cord (cervical and conus regions) or medulla i.

supratentorial hemangioblastomas occur in  5%

ii.

hemangioblastomas in the spinal cord can cause syrinx formation, and in the medulla they may cause syringobulbia

iii. hemangioblastomas are slow growing, so symptoms increase with age

3.

4.

b.

renal and pancreatic cysts

c.

tumors: renal carcinoma, pheochromocytoma (20%)

Symptoms a.

neurological symptoms: usually minimal unless a hemangioblastoma hemorrhages

b.

eye: usually asymptomatic unless the hemangioblastoma is large and centrally located, or unless it hemorrhages

c.

episodic hypertension from pheochromocytoma with associated flushing and diaphoresis; chronic hypertension from renal cysts

d.

pancreatitis from bile duct obstruction due to multiple pancreatic cysts

Diagnostic testing: contrast MRI to identify hemangioblastomas only in patients who are symptomatic; confirm with angiography

III. Aminoacidopathies (Box 12.12) 1.

Maple syrup urine disease a.

pathophysiology: caused by autosomal recessive mutations of the branchedchain ketoacid dehydrogenase (BCKD) complex, which also decarboxylates branched chain amino acids (isoleucine, valine, leucine); BCKD requires thiamine cofactor, which accounts for a thiamine-responsive variant of the disease i.

278

Figure 12–15 Tram-track calcifications of advanced Sturge-Weber syndrome. (From Citow JS et al. Neuropathology and Neuroradiology: A Review. Thieme; Stuttgart, Germany: Georg Thieme; 2001:123, Fig. 180B, Fig. 12. Reprinted by permission.)

b.

histology: immature central nervous system myelination {dysmyelination}, heterotopias, diffuse spongy degeneration, and failure to develop all cortical layers

symptoms

Box 12.12 Diseases with Hyperammonemia Aminoacidopathies—Glycine encephalopathy Disorders of urea metabolism—Argininosuccinate lyase deficiency; argininosuccinate synthase deficiency; arginase deficiency Disorders of organic acids—Isovaleric acidemia; propionic acidemia; methylmalonic acidemia Toxicities—Valproate use (the most common cause)

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neonatal onset (severe enzyme deficiency): normal at birth, but symptoms develop within days of starting a protein diet (1) general symptoms: ketoacidosis and hypoglycemia (2) neurological symptoms: hypotonia; lethargy; apnea, respiratory failure; seizures and coma, usually leading to death or mental retardation in the survivors

ii.

infant onset (moderate enzyme deficiency): symptoms usually develop after a catabolic state (e.g., febrile illness) (1) general symptoms: mild ketoacidosis (2) neurological symptoms: ataxic gait; mental retardation

c.

diagnostic testing i.

urine dinitrophenylhydrazine chromogenic test for amino acids

ii.

elevated serum branched-chain amino acid levels

d.

Aminoacidopathies

iii. neuroimaging: demonstrates areas of abnormal subcortical white matter signal at baseline, and cerebral edema that develops after a protein meal treatment i.

thiamine

ii.

low branched-chain amino acid diet; protein-free diet during acute exacerbations

iii. hemodialysis for severe ketoacidosis 2.

Phenylketonuria a.

b.

pathophysiology: autosomal recessive deficiency of phenylalanine hydroxylase prevents conversion of phenylalanine to tyrosine; high levels of phenylalanine are directly toxic to glia more so than neurons i.

phenylalanine hydroxylase requires tetrahydrobiopterin cofactor (Box 12.13)

ii.

histology: as per maple syrup urine disease

symptoms: develop 2–3 months after birth i.

general symptoms: musty body odor; dry, scaling hypopigmented skin; small stature; patients are always blonde and blue-eyed

ii.

neurological symptoms: microcephaly with failure to acquire developmental milestones and mental retardation; hyperactivity, irritability; tremor; spasticity; infantile spasms progressing to generalized tonic-clonic seizures

c.

diagnostic testing: screening blood test for blood phenylalanine taken 24 hours after protein the first feeding; if positive, phenylketonuria is confirmed by demonstrating normal urine tyrosine and tetrahydrobiopterin levels

d.

treatment: phenylalanine-restricted diet beginning by 3 weeks of age i.

e. 3.

Box 12.13 Tetrahydrobioprotein  Methylenetetrahydrofolate (used in conversion of homocysteine to methionine)

diet restrictions must be carefully monitored by a nutritionist and should be continued at least through adolescence; it is unclear if a normal diet can ever be safely instituted

prognosis: dietary management limits mental retardation

Hartnup’s disease a.

pathophysiology: abnormal function of the neutral amino acid transport protein impairs intestinal absorption and renal reabsorption of neutral amino acids, particularly tryptophan

b.

symptoms: develop in childhood, and are unrelated to diet i.

general symptoms: photosensitive dermatitis

ii.

neurological symptoms: headache; depression, psychosis; gait ataxia

c.

diagnostic testing: increased urine excretion of tryptophan and other neutral amino acids, which is constant and does not correlate with symptom severity

d.

treatment: nicotinamide and tryptophan supplementation

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Glycine encephalopathy a.

pathophysiology: caused by an unknown defect in glycine metabolism that leads to glycine accumulation

b.

symptoms: irritability, hiccupping, lethargy, and hypotonia developing within a few hours of birth; myoclonic seizures develop thereafter i.

c.

d.

e. 5.

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no ketoacidosis, as in some disorders of organic acids (i.e., isovaleric acidemia, propionic acidemia)

diagnostic testing i.

EEG: shows a burst-suppression pattern progressing to hypsarrhythmia (see p. 92)

ii.

increased serum and cerebrospinal fluid glycine level without hyperammonemia or organic acidemia (Box 12.14)

treatment i.

hemodialysis for severe encephalopathy

ii.

diazepam  benzoate for seizures; avoid valproate

Aromatic amino acid/DOPA decarboxylase deficiency a.

pathophysiology: mutations in aromatic amino acid/dihydroxyphenylalanine (DOPA) decarboxylase prevents L-DOPA conversion to dopamine (Box 12.15), and 5-hydroxytryptophan conversion to serotonin

b.

symptoms: onset  2 years of age; symptoms become worse throughout the day and improve after sleep (Box 12.16) i.

axial hypotonia with limb hypertonia; dystonia; startle myoclonus

ii.

autonomic dysfunction: diaphoresis, temperature instability, ptosis, miosis, episodic hypoglycemia

iv. c.

disturbed sleep–wake patterns

treatment: vitamin B6/pyridoxine (cofactor for the decarboxylase); monoamine oxidase (MAO) inhibitors; dopaminergic agonists (pergolide, bromocriptine); melatonin for disturbed sleep

6.

Canavan’s disease/spongy degeneration of infancy: see p. 115

7.

Homocysteinuria: see p. 72

IV. Disorders of Organic Acids

2.

280

Increased glycine and ketoacidosis occurs in propionic academia and isovaleric acidemia.

prognosis: death within a few weeks of birth

iii. mental retardation; failure to achieve motor milestones

1.

Box 12.14

Isovaleric acidemia a.

pathophysiology: caused by autosomal recessive deficiency of isovalerylCoA dehydrogenase that leads to accumulation of isovaleric acid (a fatty acid); normally this enzyme is active in a multistep pathway converting leucine to acetoacetate

b.

symptoms: lethargy and protracted vomiting developing within a few days of birth; exhibits ketoacidosis, unlike glycine encephalopathy

c.

diagnostic testing: increased isovaleryl-lysine levels, which causes the urine to smell like sweaty feet and the patient to smell like stale sweat

d.

treatment: dietary protein restriction, particularly leucine; L-carnitine and glycine supplementation

e.

prognosis: 60% 3-week mortality

Propionic acidemia a.

pathophysiology: caused by autosomal recessive deficiency of propionylCoA carboxylase; enzymatic deficiency prevents the conversion of propionic acid to methylmalonyl-CoA (Fig. 12–16)

b.

symptoms: lethargy, hypotonia, and dehydration developing within days to months of birth

c.

diagnostic testing

Box 12.15 Dopamine is formed by tyrosine hydroxylase, which is mutated in Segawa’s syndrome.

Box 12.16 Worsening of symptoms during the day is similar to Segawa’s syndrome.

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i.

hyperammonemia; ketoacidosis (unlike glycine encephalopathy)

ii.

increased serum glycine and propionate levels; increased urine glycine, methylcitrate, and -hydroxypropionate

d.

treatment i.

hemodialysis for severe encephalopathy

ii.

dietary protein  1.5 g/kg/d

restriction

iii. L-carnitine to reduce ketogenesis iv. 3.

Figure 12–16 Biosynthesis of methylmalonyl-CoA.

biotin supplementation (an enzymatic cofactor for propionyl-CoA carboxylase)

Methylmalonic acidemia a.

pathophysiology: caused by autosomal recessive deficiency of methylmalonylCoA mutase, which leads to accumulation of propionyl-CoA, propionic acid, and methylmalonic acid

b.

symptoms: lethargy, vomiting, dehydration, and hypotonia developing after the initiation of protein feeding

c.

diagnostic testing: hyperammonemia; increased serum glycine and methylmalonic acid; increased urine methylmalonic acid

d.

treatment i.

dietary protein restriction  1.5 g/kg/d

ii.

vitamin B12 supplementation (a cofactor for methylmalonyl-CoA mutase)

Disorders of Urea Metabolism

iii. increased methylcitrate levels in the amniotic fluid for prenatal diagnosis

iii. L-carnitine to reduce ketogenesis e.

prognosis: majority die within 2 months; survivors have episodic metabolic acidosis and mental retardation

V. Disorders of Urea Metabolism 1.

Pathophysiology: all exhibit autosomal recessive inheritance except for ornithine transcarbamylase deficiency, which is X-linked (Fig. 12–17)

2.

General symptoms: vomiting, lethargy, and hypotonia beginning within 24 hours of birth, due to ammonia toxicity; coma develops if ammonia  300 g/dL, and seizures if  500 g/dL

3.

Specific symptoms

4.

a.

carbamyl phosphate synthetase deficiency—abnormal eye movements

b.

ornithine transcarbamylase deficiency—respiratory alkalosis

c.

argininosuccinate synthase deficiency/citrullinemia—hepatomegaly; ataxia

d.

arginase deficiency—spastic diplegia

e.

argininosuccinate lyase deficiency—brittle hair associated with small nodules along the hair shaft {trichorrhexis nodosa}

Diagnostic testing a.

hyperammonemia without organic aciduria that is greatly increased after a protein meal

b.

elevated orotic acid levels, except in carbamyl phosphate synthetase deficiency

c.

elevated serum levels of amino acids and orotic acid, and urine amino acids

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Figure 12–17 The urea cycle.

5.

Treatment a.

hemodialysis for severe hyperammonemia

b.

dietary nitrogen intake  2 g/kg/d

c.

benzoate, phenylacetate, and arginine supplementation, for both acute hyperammonemia and chronic treatment

VI. Lysosomal Storage Disorders A. Disorders of Peroxisomes 1.

Refsum’s disease a.

pathophysiology: caused by autosomal recessive deficiency of peroxisomal phytanoyl-CoA hydroxylase that prevents the degradation of phytanic acid i.

b.

histology: diffuse lipid deposits in CNS neurons and glia, with areas of dysmyelination; peripheral nerve axons exhibit myelin onion bulbs, like the Charcot-Marie-Tooth neuropathies

symptoms: develop by 20 years of age; a slowly progressive course that is interrupted by frequent remissions and that can be exacerbated by fasting (which releases cellular stores of phytanic acid) i.

general symptoms: cataracts; cardiomyopathy, arrhythmia; dry, scaling skin {ichthyosis}

ii.

neurological symptoms (1) ataxia, nystagmus (2) retinitis pigmentosa, often presenting as night blindness (3) distal large-fiber sensorimotor polyneuropathy (4) sensorineural hearing loss

c.

282

diagnostic testing: increased blood phytanic acid levels, and reduced lowdensity lipoprotein (LDL) and high-density lipoprotein (HDL)

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treatment: dietary restriction of phytanic acid; plasmapheresis (not hemodialysis) during acute exacerbations

Zellweger’s syndrome a.

pathophysiology: caused by autosomal recessive mutations in any one of 14 proteins (“peroxins”) that prevent transport of extracellular matrix proteins into peroxisomes for degradation; malfunctional peroxisomes are empty structures {peroxisome ghosts}, and are few in number i.

b.

histology: pachygyria; polymicrogyria; heterotopias, particular in the cerebellum; malformations of the inferior olivary complex

symptoms i.

general symptoms: cirrhotic liver failure; facial malformations (micrognathia, low nasal bridge, shallow orbits, ear deformities); cataracts, glaucoma

ii.

neurological symptoms

Lysosomal Storage Disorders

2.

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(1) hypotonia, hyporeflexia (2) sensorineural hearing loss (3) failure to achieve developmental milestones (4) seizures c.

3.

diagnostic testing i.

increased levels of pipecolic acid (a very-long chain fatty acid normally metabolized by peroxisomes) in blood and urine

ii.

decreased levels of plasmalogens (which are phospholipids synthesized by peroxisomes) in erythrocytes or in cultured amniocytes

d.

treatment: mild cases may benefit from docosahexaenoic acid supplementation

e.

prognosis: death by 1 year of age in severe cases, or by 3–6 years of age in mild cases

Adrenoleukodystrophy: see p. 116

B. Disorders of Mucopolysaccharide Metabolism (Mucopolysaccharidoses) 1.

Symptoms: Course facial features; sensorineural hearing loss; behavioral regression beginning after 1 years of age, hepatosplenomegaly; dwarfism

2.

Subtypes (Table 12–2)

Box 12.17 -galactosidase is also mutated in GM1 gangliosidosis

Table 12–2 Mucopolysaccharidoses Disorder

Enzyme

Onset

Accumulates

I-H/Hurler’s syndrome

Iduronidase (AR)

 1 year of age

heparan, dermatan



I-S/Scheie’s syndrome

Iduronidase (AR)

2–5 years of age

heparan, dermatan



II/Hunter’s syndrome

Iduronate-2-sulfatase (XR)

1–3 years of age

Heparan, dermatan



III/Sanfilippo’s syndrome

(All AR) Heparan sulfatase

2–4 years of age

Heparan



1–3 years of age

Keratan

Type A

Acetylglucosaminidase

Type B

Acetyl-CoA

Type C

Glucosaminide 

IV/Morquio’s syndrome Type A

Brain involvement

Acetylgalactosamine Sulfatase (AR)

Type B

-galactosidase (AR) Box 12.17) (B

Abbreviations: AR, autosomal-recessive; XR, x-linked recessive.

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Figure 12–18 The sphingolipid metabolic pathway.

C. Disorders of Sphingolipid Metabolism (Sphingolipidoses) 1.

Pathophysiology: caused by mutations of enzymes in the sphingolipid metabolic pathway (Fig. 12–18)

2.

General symptoms: onset before 2 years of age; developmental delays and/or mental retardation (Box 12.18)

3.

Subtypes (Table 12–3)

4.

Treatment: Bone marrow transplantation for metachromatic and globoid leukodystrophies with mild neurological involvement

Box 12.18 Diseases with Cherry-Red Spots—GM-1 & GM-2 gangliosidosis; metachromatic leukodystrophy; Niemann-Pick disease

Table 12–3 Sphingolipidoses Disorder

Mutation/accumulates

Distinguishing features

Fabry’s disease

-Galactosidase (XR)/trihexosylceramide

Cutaneous angiomas, cataracts, renal failure, painful neuropathy, early-onset atherosclerosis

Farber’s lipogranulomatosis

Ceramidase (AR)/ceramide

Multiple subcutaneous nodules, interstitial lung disease, macroglossia

Gaucher’s disease

Glucocerebrosidase

Type I: visceral; IV enzyme responsive

(AR); rarely saposin C cofactor/ glucocerebrosides

Type II (infant): neurovisceral; therapy resistant

GM1 gangliosidosis

-Galactosidase (AR); rarely saposin B/GM1 ganglioside

Cherry-red macula spot similar to Hurler’s syndrome, a mucopolysaccharidosis

GM2 gangliosidosis/ Tay-Sach’s disease

Hexosaminidase A or B (AR); rarely glycoprotein activator/GM2 gangliosides

Tay-Sachs is infantile form

Niemann-Pick disease type A&B

Sphingomyelinase (AR)/sphingomyelin

MR, cachexia, cherry-red spot (50%), opisthotonos, blindness, seizures; liver failure

(Type C is a dyslipidemia, see p. 297)

284

Type III (child): neurovisceral; IV enzyme responsive

CNS: increased startle reflex, MR, motor regression; cherry-red spot on macula

Type A: onset  6 months of age Type B: like type A, but no neurological symptoms

Abbreviations: AR, autosomal recessive; CNS, central nervous system; IV, intravenous; MR, mental retardation; XR, x-linked recessive.

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1.

General histology: accumulation of autofluorescent lipid pigments (ceroid, lipofuscin) in brain, retina, and gastrointestinal tract that form inclusion bodies; degeneration of retinal photoreceptor and loss of specific layers of cortical neurons, depending upon subtype a.

epidemiology: most common in Scandinavians

2.

General symptoms: progressive dementia; progressive vision loss from retinal and optic nerve degeneration; ataxia; myoclonus

3.

Subtypes a.

b.

c.

d.

4.

5.

Disorders of DNA Repair and Nucleoside Metabolism

D. Neuronal Ceroid Lipofuscinosis (NCL)

early-infantile NCL: onset 1–2 years of age i.

pathophysiology: caused by mutation in the palmitoyl protein thioesterase (CLN1) gene, the protein of which removes fatty acids from lipoproteins

ii.

specific symptoms: hyperactivity; hypotonia

late-infantile NCL: onset 2–3 years of age i.

pathophysiology: caused by mutations in the CLN2 gene, which encodes tripeptidyl peptidase that removes N-terminal tripeptides from polypeptides

ii.

specific symptoms: seizures; dementia progressing to a vegetative state

juvenile NCL: onset 4–9 years of age i.

pathophysiology: caused by mutations in CLN3 gene, which encodes a lysosomal membrane protein of unknown function

ii.

specific symptoms: Parkinsonism; tonic-clonic seizures

adult NCL: onset  40 years of age i.

pathophysiology: unknown

ii.

specific symptoms: seizures; peripheral neuropathy

Diagnostic testing a.

reduced palmitoyl protein thioesterase and tripeptidyl peptidase levels (infantile NCLs)

b.

neuroimaging: diffuse atrophy, usually cerebral  cerebellar; increased T2 signal in the thalami and deep white matter

c.

EEG, visual evoked potentials, and electroretinograms exhibit increased responsiveness to photostimulation

d.

tissue biopsy of muscle, skin, conjunctiva, or rectum for inclusion bodies

Treatment: None specific

VII. Disorders of DNA Repair and Nucleoside Metabolism 1.

Xeroderma pigmentosa a.

pathophysiology: caused by abnormalities of DNA repair throughout the genome (i.e., in actively transcribed and inactive regions); the majority of cases with neurological disease have autosomal recessive mutations in DNA helicase (Box 12.19) i.

b.

c. 2.

histology: pronounced neuron loss in the cortex, basal ganglia, and cerebellum causes generalized atrophy; also exhibits anterior horn and dorsal root ganglia neuron loss, and cochlear hair cell atrophy

Box 12.19 Certain mutations in DNA helicase may cause a Cockayne-like syndrome.

symptoms i.

general symptoms: sun sensitivity causing premature skin aging and an increased incidence of skin cancers

ii.

neurological symptoms: microcephaly with progressive dementia; sensorineural hearing loss; spastic weakness that ultimately become areflexic due to a sensorimotor neuropathy; ataxia, dysarthria

treatment: avoid sun exposure

Cockayne’s syndrome

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pathophysiology: caused by abnormalities of the DNA excisional repair system in actively transcribed genes i.

12 Developmental and Metabolic Diseases of the Nervous System

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subtypes: both exhibit autosomal recessive inheritance (1) type I/juvenile-onset (rare): mutation of the CSA gene on chromosome 5 (2) type II/infantile-onset (common): mutation of the CSB gene on chromosome 10

ii.

histology: death of oligodendrocytes and Schwann cells; gliosis involves pleomorphic astrocytes that are preneoplastic in appearance (1) atrophy with calcifications are pronounced in cerebellum  cortex or basal ganglia (2) neurofibrillary tangles and Hirano bodies are present in neurons (3) premature atherosclerosis with calcification, particularly in the basal ganglia

b.

symptoms i.

general symptoms: dwarfism, often with skeletal abnormalities; cachexia; minor skin pigmentation, premature skin aging, and increased cancer risk

ii.

neurological symptoms (1) acquired microcephaly: head circumference is normal at birth but fails to increase; occurs despite normal pressure hydrocephalus (2) progressive dementia that is not as severe as the microcephaly would suggest (3) vision loss from cataracts and pigmented retinopathy

c.

d. 3.

diagnostic testing i.

neuroimaging: basal ganglia calcifications on CT; meningeal thickening and tigroid leukodystrophy on MRI (Fig. 12–19)

ii.

nerve conduction study: demyelinating neuropathy, which is rarely symptomatic (unlike xeroderma pigmentosa)

treatment: avoid sun exposure

Lesch-Nyhan disease a.

b.

pathophysiology: caused by X-linked mutations in the hypoxanthine-guanine phosphoribosyl transferase (HGPRT) enzyme, which normally converts hypoxanthine and xanthine into nucleic acids; HGPRT deficiency allows for accumulation of hypoxanthine and xanthine that become converted to uric acid by xanthine oxidase i.

hypoxanthine, xanthine, and uric acid levels are related to nephropathy but not to central nervous system dysfunction

ii.

partial HGPRT deficiency may cause only mild mental retardation, gout, and asymptomatic hyperuricemia, as in the female carrier state

symptoms: develops by 2–3 years of age i.

general symptoms: gout; renal stones

ii.

neurological symptoms (1) neonatal hypotonia developing into spasticity and opisthotonos (2) mental retardation with aggressive and self-mutilation behaviors despite sensitivity to pain (e.g., chewing off finger tips) (3) choreoathetosis, dystonia

286

c.

diagnostic testing: elevated blood uric acid levels

d.

treatment: no effective treatment for neurological symptoms

Figure 12–19 Tigroid leukodystrophy of Cockayne’s syndrome. (From Menges-Wenzel E et al. Cockaynesyndrom mit betonter zerebraler symptomatik verlaufsbeobachtung bei zwei schwestern. Klinische Padiatrie 2001, 213:136, Fig. 3a. Reprinted by permission.)

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VIII. Disorders of Oxidative Phosphorylation Causing Lactic Acidosis

2.

General pathophysiology: caused by enzymatic deficiencies in the Kreb’s cycle or mitochondrial electron transport chain that allow the accumulation of lactate, which is neurotoxic; failure of oxidative phosphorylation may also directly cause cellular death a.

neurons in the basal ganglia (particularly the putamen) are susceptible to lactate

b.

histological changes are similar to thiamine deficiency (i.e., Wernicke’s encephalopathy), although the mamillary bodies are spared

Major subtypes a.

pyruvate dehydrogenase deficiency—the clinical course is variable and proportionate to the degree of enzyme deficiency i.

b. 3.

4.

Developmental Delays and Regression

1.

specific symptoms: often the lactic acidosis is fatal in the neonatal period; survivors exhibit mental retardation, hypotonia, choreoathetoid cerebral palsy, and a demyelinating polyneuropathy

Leigh’s disease (see p. 48), a subset of which is caused by pyruvate dehydrogenase deficiency

Diagnostic testing a.

elevated fasting lactate and reduced pyruvate in blood, which may require preceding ingestion of carbohydrates to detect

b.

skin and muscle biopsy for identification of enlarged mitochondria

Treatment: Multivitamin, L-carnitine, and coenzyme Q10 supplementation; bicarbonate; dietary carbohydrate restriction; dichloroacetic acid for pyruvate dehydrogenase deficiency

IX. Developmental Delays and Regression A. Normal Developmental Milestones (Table 12–4) B. Abnormal Development 1.

Language delay: causes include a.

hearing impairment: the most common cause of language delay; commonly occurs after intrauterine cytomegalovirus infection, neonatal meningitis, or kernicterus i.

b.

even mild hearing loss can cause language delay if the loss is concentrated in the high-frequency tones

bilateral hippocampal sclerosis: usually presents with seizures; one normally functioning medial hippocampal gyrus is necessary for language development

Table 12–4

Normal Developmental Milestones

Skills

3 months

6 months

9 months

12 months

15 months

18 months

24 months

Gross motor

Sits with support

Sits unsupported

Stands unaided

Walks

Runs

Climbs steps

Throws

Fine motor

Puts hands together

Reaches

Pincer grasp

Scribbles

Stacks two cubes

Stacks six cubes

Copies straight line

Social

Social smile, recognizes parents

Stranger anxiety begins

Indicates desires

Imitates others

Removes clothes

Helps clean self

Puts on clothes

Language

Laughs

Monosyllabic utterances

“Dada” & “mama”

Two words

Six words

Combines words

Picture naming

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12 Developmental and Metabolic Diseases of the Nervous System

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c.

focal lesions in cortical language areas: produce language delay only in children  5 years of age; lesions in children  5 years of age displace language functions to the contralateral hemisphere

d.

autism: see p. 290

Motor delay a.

cerebral palsy i.

pathophysiology: likely causes are in utero/pre-labor injuries (e.g., twining, in utero stroke, congenital malformations); not related to birth injury or obstetrical procedures (1) the incidence of cerebral palsy has not changed except for the choreoathetotic subtype, which has been decreased by treatment of hyperbilirubinemia that prevents development of kernicterus

ii.

general symptoms: usually identifiable only after 6 months of age; choreoathetotic subtype can be identified only by 12–18 months of age; 20% have coincidental mental retardation

iii. subtypes (1) paraplegic cerebral palsy—associated with white matter damage high in centrum semiovale (i.e., a periventricular leukomalacia), specifically in the area above and lateral to the caudate nucleus; lesions damage the corticospinal tract fibers issuing from the lower extremity region of the motor cortex more so than upperextremity region (2) hemiplegic cerebral palsy: likely caused by embolisms from the placenta; 70% involve the left hemisphere because the majority of flow of the fetal circulation through the patent ductus arteriosus goes straight into the left carotid artery (a) may give the appearance of handedness in neonates (a pathological observation) (3) quadriplegic cerebral palsy: usually caused by hypoxic-ischemic encephalopathy (4) choreoathetotic cerebral palsy: caused by injuries to the basal ganglia; historically was due to erythroblastosis fetalis/Rh incompatibility causing kernicterus, but now is usually an idiopathic condition (a) status marmoratus: a marble-like histological appearance of basal ganglia, due to oligodendrocytes that myelinate astrocytes in the absence of neurons iv.

diagnostic testing (1) neuroimaging to assess for brain malformations or injury; metabolic and genetic testing should be considered if neuroimaging does not define a structural abnormality (2) evaluation for a hypercoagulable state

b.

hypotonic motor delays i.

general symptoms: all causes involve a loss of postural tone (1) reduced spontaneous movements (2) absence of neck and limb flexion when pulling the infant upright {traction response} (Box 12.20) (3) hip dislocation and pectus excavatum due to regional muscle weakness (4) joint contractures causing congenital limb deformities {arthrogryposis}

ii.

upper motoneuron hypotonic disorders (1) specific symptoms (a) seizures

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(b) decorticate and/or decerebrate posturing, often induced by passive head movements

Box 12.20 The Traction Response Not present in premature infants; better than horizontal suspension for hypotonia

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(c) persistence of fisting of the hand that encloses the thumb {cortical hand} (which is a normal finding only at  3 months of age); crossing of the thighs {scissoring}; hyperreflexia despite hypotonia (2) subtypes: from cerebral palsy, leukoencephalopathies, or chromosomal disorders (e.g., Down’s syndrome/trisomy 21); also (i)

pathophysiology: partial deletion of chromosome 15 (70%) or else disomy of the maternal chromosome 15; may involve the necdin gene, which encodes a growth suppressor protein that interacts with p53 cell cycle protein (Box 12.21)

(ii) symptoms: hypotonia, obesity and hyperphagia, mental retardation, hypogonadism and cryptorchidism iii. lower motoneuron hypotonic disorders: perinatal asphyxia or trauma after breech presentation, or inherited (e.g., the spinal muscular atrophies) iv.

peripheral nerve hypotonic disorders: Charcot-Marie-Tooth neuropathies; Guillain-Barre syndrome; leukodystrophies

v.

neuromuscular junction hypotonic disorders: botulism, myasthenia gravis

Box 12.21 Paternal chromosome disomy 15 produces Angelman’s syndrome, which has mental retardation, microcephaly, and myoclonus.

vi. myopathies and muscular dystrophies c. 3.

Developmental Delays and Regression

(a) Prader-Willi syndrome

ataxic motor delays: spinocerebellar degeneration, Friedreich’s ataxia, ataxia telangiectasia, abetalipoproteinemia, Refsum’s disease, aminoacidopathies

Global developmental delay a.

static encephalopathy: caused by i.

cerebral malformations from intrauterine infections, alcohol, lead, drug abuse

ii.

genetic abnormalities (1) chromosomal abnormalities: the most common cause of mental retardation (a) risk factors: affected family members; parental consanguinity; organomegaly (b) symptoms suggestive of chromosomal abnormalities (i)

head and neck abnormalities: microphthalmia, slanted eyes, small mandible, small/low-set ears, webbed neck

(ii) limb abnormalities: low-set thumb, polydactyly, radial hypoplasia, rocker-bottom feet (iii) genitourinary abnormalities: ambiguous genitalia, polycystic kidney (c) subtypes (i)

Down’s syndrome/trisomy 21—hypotonia, typical facies, Brushfield spots (Box 12.22), flat nape of neck

(ii) trisomy 18: pointed ears, micrognathia, occipital protuberance, narrow pelvis, rocker-bottom feet (iii) 5p monosomy: “cri du chat,” moonlike facies, hypertelorism, microcephaly

Box 12.22 Brushfield spots Small white spots around the edges of the iris, caused by stromal hyperplasia centered in areas of hypoplasia

(2) focal genetic abnormalities: fragile X syndrome (a) pathophysiology: caused by a trinucleotide repeat in the FMR1 gene, which encodes a protein that likely functions in translational regulation; exhibits X-linked inheritance, but 80% of males and 30% of females are affected (b) specific symptoms: autistic-like behavior, long faces, enlarged ears, macroorchidism iii. intrauterine infections: previously referred to as the “TORCH” infections, now considered the “STaRCH” infections

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(1) syphilis (see p. 254)

12 Developmental and Metabolic Diseases of the Nervous System

(a) symptoms: sensorineural hearing loss, interstitial keratitis, peg-shaped upper incisors {Hutchinson’s triad} (b) high coincidence with HIV infection (2) toxoplasmosis (see p. 264) (3) rubella: symptoms include . . . (a) growth retardation, cataracts, congenital heart malformations (b) chorioretinitis, hypotonia, seizures, somnolence from increased intracranial pressure, and sensorineural hearing loss (4) c ytomegalovirus/cytomegalic inclusion disease (see p. 257) (5) HIV: neonatal infection can also occur via infected breast milk (a) symptoms: onset between 2 months to 5 years of age (i)

encephalitis leading to failure to thrive with microcephaly

(ii) transverse myelitis (iii) opportunistic infections, particularly with bacteria (b) diagnostic testing: neonates of HIV-positive mothers will express HIV antibodies by passive transfer, therefore diagnose with HIV polymerase chain reaction (PCR) or culture iv.

subacute sclerosing panencephalitis (see p. 259)

v.

other white matter diseases: adrenoleukodystrophy, Alexander’s disease

vi. other gray matter diseases: neuronal ceroid lipofuscinosis; xeroderma pigmentosum; mitochondrial disorders; spinomuscular atrophies vii. other disorders: lead poisoning; hypothyroidism b.

autism (Box 12.23) i.

pathophysiology: possibly a first trimester disease process based on the high coincidence of minor physical malformations; not associated with childhood vaccinations (1) anatomical abnormalities are rare, but can include (a) ventriculomegaly (b) decreased cerebellar Purkinje cell number; hypoplasia of cerebellar vermis is not a consistent finding (c) decreased number of neurons and reduced dendritic arborizations in the subcortical limbic system (amygdala, hippocampus, septum) and the anterior cingulated cortex (d) polymicrogyria (e) increased volume of temporal, parietal, and occipital lobes (2) immunologic abnormalities include a high coincidence of inflammatory bowel disease that suggests immunologic reaction to dietary factors; also associated with HLA-DRB1 allele (3) genetic factors: multifactorial inheritance; monozygotic  dizygotic concordance (4) psychodynamic abnormalities: parents of autistic children exhibit poor language abilities, decreased social interaction, and a tendency toward routine, but this likely represents a mild, inherited autistic phenotype

ii.

epidemiology: 3:1 male preference

iii. symptoms: generally begin  3 years of age; symptoms are more severe in females (1) diagnostic symptoms (a) abnormal social interactions: involves at least two of the following (i)

290

failure to use eye contact, facial expression, body posture, or gestures

Box 12.23 Diseases with autistic features: phenylketonuria; intrauterine infections (rubella, cytomegalovirus (CMV); neurofibromatosis, tuberous sclerosis; Rett’s syndrome; fragile X syndrome

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(ii) failure to develop relationships with peers (iii) abnormal social or emotional responses to other peoples’ emotions (iv) lack of expression of personal interests (b) abnormal communication skills: involves at least one of the following (i)

delayed or deficient speech without compensatory gesturing

(ii) failure to initiate or sustain conversation (iii) stereotyped or repetitive use of words or phrases (iv) lack of imitative play (c) stereotyped or repetitive behaviors: involves at least one of the following (i)

preoccupation with specific, nonfunctional interests

(ii) preoccupation with nonfunctional elements of normal objects (iii) compulsive performance of inappropriate routines (iv) stereotyped or repetitive motor movements (2) other symptoms (Box 12.24) (a) mental retardation (70%)

Asperger’s syndrome

(b) seizures (30%)

Pathophysiology—Unknown, but occurs frequently in families with autism Symptoms—As for autism, except that language ability is normal and there is no mental retardation or seizures; children with Asperger’s syndrome exert more effort in making social contacts than those with autism; language development may be delayed, but will ultimately obtain normal levels; thinking often appears illogical Treatment—As per autism

(c) echolalia, dysarthria (d) decreased pain sensitivity (e) bulbar affect; hyperactivity, aggressiveness, self-injury (f) precocious abilities/splinter functions of the idiot savant (rare): photographic memory, mathematical ability, musical skill, early reading ability (may or may not have comprehension) (g) GI symptoms: nausea, diarrhea, constipation iv.

Box 12.24

Developmental Delays and Regression

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treatment (1) language development programs; encourage social behavior (2) antipsychotics (haloperidol, risperidone) for hyperactivity, repetitive and self-injury behaviors, and irritability (3) SSRIs for compulsive and repetitive behaviors

v.

prognosis (1) some symptomatic improvement occurs over time, particularly repetitive behaviors; rarely high-functioning autistic children outgrow the diagnosis (2) majority of autistic patients will require an assisted-living environment

c.

Rett’s syndrome i.

pathophysiology: almost all cases are associated with mutation of the MECP2 gene, which encodes a methylated DNA-binding protein that acts as a transcriptional repressor (Box 12.25) (1) exhibits X-linked recessive inheritance, therefore the disease is most commonly observed in homozygous girls, although it can occur in heterozygous boys

Box 12.25 Other diseases associated with MECP2 mutations: autism; childhood-onset schizophrenia; an Angelman’s-like syndrome (but not real Angelman’s syndrome)

(a) asymptomatic heterozygous females exhibit mosaicism caused by random X chromosome inactivation (2) histology: reduced dendritic arborizations in the cortex and hippocampus ii.

symptoms: grossly normal development until  6 months of age, although subtle abnormalities of movement and posture are observable and fine motor skills fail to develop

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12 Developmental and Metabolic Diseases of the Nervous System

(1) diagnostic symptoms

292

(a) motor regression with loss of purposeful hand movements followed by development of repetitive and stereotypic movements (b) failure to develop further language abilities (c) gait apraxia, ultimately developing spasticity and muscle wasting (d) loss of social interaction (e) failure of normal head growth leading to microcephaly (2) other symptoms (a) seizures (b) irregular breathing pattern when awake, often involving breath holding and apnea; breathing normalizes during sleep iii. treatment: none specific iv.

prognosis: stabilization of the disease by 20 years of age, with decreasing seizure frequency and improved social and motor function (1) 1% death rate per year, typically from malnourishment or sudden cardiac death (2) progressive muscle wasting will require use of a wheelchair

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13 Note: Significant diseases are indicated in bold and syndromes in italics.

I. Diabetes Mellitus (DM) 1.

Subtypes a.

b.

type I/insulin-dependent DM: caused by autoimmune destruction of  islet cells of the pancreas leading to insulin deficiency i.

common antibodies include those against insulin and glutamate decarboxylase (Box 13.1)

Box 13.1

ii.

typical patient is  45 years of age, thin, and prone to ketosis; frequently associated with other autoimmune diseases

Antibodies against glutamate decarboxylase also occur in stiff man’s syndrome.

type 2/noninsulin-dependent DM: caused by peripheral tissue insulin resistance; not associated with autoimmune diseases i.

c. 2.

Diabetes Mellitus (DM)

Systemic Diseases Affecting the Nervous System

typical patient is  30 years of age, obese, and ketosis-resistant

secondary diabetes: from glucocorticoid administration, Cushing’s syndrome, acromegaly, or pheochromocytoma

Diabetic neuropathies: identification of diabetic neuropathy is complicated by the association of DM with other neuromuscular diseases (ataxia telangiectasia, Friedreich’s ataxia, myotonic dystrophy, amyloidosis, porphyria, glycogen storage diseases, mitochondrial myopathies, and stiff man’s syndrome) a.

subtypes i.

symmetric diabetic neuropathies (1) diabetic chronic sensorimotor neuropathy—most common form of DM neuropathy (30% of all DM neuropathy) (a) pathophysiology: glucose is converted to sorbitol by aldose reductase and sorbitol dehydrogenase, and the accumulation of intracellular sorbitol causes cellular edema that injures primarily the vasculature and the Schwann cells (i)

histology: microvascular thickening with hyalinization, and axonal degeneration of large and small fibers; complement deposition occurs in the microvasculature with inflammatory infiltrates

(ii) risk factors include obesity, diastolic hypertension, dyslipidemia, inadequate glucose control, and other end-organ damage (albuminuria, retinopathy) (b) symptoms (i)

distal pain and paresthesias

(ii) distal sensory loss leading to foot ulcerations and neuropathic osteoarthropathy (Charcot’s joints) (iii) mild weakness; areflexia (iv) may have some dysautonomia (2) diabetic autonomic neuropathy (a) pathophysiology: degeneration of CN X and other autonomic nerves

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(i)

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10-year risk  5%, for clinical manifestations, 30% for subclinical manifestations; more common in type I DM

(ii) risk factors include duration of diabetes, adequacy of glucose control, diabetic end organ damage (albuminuria, retinopathy), age, obesity, and dyslipidemia (b) symptoms (i)

cardiovascular: high resting heart rate, orthostatic hypotension

(ii) genitourinary: erectile dysfunction with preserved ejaculation and orgasm; urinary retention (rare) (iii) gastrointestinal: constipation; gastroparesis, nocturnal diarrhea (rare) (3) diabetic acute painful neuropathy (a) risk factors include inadequate glucose control, rapid weight loss, and the recent initiation of insulin therapy (b) symptoms: distal pain with mild sensory loss ii.

asymmetric and focal diabetic neuropathies (1) proximal diabetic plexopathy/diabetic amyotrophy/BrunsGarland syndrome (a) pathophysiology: immunoglobulin M (IgM) and complement deposition in endoneurium leading to macrophage infiltration of the microvasculature of the lumbosacral plexus and/or upper lumbar roots (i)

more common in type II DM

(ii) risk factors include inadequate glucose control and rapid weight loss (b) symptoms (i)

pain in the hip, buttocks, or thigh

(ii) weakness in the proximal lower extremity muscles that usually involves muscles not innervated by the femoral nerve, therefore it is not equivalent to a diabetic femoral neuropathy (iii) minimal sensory loss (c) diagnostic testing: EMG demonstrates multifocal denervation in the paraspinous muscles indicating the involvement of the nerve roots (2) diabetic mononeuropathy (a) epidemiology: tends to occur in older patients (b) symptoms: neuropathies are generally painful; commonly involves (i)

CN III (pupil-sparing)

(ii) CN VII (iii) peripheral nerves (particularly those of the lumbosacral plexus) that often mimic an entrapment neuropathy (e.g., median nerve at the carpel tunnel, ulnar nerve at elbow, posterior tibial nerve at tarsal tunnel) (Box 13.2) (iv) peripheral nerves of the trunk, wherein the weakened abdominal muscles allow for hernia formation b.

treatment: intensive control of blood glucose, which reduces neuropathy risk by 60% i.

3.

Diabetic myopathy ( diabetic amyotrophy) a.

294

target HgA1c (a glycosylated hemoglobin) to  7%, although there is no threshold for developing neuropathy

pathophysiology: unknown, but likely due to a microangiopathy in the muscle

Box 13.2 Multiple mononeuropathies can give the appearance of a mononeuritis multiplex.

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Table 13–1 Diabetic and Hypoglycemic Comas

Cause

Diabetic ketoacidosis

Hyperosmolar nonketotic coma

Hypoglycemic coma

↓ Insulin  ↑ glucagon levels causes . . .

Sustained hyperglycemia induces diuresis, leading to hypovolemia

Postprandial: GI surgery, vagotomy

gluconeogenesis and ↓ glucose use → hyperglycemia and diuresis

Fasting: hypopituitarism, adrenal failure, catecholamine deficiency

Nausea and shortness of breath; hypo- or hyperthermia

No nausea and shortness of breath

Sympathetic hyperactivity

Diagnostic testing

Anion gap; metabolic acidosis; blood and urine ketones; hypertriglyceridemia

Glucose typically  1000 mg/dL; only mild metabolic acidosis

Glucose typically  45 mg/dL; rule out factitious hypoglycemia with C-peptide and sulfonylurea

Treatment

Fluids; insulin; potassium supplementation; bicarbonate

Fluids (typically  10 L); insulin; potassium supplementation

IV glucose until taking PO

Neurological complications

Cerebral edema can develop in a delayed fashion; ↑ acute stroke risk

↑ acute stroke risk

Abbreviations: GI, gastrointestinal; IV, intravenously; PO, orally.

i.

risk factors include inadequate glucose control, other end organ damage (retinopathy, nephropathy, neuropathy), and hypertension

ii.

epidemiology: more common in women and type I diabetics

b.

symptoms: acute pain, tenderness, and swelling of the muscle, which is exacerbated by movement; usually located in the anterior or medial thigh  calf

c.

diagnostic testing i.

normal or elevated CK

ii.

elevated erythrocyte sedimentation rate (ESR), usually  100

Hypertension

Ketogenesis causes acidosis Key pre-coma symptoms

iii. plain films can demonstrate vascular mineralization

4.

iv.

MRI: demonstrates edema in muscle and perifascial space with fluid collection in tissue planes; minimal contrast enhancement

v.

muscle biopsy shows necrotic muscle fibers, hyaline thickening of the arterioles, and perivascular inflammation

d.

treatment: rest; analgesics; gradual mobilization

e.

prognosis: spontaneous resolution over weeks to months; recurs in 60%, but not necessarily in the same muscle group

Diabetic and hypoglycemic comas (Table 13–1)

II. Hypertension 1.

Pathophysiology a.

b.

definitions: normal blood pressure is defined as systolic  130 mmHg and diastolic  85 mmHg; mild hypertension begins at systolic  140 mmHg and diastolic  90 mmHg i.

hypertensive urgency: hypertension without significant symptoms or laboratory abnormalities

ii.

hypertensive emergencies: stage III hypertension that involves endorgan failure

causes i.

primary/essential hypertension (95%)

ii.

secondary hypertension (1) renal parenchymal diseases  renovascular diseases (2) endocrine: primary aldosteronism, Cushing’s disease, pheochromocytoma, hypercalcemia during hyperparathyroidism, oral contraceptive use

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(3) aortic dissection or coarctation

13 Systemic Diseases Affecting the Nervous System

(4) iatrogenic: hypercarbia, hypoxia, hypoglycemia, pulmonary edema (5) neurological (rare): status epilepticus, elevated intracranial pressure (a) Cushing reflex—hypertension  bradycardia  respiratory irregularity, reflecting dysfunction of the medulla (i)

2.

development of the Cushing reflex is predominantly related to the size of an intracranial mass, not the rate of its expansion

Symptoms a.

central nervous system i.

headache, typically occipital and most severe in the morning

ii.

lightheadedness and syncope; vertigo, tinnitus; visual blurring

iii. stroke iv.

hypertensive encephalopathy (1) pathophysiology: the blood pressure exceeds the cerebral autoregulatory limit, allowing for proportionate increases in cerebral blood flow and volume; typically occurs with damage to other end organs (e.g., proteinuria, angina) (a) rate of change of blood pressure is better related to development of encephalopathy than is the maximum blood pressure; the absence of preexisting chronic hypertension allows for the encephalopathy to develop at lower, near-normal blood pressures (i.e., 160/100 mmHg) (b) symptoms relate to endothelium damage that causes microhemorrhages and increased intracranial pressure from vasogenic cerebral edema; the posterior circulation may be more susceptible than the anterior circulation to these effects because of a relative lack of sympathetic innervation modulates the range of cerebrovascular autoregulation (2) specific symptoms: acute to subacute onset of lethargy, confusion, headache, visual disturbances (blurring to blindness); may ultimately involve seizures and stroke (3) diagnostic testing for hypertensive encephalopathy (a) neuroimaging: increased T2 signal mostly in the white matter of the parietal and occipital lobes suggests edema {posterior reversible leukoencephalopathy} (Box 13.3) (i)

despite its name, posterior reversible leukoencephalopathy ✧

involves gray matter and white matter

✧

can involve the brainstem

✧

is not limited to the posterior cerebrum

(b) EEG: shows loss of the posterior alpha rhythm, diffuse slowing, and posterior epileptiform activity

3.

296

b.

retina: vascular changes observed by funduscopy directly parallel arteriosclerosis in other organs

c.

dilated cardiomyopathy and congestive heart failure; angina progressing to myocardial infarction; aortic dissection

Treatment: rapid reductions in blood pressure may precipitate end organ hypoperfusion, causing myocardial infarction, stroke, or renal ischemia; recommend use of nitroprusside, labetalol, or hydralazine a.

hypertensive urgency: reduce the mean arterial pressure over hours to days; patients are typically volume depleted, which would require careful rehydration

b.

hypertensive emergency: reduce the mean arterial pressure by 25% within a period of minutes to hours; avoid the use of centrally acting antihypertensives in cases with hypertensive encephalopathy (e.g., clonidine)

Box 13.3 Other causes of posterior reversible leukoencephalopathy—immunosuppressant medications; HIV/AIDS; post-carotid endarterectomy reperfusion; thrombotic thrombocytopenic purpura

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Disease

Abnormality

Symptoms and signs

Treatment

Abetalipoproteinemia

Absence of apoprotein B causes ↓ cholesterol and vitamin E

Fat malabsorption; acanthocytosis; demyelinating polyneuropathy; spinocerebellar ataxia; retinitis pigmentosa

Vitamin E

Cerebrotendinous xanthomatosis

Decreased liver bile secretion causes ↑ cholesterol

Tendon xanthomas; cataracts; dementia; ataxia from spinal cord degeneration

Chenodeoxycholic acid

Niemann-Pick type C (Types A and B are sphingolipidoses) (see p. 285)

Inability to esterify cholesterol causes ↑ cholesterol

Liver failure; dementia; psychosis; vertical gaze palsy; dystonia; seizures; cataplexy

None specific

Smith-Lemli-Opitz syndrome

Deficiency of dehydrocholesterol reductase prevents cholesterol biosynthesis

Craniofacial deformity; syndactyly; cardiac and genital malformations; mental retardation from microcephaly  holoprosencephaly

Cholesterol and bile acids

Tangier’s disease

Mutations of ATP-binding cassette transporter A1 (ABCA1) protein causes ↓ cholesterol

Orange tonsils; organomegaly; polyneuropathy (may be recurrent)

None specific

III. Dyslipidemias (Table 13–2) IV. Autoimmune Disorders 1.

Autoimmune Disorders

Table 13–2 Rare Disorders of Lipid Metabolism that Affect the Nervous System

Rheumatoid arthritis a.

pathophysiology: thought to be induced by an unknown infection in genetically susceptible people, wherein antibodies against the Fc portion of IgG {rheumatoid factor} (which normally act to increase the inflammatory process) become nonspecific and begin to injure tissues

b.

symptoms i.

arthritis with joint erosions, ligament laxity, and muscle spasms; associated with (1) cervical spine instability: destruction of the transverse ligament of C1 or by erosion of the odontoid process causes instability of C1–2 articulation; rupture of the transverse ligament can directly cause subluxation and cord compression (2) entrapment neuropathies in the wrist, elbow, and ankle

ii.

mononeuritis multiplex

iii. rheumatoid nodules; pleuritis; pericarditis (1) painful hoarseness and dysphonia is from vocal cord inflammation, not from vagus neuropathy (Box 13.4) 2.

Juvenile rheumatoid arthritis a.

symptoms: onset  16 years of age, typically  3 years of age i.

entrapment neuropathies and atlantoaxial subluxation from arthritis (1) developmental motor delay may occur as a result of severe arthropathy

ii.

acute encephalitis involving seizures

iii. chronic meningitis causing seizures, hydrocephalus, and developmental delays iv.

Reye’s-like syndrome—liver failure, hyponatremia, and headache from increased intracranial pressure; may develop disseminated intravascular coagulation (DIC) that causes intracranial hemorrhage

v.

dystonia from transient bilateral basal ganglia dysfunction

Box 13.4 Autoimmune sensory trigeminal neuropathy Pathophysiology—Unknown; can be associated with any autoimmune disease Symptoms—Bilateral sensory loss with pain and paresthesias; masticatory muscles are spared; reduced blink reflex leads to corneal abrasions Treatment—None

vi. rash; lymphadenopathy; recurrent fevers; hepatosplenomegaly; iritis b.

diagnostic testing for neurological disease: EEG demonstrate focal or generalized slowing irrespective of seizures in 50%

c.

treatment: glucocorticoids for neurological complications

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Systemic lupus erythematosus a.

pathophysiology: caused by autoantibodies directed against cellular and blood-borne elements; immune complex deposition (IgM, IgG, IgA) causing complement formation and inflammation (i.e., a necrotizing vasculitis)

b.

histology

c.

i.

immune complex deposits are observed in the choroids plexus but not in the brain parenchyma; multiple microvascular infarcts are the most common CNS abnormality, although vasculitis in the CNS is very uncommon

ii.

Libman-Sacks vegetations are formed by inflammatory cells and fibrin and are typically located on the mitral valve; may become infected or directly erode the valve

symptoms i.

general symptoms: fatigue; lymphadenopathy; arthritis; serositis (pericarditis, pleuritis, pericarditis); rash, alopecia, oral and genital ulcers; myocarditis causing arrhythmias and a dilated cardiomyopathy

ii.

psychiatric symptoms: often fluctuate and involve mood disorders (major depression, bipolar disorders) or psychosis (1) similar to glucocorticoid-induced behavioral changes but symptoms get worse with discontinuation of glucocorticoids

iii. neurological symptoms (1) headache (40%) (2) seizures (15%) (3) organic brain syndromes (15%): commonly manifests as an amnestic syndrome, dementia, or encephalopathy {lupus delirium} (4) stroke (5%): due to a hypercoagulable state, marantic endocarditis, advanced atherosclerosis, and/or bland vasculopathy (Box 13.5) (5) chorea and dystonia (6) sensorimotor polyneuropathy (15%); rarely mononeuropathy from vasculitis d.

4.

Stroke is particularly common with antiphospholipid antibody syndrome (see p. 73).

diagnostic testing for neurological disease i.

cerebrospinal fluid analysis and EEG are nonspecific

ii.

neuroimaging: atrophy is common, but does not reflect the severity of neurological or psychiatric disease; MRI shows areas of increased T2 signal in the subcortical white matter that typically resolve with glucocorticoid treatment

Sarcoidosis a.

pathophysiology: non-caseating granuloma formation predominantly in the lung, skin, lymph nodes, and eye, but potentially occurring in any organ i.

b.

neurosarcoidosis generally occurs in the presence of non-pulmonary systemic disease, but it may be the sole location of the disease in 10% of cases

symptoms i.

general symptoms: fatigue, weight loss; dyspnea, hemoptysis; arthritis; uveitis

ii.

neurological symptoms (Box 13.6) (1) cranial neuropathy (70%, usually CN VII) or peripheral neuropathy (10%) (a) vision loss and ophthalmoplegia can alternatively be caused by direct orbital disease (2) central nervous system involvement (5%): typically located along the basal surfaces, and presents as (a) an acute or chronic meningitis

298

Box 13.5

(b) an intracranial mass (e.g., secondary hypopituitarism from hypothalamic dysfunction)

Box 13.6 Heerfordt syndrome Sarcoid presenting as uveitis, salivary gland inflammation, and multiple cranial nerve palsies

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(c) focal spinal cord injury resembling transverse myelitis (d) mild personality changes iii. myopathy, but never involving the ocular motor muscles c.

diagnostic testing for neurological disease i.

neuroimaging may demonstrate granulomas

ii.

cerebrospinal fluid analysis demonstrates lymphocytic pleocytosis, increased angiotensin-converting enzyme (40%), increased protein (70%), and/or decreased glucose (20%) levels (1) may exhibit oligoclonal bands like multiple sclerosis

iii. muscle and nerve biopsy demonstrates granulomas in mononeuropathies or vasculitis in symmetric polyneuropathies

e. 5.

i.

brain involvement: glucocorticoids

ii.

peripheral neuropathy: glucocorticoids; immunosuppressants

prognosis: 10% mortality in cases with neurological involvement

Sjögren’s syndrome a.

pathophysiology: autoimmune destruction of the lacrimal and salivary glands involving T lymphocyte and plasma cell infiltration; affected peripheral nerves also demonstrate perivascular lymphocyte infiltration

b.

symptoms

c. 6.

treatment

Nutritional Disorders

d.

i.

dry eyes and mouth {sicca syndrome}

ii.

large and small fiber sensory neuropathy (20%), which may precede the sicca syndrome; may present as a polyradiculoneuropathy with pronounced large fiber sensory deficits causing ataxia

treatment: neuropathy is generally resistant to glucocorticoids

Antiphospholipid antibody syndrome (see p. 73)

V. Nutritional Disorders 1.

Celiac disease/gluten-sensitive enteropathy a.

pathophysiology: caused by an immune reaction against gluten proteins (e.g., gliadin)

b.

symptoms

c.

d. 2.

i.

general symptoms: episodic malabsorption

ii.

neurological symptoms (10%): progressive ataxia (Box 13.7) and cerebellar dysarthria, and myoclonus; rarely associated with neuropathy, myelopathy, and/or dementia

Box 13.7 Celiac disease may account for 40% of sporadic idiopathic ataxias.

diagnostic testing for neurological disease i.

serum antigliadin antibodies, and IgA antibodies against smooth muscle endomysium

ii.

neuroimaging demonstrates atrophy of the cerebellum and cerebral cortex with white matter lesions and calcifications

treatment: gluten-free diet; (oats are the only safe grain)

Vitamin B1/thiamine deficiency a.

biochemical actions: thiamine is a cofactor in the conversion of pyruvate to -ketoglutarate in TCA cycle (pyruvate decarboxylase) and in the pentose phosphate shunt (transketolase)

b.

thiamine deficiency is caused by malnutrition

c.

symptoms: become pronounced during glucose administration i.

beriberi (1) general symptoms: cardiomyopathy; muscle cramps (2) neurological symptoms: sensorimotor polyneuropathy; optic neuropathy

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Wernicke’s encephalopathy—symptoms include

13 Systemic Diseases Affecting the Nervous System

(1) ataxia with minimal limb dysmetria (2) nystagmus: horizontal  vertical (3) ophthalmoplegia: horizontal paralysis  other directions; light-near dissociation (4) encephalopathy, but coma is rare (5) autonomic instability iii. Korsakoff’s syndrome—always develops from a Wernicke’s encephalopathy; symptoms include anterograde and retrograde amnesia, confabulation, and residua from Wernicke’s encephalopathy (lateral nystagmus, ataxia) 3.

Vitamin B6/pyridoxine deficiency (Box 13.8) a.

biochemical action: vitamin B6 is a necessary cofactor of several enzymes involved in amino acid metabolism

b.

causes of vitamin B6 deficiency

c.

4.

i.

neonates: breastfeeding from malnourished mothers

ii.

adults: hydralazine, isoniazid, or penicillamine use

symptoms i.

neonates: irritability with excessive auditory startle; medicationresistant seizures

ii.

adults: painful sensorimotor neuropathy

Vitamin B12 deficiency a.

biochemical actions: vitamin B12 is a cofactor in the conversion of homocysteine to methionine (cystathionine -synthase) and the conversion of methylmalonyl CoA to succinyl CoA (methylmalonyl-CoA mutase; see p. 73)

b.

causes of vitamin B12 deficiency include i.

intrinsic factor deficiency due to parietal cell destruction in the stomach

ii.

ileum resection leading to malabsorption of the vitamin

iii. HIV/AIDS iv. c.

nitrous oxide intoxication

symptoms: anemia and neurological symptoms are not necessarily correlated i.

general symptoms: pernicious/megaloblastic anemia, which may be masked by folate supplementation

ii.

neurological symptoms: not affected by folate supplementation (1) myelopathy/subacute combined degeneration—symptoms include (a) distal paresthesias and pain (b) spastic weakness in the lower  upper extremities due to corticospinal tract degeneration; reflexes may be diminished, not increased, due to a coincident peripheral neuropathy (c) ataxia from degeneration of the spinocerebellar tracts (d) loss of vibratory and position sense in the lower  upper extremities that often extend onto the trunk, from degeneration of the dorsal columns; may give the false appearance of a sensory level (2) large fiber sensory neuropathy

300

Box 13.8 Vitamin B6 overdose can cause peripheral neuropathy.

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Table 13–3 Other Vitamin Deficiencies Biochemical use

Cause of deficiency

Symptoms

Niacin/nicotinic acid

Precursor for NAD and NADP

Chronic malnutrition; high corn intake

Diarrhea, anorexia, keratotic skin {pellagra}; encephalopathy, myoclonus, spasticity

Folate

Conversion of homocysteine to methionine

Chronic malnutrition; inflammatory bowel disease

Megaloblastic anemia; mild subacute combined degeneration

Vitamin E

Free radical scavenger

Fat malabsorption syndromes; tocopherol transferase protein mutations; abetalipoproteinemia

Acanthocytosis; weakness, ataxia; ophthalmoplegia, neuropathy

(3) encephalopathy involving depression and psychosis that may progress to coma (4) dementia (5) optic neuropathy with atrophy iii. spina bifida in cases of prenatal deficiency 5.

Other vitamin deficiencies (Table 13–3)

Nutritional Disorders

Abbreviations: NAD, nicotinamide adenine dinucleotide; NADP, nicotinamide adenine dinucleotide phosphate.

Appendix 13–1 Electrolyte Abnormalities Relevant to the Nervous System Too little

Electrolyte

Too much

Lethargy, confusion, coma; fasciculations; seizures

Sodium

Lethargy, confusion, coma; fasciculations; seizures

Athetosis, fasciculations, muscle cramps; tetany (Trousseau and Chvostek signs); cardiac arrhythmia (long QT); seizure

Calcium

Nausea, constipation, polyuria; fatigue; cardiac arrhythmia (short QT); confusion → coma

Loss of proprioception and vibration LE  UE, gait ataxia, spastic weakness LE  UE (like subacute combined degeneration)

Copper

Hypotension; liver failure; coma

Anorexia, nausea; weakness, muscle cramps; lethargy, irritability, confusion

Magnesium

Sedation → coma; hypoventilation; decreased reflexes, weakness; hypotension, bradycardia

Myopathy, rhabdomyolysis, dilated cardiomyopathy

Phosphate

None in particular

Growth retardation; alopecia, dermatitis

Zinc

Fevers, chills; salivation; lethargy; headache; usually causes copper deficiency

Coagulopathy

Manganese

Confusion; headache; muscle cramps; impotence; dysarthria

Myopathy with multifocal myocardial necrosis

Selenium

Alopecia, emotional lability, garlic halitosis

Abbreviations: LE, lower extremity; UE, upper extremity.

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Index

A Abdominal migraine, 138 Abducens nucleus, 23, 44, 44b neurons of, 44 pathophysiology in, 44 Abducent nerve (CN VI), 24f, 32, 43, 43f disorders/syndromes of, 34t palsy of, 43 Abductor digiti quinti, 213f Abductor pollicis brevis, 210f, 211, 214f, 229t Abductor pollicis longus, 214f, 216f, 229t Abetalipoproteinemia, 297t Abilify. See Aripiprazole Abs-and-jolts syndrome, 143 Abscess, brain, 249–251 Absence seizures, 95 childhood and juvenile, 95 versus complex partial seizures, 85t diagnostic testing in, 95 EEG findings in, 95, 95f eyelid myoclonus with, 95b pathophysiology of, 95 symptoms of, 95, 95b treatment of, 95 Absent muscles, diseases of, 248t Abulia, lesions causing, 12 Acamprosate, for alcohol dependence, 179 Acanthamoeba, 264 Accessory nerve (CN XI), 26, 26f, 32, 33f disorders/syndromes of, 34t Accessory ocular motor nuclei, 22, 44–45 medullary, 44–45 mesencephalic, 44 pathophysiology involving, 45 pontine, 44–45 Accessory olivary nucleus, 26f Acephalgic migraine, 138 Aceruloplasminemia, 195b Acetaminophen for migraine, benefit not clear with, 140b for tension-type headache, 141

Acetazolamide for absence seizures, 95 for Canavan’s disease, 115 for episodic ataxia, 201 for myotonic dystrophy, 239 for pseudotumor cerebri, 147 Acetylcholine, in aspiny neurons, 11 Acetylcholine receptor, in myasthenia gravis, 235 Acetylcholinesterase inhibitors for Alzheimer’s disease, 158 for Lambert-Eaton myasthenia, 237 for Lewy body dementia, 163 for vascular dementia, 160 Achromatopsia, 42 Acidemia(s) isovaleric, 280–281, 280b propionic, 280b, 281 Aciduria, methylmalonic, 281 Acinteobacillus, 69 Acquired epileptiform aphasia, 95–96 Acquired epileptiform opercula syndrome, 96 diagnostic testing in, 96 EEG findings in, 96 pathophysiology of, 96 symptoms of, 96 treatment of, 96 Acquired immunodeficiency syndrome. See Human immunodeficiency virus Action potential(s) compound muscle, 204, 206, 215 conduction of, 203f Activated protein C resistance, 72 Acute disseminated encephalomyelitis (ADEM), 111–112 diagnostic testing for, 111–112 epidemiology of, 111 histology of, 111 versus multiple sclerosis, 110 neuroimaging of, 112, 112f pathophysiology of, 111 prognosis of, 112 versus Reye syndrome, 112 symptoms of, 112 treatment of, 112

Index

Page numbers followed by b, f, or t indicate entries in boxes, figures, or tables, respectively.

303

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Acute inflammatory demyelinating polyneuropathy (AIDP), 221–222 diagnostic testing for, 222 electromyography of, 222 nerve conduction studies of, 222 prognosis of, 222 serology in, 222 symptoms of, 222 Acute motor axonal neuropathy (AMAN), 221–223 diagnostic testing for, 223 electromyography of, 223 nerve conduction studies of, 223 prognosis of, 223 symptoms of, 222 Acute motor-sensory axonal neuropathy (AMSAM), 221, 223 diagnostic testing for, 223 electromyography of, 223 nerve conduction studies of, 223 prognosis of, 223 symptoms of, 223 Acute necrotizing hemorrhagic encephalomyelitis, 112 diagnostic testing for, 112 histology of, 112 pathophysiology of, 112 prognosis of, 112 symptoms of, 112 treatment of, 112 Acute panautonomic neuropathy, 223 Acyclovir for Bell’s palsy, 34 for herpes simplex virus, 256 for herpes zoster virus, 257 Adamkiewicz, artery of, 31f Adductor muscles, 229t Adductor pollicis, 213, 213f, 229t Adenoma(s), 132–133 epidemiology of, 133 genetics of, 133 GnRH-secreting, 133 histology of, 132 pathophysiology of, 132 prolactin-secreting, 133 symptoms of, 133 treatment of, 133 Adenoma sebaceum, in tuberous sclerosis, 277, 277f Adenosyl-methionine, for fibromyalgia, 151 Adie’s tonic pupil, 224 Adrenocorticotropic hormone (ACTH) in chronic fatigue syndrome, 151 for infantile spasms, 93 Adrenoleukodystrophy, 116–117, 290 adult-onset, 117 childhood, 116–117 diagnostic testing for, 117 pathophysiology of, 116 symptoms of, 116–117 treatment of, 117 Adrenomyeloneuropathy, 117 Advanced sleep phase syndrome, 169 Affective prosody, 6 Afferent(s) cerebellar, 18–19 cortical, 1 hypothalamic, 18f reticular formation, 29 subcortical, 4

Age and Alzheimer’s disease, 157 and electromyography, 233–234 and ischemic stroke, 55 and multiple sclerosis, 104 and nerve conduction studies, 206 Age-related memory loss, 154 Aggrenox (dipyridamole  aspirin), for stroke prevention, 60 Aggression in Alzheimer’s disease, 157 lesions causing, 8 Agitation in Alzheimer’s disease, 157–158 treatment of, 158 Agnosia(s). See also specific types in Alzheimer’s disease, 157b auditory, 51 Agoraphobia, 175 Aicardi-Goutieres syndrome, 116 diagnostic testing for, 116 histology of, 116 pathophysiology of, 116 symptoms of, 116 Aicardi’s syndrome, 92b, 271b AIDS. See Human immunodeficiency virus (HIV) AIDS dementia complex, 260–261 Akinesia, global, 3 Akinetopsia, 42 Akisthesia, 169 Albendazole, for cysticercosis, 264 Albumin, in multiple sclerosis, 108 Albuterol, for facioscapulohumeral muscular dystrophy, 241 Alcohol, 178–179 abuse and dependence, 178–179 neurological complications of, 178 treatment of, 178–179 acute intoxication, 178 biochemical effects of, 178 and central pontine myelinosis, 112, 178 chronic use, 178 and intracranial hemorrhage, 66 and ischemic stroke, 56 and Marchiafava-Bignami disease, 113, 178 in schizophrenia, 171 Alcoholic neuropathy, 178, 178b Alcohol withdrawal, 179 and REM sleep behavior disorder, 170 seizures with, 179, 179b Alexander’s disease, 114–115, 290 adult form of, 114–115 diagnostic testing for, 115 histology of, 114 infantile form of, 114 juvenile form of, 115 pathophysiology of, 114 prognosis of, 115 symptoms of, 114–115, 114b treatment of, 115 Alexia, lesions causing, 5 Alien hand syndrome, 10, 188 Allocortex, 2 Almotriptan, 140t Alobar prosencephaly, 270 Alpha frequency, in EEG, 80b in schizophrenia, 171 Alprazolam, for tinnitus, 51

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Alzheimer glia type 1, 194 Alzheimer glia type 2, 194, 194b Alzheimer’s disease, 155–159 age and, 157 behavioral impairment in, 157–158 CSF analysis in, 158 diagnostic testing for, 158 differential diagnosis of, 159t EEG findings in, 158 epidemiology of, 155f, 157 executive impairment in, 157 familial/early-onset, 156–157 genetics of, 156–157, 157f, 158 Hirano bodies in, 156, 156f histology of, 155–156, 155b, 155f–156f language impairment in, 157 memory loss in, 157 neurofibrillary tangles in, 155, 155f neuroimaging in, 158, 158f neurological signs in, focal and nonfocal, 158, 158b plaques in, 155–156 prevention of, 158 prognosis of, 159 progression of mild cognitive impairment to, 154 risk factors for, 156 sporadic, 156 subtypes of, 156–157 symptoms of, 157–158 treatment of, 158 visuospatial impairment in, 157 Amantadine for cocaine dependence, 180 for drug-induced parkinsonism, 202 for multiple sclerosis, 109 for Parkinson’s disease, 186, 186t Ambien. See Zolpidem Amebiasis, 264 Amelodia, lesions causing, 6–7 Aminoacidopathies, 279–280 Aminoglycoside(s), and vertigo, 54 Aminopyridine, for multiple sclerosis, 109 Amiodarone, and parkinsonism, 202 Amitriptyline, 174t for chronic headache, 144–145 for insomnia, 167 for migraine prophylaxis, 140 for vertigo, 52 Amnesia(s). See also specific types antero- and retrograde, 13 anterograde, 13, 15, 178 transient global, 7–8 Amnestic mild cognitive impairment, 154 Amoxapine, for insomnia, 167 AMPA receptors, in ALS, 196 Amphetamine(s) abuse and dependence, 180–181 acute intoxication, 180 biochemical effects of, 180 chronic use of, 180 and dystonia, 191 and intracranial hemorrhage, 66 for narcolepsy, 168 and restless legs syndrome, 169 and subarachnoid hemorrhage, 63 and tics, 193

and vasculitis, 77 withdrawal from, 181 Amphotericin, and parkinsonism, 202 Amplitude asymmetries, in EEG, 80–81 Ampulla, 49 Ampullary crests, 49f Amusia, 7, 51b Amygdala, 8 functions of, 8 lesions of, 8 subdivisions of, 8 -Amyloid, in Alzheimer’s disease, 156 Amyloid angiopathy, 65–66, 65b Dutch-type, 66 Icelandic-type, 66, 95b Amyloidosis, monoclonal gammopathy in, 226 Amyloid precursor protein (APP), 66, 156, 157f Amyotrophic lateral sclerosis (ALS), 196–197 adult, 197t childhood, 197t dementia in, 196 diagnostic testing for, 196–197 familial, 196 histology of, 196 pathophysiology of, 196 prognosis of, 197 sporadic, 196 subtypes of, 196 symptoms of, 196, 196b treatment of, 197 variants of, 197, 197t Analgesic(s). See also specific types overuse of, and chronic headache, 144 Anaplastic astrocytoma, 121 Anaplastic meningioma, 124 Anaplastic oligodendroglioma, 122–123 Androgen(s), in adrenoleukodystrophy, 117 Androgenic steroids, for Duchenne’s muscular dystrophy, 238 Anencephaly, 274b Anesthesia dolorosa, 15 Anesthetic coma, for status epilepticus, 89t Aneurysm(s), 77–78 anterior circulation, 77 conditions associated with, 77 fusiform, 78 locations of, 77 oculomotor nerve palsy and, 43 pathophysiology of, 77 posterior circulation, 77 saccular/berry, 78 serpentine, 78 shape of, 78 size of, 77 and subarachnoid hemorrhage, 63–65, 77 Angelman’s syndrome, 289b Angiofibromas, facial, in tuberous sclerosis, 277, 277f Angiography of arterial dissection, 70, 71f of arteriovenous malformations, 78f of carotid stenosis, 57 of fibromuscular dysplasia, 70, 70f of infectious endocarditis, 69 of Moyamoya disease, 79, 79f stroke risk with, 55b of subarachnoid hemorrhage, 63 of tuberous sclerosis, 277

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Angioma(s) cavernous, 79, 79f in Sturge-Weber syndrome, 277–278, 278f venous, 79 Angiomatous meningioma, 123 Angiopathy amyloid, 65–66, 65b, 95b hypertensive, 65 Angiotensin-converting enzyme (ACE) inhibitors, for stroke prevention, 62 Anomia in Alzheimer’s disease, 157 lesions causing, 6 Anorexia nervosa, and central pontine myelinosis, 112 Anosognosia for blindness, 42–43 lesions causing, 5 Ansa lenticularis, 13, 13b Antabuse (disulfiram), for alcohol dependence, 179 Anterior cerebral artery, 15f, 43f, 57f Anterior choroidal artery, 15f, 39f, 40, 57f infarction of, 40, 40f Anterior cingulate gyrus, 7 Anterior cochlear nucleus, 48f Anterior commissure, 10, 10f Anterior communicating artery (ACA), 39, 39f Anterior cord syndrome, 31 Anterior corticospinal tract, 29, 30f Anterior funiculus, 29 Anterior horn, 31 Anterior inferior cerebellar artery, 21f Anterior interosseous nerve, 229t Anterior interosseous syndrome, 211–212 diagnostic testing for, 212 electromyography of, 212 Martin-Gruber anastomosis in, 212, 212f nerve conduction study of, 212 pathophysiology of, 211 symptoms of, 211 treatment of, 212 Anterior ischemic optic neuropathy (AION), 38–39 arteritic, 38 non-arteritic, 39 Anterior mesencephalic syndromes, 22–23, 22f Anterior nuclei group (ANG), thalamic, 13, 14f bilateral lesions of, 13 subcortical afferents of, 13 Anterior spinal artery, 21f, 31f Anterior thalamic nucleus, 18f Antero- and retrograde amnesia (Korsakoff’s syndrome), 13 Anterocollis, 191 Anterograde amnesia alcohol abuse and, 178 lesions causing, 13, 15 Anterograde memory, 154b Anticardiolipin antibody, 73 Anticholinergic agents and dementia, 155 for dystonia, 192 Anticoagulant(s) for antiphospholipid antibody syndrome, 73 for arterial dissection, 71 for brain tumors, 132 for fibromuscular dysplasia, 70 for inherited coagulation disorders, 72 and intracranial hemorrhage, 66–67

for ischemic stroke, 59 mechanism of action, 60f for stroke prevention, 60 for venous infarction, 75 Anticoagulation cascade, 60f Anticonvulsant(s). See Antiepileptic(s) Antidepressants, 174t benefits of, specific, 174t for conversion disorder, 177 for fibromyalgia, 151 for insomnia, 167 for major depressive disorder, 173 for migraine prophylaxis, 140 in multiple sclerosis, 109 and restless legs syndrome, 169 second generation, 174t side effects of, 174t for tinnitus, 51 tricyclic benefits of, specific, 174t for cataplexy, 168 for chronic fatigue syndrome, 151 for complex regional pain syndrome, 150 side effects of, 174t Antidiuretic hormone (ADH), 17t inappropriate secretion of, 16t Antiemetics for Meniere’s disease, 53 for migraine, 140 for vertigo, 52 for vestibular neuronitis, 53 Antiepileptic(s), 101, 101f, 102t–103t. See also specific drugs for bipolar disorder, 174 for brain tumors, 132 for chronic headache, 144–145 discontinuation of, 101 failure of, management of, 101 for febrile seizures, 92 for ischemic stroke, 60 for Landau-Kleffner syndrome, 96 for metastasis, 131 for migraine prophylaxis, 140 for multiple sclerosis, 109 for neuromyotonia, 246 remission achieved with, 101, 101b for schizophrenia, 172 and tics, 193 for tonic-clonic seizures, 88 for trigeminal neuralgia, 148 and vertigo, 54 Antihypertensive(s), 296 for ischemic stroke, 59 for stroke prevention, 61–62 for subarachnoid hemorrhage, 63 and vertigo, 54 Anti-myelin antibodies, in multiple sclerosis, 108 Antiphospholipid antibody(ies), in ischemic stroke risk, 58 Antiphospholipid antibody syndrome, 73, 298b diagnostic testing for, 73 epidemiology of, 73 pathophysiology of, 73 prognosis of, 73 symptoms of, 73 treatment of, 73 Antiplatelet agent(s) for arterial dissection, 71

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for fibromuscular dysplasia, 70 for inherited coagulation disorders, 72 for stroke prevention, 60 Antipsychotic(s), 172t atypical, 172, 172t, 201 for Alzheimer’s disease, 158 for Lewy body dementia, 163 for major depressive disorder, 173 for autism, 291 benefits of, specific, 172t for bipolar disorder, 174 for cocaine intoxication, 180 and dystonia, 191 for Huntington’s disease, 194 and parkinsonism, 202 for Parkinson’s disease, 186, 186t for PCP/ketamine dependence, 182 receptor effect of, 172t for schizophrenia, 172 for schizophreniform disorder, 172 side effects of, 172t and tardive dyskinesia, 172, 201–202 for tic disorders, 193 typical, 172, 172t, 201 Antiretroviral drugs, for HIV infection, 260 Antithrombin III deficiency, 71–72 Antivert. See Meclizine Antoni types A and B, of schwannoma, 134, 134f Anton’s syndrome, 42–43 Anxiety disorder(s), 175–176 in complex regional pain syndrome, 150 generalized, 175 genetics of, 175 pathophysiology of, 175 subtypes of, 175–176 Aorta, 31f Aortic arch, 31f calcifications and atheroma of, and ischemic stroke, 56 Apert’s syndrome, 271 Aphasia(s). See also specific types acquired epileptiform, 95–96 in Alzheimer’s disease, 157 Broca’s, 5 conduction, 6, 9 in MASA syndrome, 271 primary progressive, 161 in striatocapsular syndrome, 9 subcortical, 13b transcortical, 6 Wernicke’s, 6 Aphemia, 6 Apnea. See also Sleep apnea pediatric syndrome of, 99 in Rett’s syndrome, 292 Apoliprotein E in Alzheimer’s disease, 156 and intracranial hemorrhage, 66 in mild cognitive impairment, 154 in vascular dementia, 159 Apomorphine, for Parkinson’s disease, 186t Apparent diffusion coefficient (ADC), in cerebral infarction, 57, 58f Apraxia(s). See also specific types constructional, 5 dressing, 5 ideomotor, 3

ocular, 43 orolingual, in Huntington’s disease, 194 in Rett’s syndrome, 292 somatotopic ideomotor, 5 Aqueduct stenosis, X-linked, 271 Arboviruses, 251t, 258 Arcade of Frohse, 216, 217f Arcuate bundle, 38f injury of, 37–38, 38f Arcuate fasciculus, 9, 9f Arcuate nucleus, 17–18, 18b, 28 Area postrema, 26 Arginase deficiency, 282 Arginine supplementation, 282 Argininosuccinate lyase deficiency, 282 Argininosuccinate synthase deficiency, 282 Argyll-Robinson pupil, 44–45 Aricept. See Donepezil Aripiprazole, 172t Arm pain, 153f Aromatic amino acid decarboxylase deficiency, 280 Arousing systems, 164 Arrhythmia(s) in facioscapulohumeral muscular dystrophy, 241 in myotonic dystrophy, 239 in polymyositis, 245 in subarachnoid hemorrhage, 65 Artane. See Trihexyphenidyl Artemether, for malaria, 264 Arterial dissection, 70–71 angiography of, 70, 71f diagnostic testing for, 70–71 epidemiology of, 71 location of, 70 magnetic resonance imaging of, 70, 71f pathophysiology of, 70–71 prognosis of, 71 symptoms of, 71 treatment of, 71 Arterial thoracic outlet syndrome, 208b Arteriovenous malformations (AVMs), 78–79 angiography of, 78f histology of, 79 magnetic resonance imaging of, 78f pathophysiology of, 78 size of, 79 unruptured, surgical treatment of, 64 Arteritic anterior ischemic optic neuropathy, 38 Arteritis. See also specific types Takayasu’s, 76 temporal, 75–76 Arthritis, rheumatoid, 297 Arthrogryposis, 289 Arylsulfatase mutations, 117, 117b Ascending cervical artery, 31f Ascending reticular activating system (ARAS), 29, 164, 166 Ash-leaf patch, in tuberous sclerosis, 276, 276f Asomatognosia, with seizures, 84 Aspartoacylase deficiency, in Canavan’s disease, 115 Asperger’s syndrome, 291b Aspergillus, 262f, 263 Aspiny neurons, 11–12 type I, 11 type II, 11 type III, 11

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Aspirin for ischemic stroke, 59 for stroke prevention, 60 versus Coumadin, 61, 61t Association area(s). See also specific areas heteromodal, 2, 4–5 monomodal auditory, 48f monomodal motor, 2 monomodal sensory, 2 unimodal somatosensory, 4 Association fibers, 9–10 long, 9–10, 9f short, 9 Association nuclei, thalamic, 15 Association visual cortex, 42–43 pathophysiology in, 42–43 subdivisions of, 42 Astereognosis, lesions causing, 4 Astrocytic tumors, 119–121 Astrocytoma(s), 119–121 anaplastic, 121 epidemiology of, 120 fibrillary, 119–121 genetics of, 119–120, 120f, 125b grading of, 119, 119b, 119t infratentorial, 120 juvenile pilocytic, 121, 121f location of, 120 MIB-1 antibody labeling of, 119, 119b nuclear atypia in, 119, 120f pituitary, 132b prognosis of, 121 subependymal giant cell, 121, 121f supratentorial, 120 treatment of, 121 uncommon types of, 121 Ataxia(s), 198–201. See also specific types in Alexander’s disease, 115 autosomal dominant, 198–200 autosomal recessive, 199–200 Bruns’ frontal lobe, 5, 36, 163 in celiac disease, 299, 299b childhood, with central nervous system hypomyelination, 115–116 episodic, 200–201 Friedreich’s, 199–200 gait, 19–20 limb, 19 in Miller-Fisher syndrome, 223 in multiple sclerosis, 106 ocular, 43 in paroxysmal choreoathetosis, 190t spinocerebellar, 198–199 Ataxia-hemiparesis, 25 Ataxia-telangiectasia (AT), 200 diagnostic testing for, 200 histology of, 200 pathophysiology of, 200 prognosis of, 200 symptoms of, 200 treatment of, 200 Ataxic motor delays, 289 Ataxic telangiectasia, dystonia in, 191 Atherosclerosis, intracranial, and ischemic stroke, 55 Ativan. See Lorazepam Atonia, in REM sleep, 166

Atonic seizures, 89 diagnostic testing in, 89 symptoms of, 89 Atrial fibrillation, and ischemic stroke, 55 Atypical meningioma, 124 Audiometry, in Meniere’s disease, 53 Auditory agnosia, 51 Auditory association area, monomodal, 48f Auditory hallucinations, 4b in schizophrenia, 171 in temporal lobe seizures, 85 Auditory hallucinosis cortical, 51 pontine, 51b Auditory nuclei, 25 Auditory system, 48f, 49 diagnostic testing of, 49, 49f end organs of, 49 Aura with migraine, 137–139 without migraine, 138 Autism, 290–291 communication skills in, 291 epidemiology of, 291 genetics of, 290 pathophysiology of, 290 prognosis of, 291 psychodynamic abnormalities in, 290 social interactions in, 291 stereotyped or repetitive behaviors in, 291 symptoms of, 291 treatment of, 291 Autistic features, diseases with, 290b Autoimmune disease, 297–299. See also specific types with myopathy, 244b Autoimmune hypothesis, of multiple sclerosis, 104 Automatism perseverative, 85 reactive, 85 Autonomic dysreflexia, syndrome of, 34 Autonomic nervous system, 34 pathophysiology in, 34 in sexual function, 34 in urination, 34 Autonomic regulation, by hypothalamus, 16, 16b Autonomic testing, in complex regional pain syndrome, 150 Autosomal dominant partial epilepsy with auditory features, 98 genetics of, 98, 98b, 120b symptoms of, 98 Aversive movements, in tonic-clonic seizures, 86 Axillary nerve, 207f, 227f–228f, 229t Axonopathic nerve conduction studies, 205b Azathioprine for chronic inflammatory demyelinating polyneuropathy, 225 for dermatomyositis, 245 for Devic’s disease, 110 for myasthenia gravis, 235 B Babinski-Nageotte syndrome, 28 Babinski sign in ataxia-telangiectasia, 200 with primary motor cortex lesions, 2 Back pain in Devic’s disease, 110 low, 151–153

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Baclofen for dystonia, 192 for multiple sclerosis, 109 for stiff man’s syndrome, 201 for trigeminal neuralgia, 148 Bacterial encephalitis, 251–252 Bacterial infections, 249–252. See also specific types Bacterial meningitis, 249 diagnostic testing for, 249 pathophysiology of, 250t symptoms of, 249 treatment of, 249 vasculitis with, 77t Bacteroides, and brain abscess, 250 Bactrim, prophylactic, for cancer patients, 132 Baillarger, line of, 2, 2f Balamuthia, 264 Balint’s syndrome, 43, 43b Ballismus, 12–13 Balo’s concentric sclerosis, 111 diagnostic testing for, 111 histology of, 111 neuroimaging of, 111, 111f prognosis of, 111 symptoms of, 111 treatment of, 111 Band of Gennari, 2 Bands of Bungner, 210 Barbiturate(s) abuse and dependence, 179–180 biochemical effects of, 179 detoxification, in chronic headache, 146 Barkhof MRI criteria, for multiple sclerosis, 108 Bartonella henselae, 251–252 Basal forebrain, 10f, 11 in arousal/sleep, 164 septal region of, 11 Basal ganglia, 11–13, 11f circuitry of, 12t, 13, 13b components of, 11–13, 11f lesions of, 11–13 ocular motor circuit of, 45 in Parkinson’s disease, 183, 184f Basal ganglia-thalamocortical loops, 11, 12t Basilar artery, 15f, 21f, 39f aneurysm of, 43 Basilar migraine, 138 Basket cell, 19f Basolateral amygdala, 8 Basophilic inclusions, in ALS, 196 Bassen-Kornzweig disease, 297t Becker’s muscular dystrophy, 238 diagnostic testing for, 238 muscle biopsy in, 238 pathophysiology of, 238 symptoms of, 238 treatment of, 238 Behavioral impairment, in Alzheimer’s disease, 157–158 Behavioral neurology, 154–182. See also specific disorders and therapies Behçet’s syndrome, pseudotumor cerebri with, 147 Bell’s palsy, 32–34 epidemiology of, 32 prognosis of, 34 symptoms of, 32 treatment of, 34

Benedikt’s syndrome, 22, 22f Benign familial neonatal convulsions, 98 hemiplegic migraine with, 138 Benign familial neonatal-infantile convulsions, 98–99 Benign myoclonic epilepsy, 93–94 diagnostic testing in, 94 EEG findings in, 94 symptoms of, 93–94 treatment of, 94 Benign occipital epilepsy, 96–97 diagnostic testing in, 97 EEG findings in, 97 pathophysiology of, 96 symptoms of, 96 Benign paroxysmal positional vertigo (BPPV), 51–52 diagnostic testing for, 52 pathophysiology of, 51–52 prognosis of, 52 symptoms of, 52 treatment of, 52 Benzoate, for urea metabolism disorders, 282 Benzodiazepine(s) abuse and dependence, 179–180 for alcohol withdrawal, 179 biochemical effects of, 179 for cocaine intoxication, 180 contraindicated in Alzheimer’s disease, 158 and dementia, 155 detoxification, in chronic headache, 146 for generalized anxiety disorder, 175 for insomnia, 167, 167b for multiple sclerosis, 109 for PCP/ketamine dependence, 182 for phobias, 175 for schizophrenia, 172 for status epilepticus, 89t for stiff man’s syndrome, 201 for tardive dyskinesia, 202 for vertigo, 52 Benztropine for drug-induced parkinsonism, 202 for dystonia, 192 for Parkinson’s disease, 186t Bergman glia, 18 Beriberi, 299 Berry aneurysm, 78 Beta blockers for alcohol withdrawal, 179 for chronic headache, 144 for migraine prophylaxis, 140 for phobias, 175 for posttraumatic stress disorder, 176 Beta frequency, in EEG, 80b in tonic-clonic seizures, 88, 88b Betz cells, 1 Biceps brachialis, 229t Biclonal gammopathy, 225 Binswanger’s disease, 8 Biofeedback for insomnia, 167 for tinnitus, 51 Biopterin deficiency, 191 Biotin supplementation, for propionic acidemia, 281 Bipolar disorder(s), 173–174 in migraine sufferers, 139 prognosis of, 174

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Bipolar disorder(s) (Continued) rapid cycling in, 174 subtypes of, 173–174 symptoms of, 173 treatment of, 174 type I, 173–174 type II, 174 Birds, as vector of disease, 251t Bjerrum scotoma, 38, 38f Blackouts, alcoholic, 178 Bladder dysfunction of, 34, 36t in multiple sclerosis, 106, 109 flaccid, 36t hypotonic, in multiple sclerosis, 109 motor innervation of, 34, 35f sensory innervation of, 34 sensory paralytic, 36t spastic, 36t in multiple sclerosis, 109, 109b in normal pressure hydrocephalus, 36, 163 Bladder areflexia, 36t Bladder dyssynergy, 36t Bladder hyperactivity, in Parkinson’s disease, 185 Blepharoplasts, in ependymoma, 127 Blepharospasm, 191–192 Blindness, denial of (Anton’s syndrome), 42–43 Blink reflex, 25t Blood pressure. See also Hypertension management of for ischemic stroke, 59 for stroke prevention, 61–62 for subarachnoid hemorrhage, 63 Blood transfusion, for sickle cell disease, 74 Body temperature, regulation of, 17, 17b Bone marrow transplantation for adrenoleukodystrophy, 117 cytomegalovirus with, 257–258 for Krabbe’s disease, 118 for metachromatic leukodystrophy, 117 for sickle cell disease, 74 for sphingolipidoses, 284 Borrelia burgdorferi, 253–254 Botulinum toxin for chronic headache, 145 for dystonia, 192 for multiple sclerosis, 109 for tension-type headache, 141 Botulism, 267t Bowel dysfunction, in multiple sclerosis, 106 Brachial plexus, 207–209 anatomy of, 207, 207f birth injury to, 208 lesions of diagnostic testing for, 209 electromyography of, 209 infraclavicular, 208 internal cord, 209 lower trunk/C8-T1 root injury, 208 middle trunk/C7 root injury, 208 nerve conduction studies of, 209 neuroimaging of, 209 subtypes of, 208 supraclavicular, 208 symptoms of, 207–208 treatment of, 209

versus ulnar nerve entrapment, 214f upper trunk/C5-C6 root injury, 208 traction trauma to, 208 Brachioradialis muscle, 216f, 229t Brachium conjunctivum, 21b Bradykinesia, in Parkinson’s disease, 185, 186t, 187 Brain abscess, 249–251 causative agents of, 250 contiguous spread and, 249 diagnostic testing for, 250–251 hematogenous spread and, 250 neuroimaging staging system for, 251 pathophysiology of, 249–250 symptoms of, 250 treatment of, 251 Brain metastasis, 130 Brainstem, 21–29 projections from, 1 Brainstem auditory evoked potentials (BAERs), 49, 49f in multiple sclerosis, 108 Brainstem encephalitis, in paraneoplastic syndromes, 136t Brainstem malformations, 271–273 Brain tumor(s), 119–132. See also specific types general medical therapies for, 132 intracranial hemorrhage with, 66 Branched-chain ketoacid dehydrogenase (BCKD) complex, 279 Breath-holding spells, 99, 292 cyanotic, 99 pallid, 99 pathophysiology of, 99 subtypes of, 99 Breathing, periodic, 99 Breech rhythm, in EEG, 80 Brevitoxin, 267t Broca, nucleus of diagonal band of, 11 Broca’s aphasia lesions causing, 5 symptoms of, 5 Broca’s area, 5–6 lesions of, 5–6 subcortical connections of, lesions of, 6 Brodmann area(s), 1, 1f Brodmann area 1, 3–4 as focus of simple partial seizures, 84 Brodmann area 2, 3–4 as focus of simple partial seizures, 84 Brodmann area 2v, 50 Brodmann area 3, 3–4 as focus of simple partial seizures, 84 somatotopic organization of, 3f, 4 Brodmann area 4 (primary motor cortex), 1–2 as focus of simple partial seizures, 84 Brodmann area 5, 4 Brodmann area 6, 2, 46 as focus of complex partial seizures, 86 as focus of simple partial seizures, 84 Brodmann area 8, 2, 45 as focus of simple partial seizures, 84 Brodmann area 17 (primary visual cortex), 2, 41–42 as focus of simple partial seizures, 84 Brodmann area 18, 42 Brodmann area 19, 42 Brodmann area 36, 42 Brodmann area 37, 42 Brodmann area 39, 6, 46

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Brodmann area 40, 4, 6 as focus of simple partial seizures, 84 Brodmann area 41, 50 Brodmann area 42, 6, 48f, 50 Brodmann area 43, 4 Brodmann area 44, 5, 5b Brodmann area 45, 5 Bromocriptine for adenoma, 133 for cocaine dependence, 180 for Parkinson’s disease, 186t Brown-Sequard syndrome, 32 Brueghel syndrome, 191 Bruns’ frontal lobe ataxia lesions causing, 5 normal pressure hydrocephalus and, 36, 163 Bruns-Garland syndrome, 206, 294 Bruns’ nystagmus, 46f–47f Brushfield spots, 289 Budd-Chiari syndrome, 73 Bulbospinal neuronopathy, 197t Bungarotoxin, 267t Bungner, bands of, 210 Bunina bodies, in ALS, 196 Buprenorphine, for opioid dependence, 181 Bupropion, 174t for bipolar disorder, 174 in multiple sclerosis, 109 Burn injury, and central pontine myelinosis, 112 Buspirone for Alzheimer’s disease, 158 for generalized anxiety disorder, 175 Butterbur extract, for migraine prophylaxis, 141 C CADASIL syndrome, 67 diagnostic testing for, 67 histology of, 67 magnetic resonance imaging of, 67 pathophysiology of, 67, 67b symptoms of, 67 Café au lait spots, 275, 275f Caffeine avoidance, for insomnia, 167 for orthostatic hypotension, 185 and restless legs syndrome, 169 for spontaneous intracranial hypotension, 148 for tension-type headache, 141 Caffeine withdrawal, and REM sleep behavior disorder, 170 Cajal, interstitial nucleus of, 44 Calcaneal nerve, 227f Calcarine artery, 41 Calcified tumors, 136t Calcitonin gene related-peptide (CGRP), in migraine, 139 Calcium, abnormal levels of, 301t Calcium channel(s), diseases of, 200, 200b, 247–248 Calcium gluconate, for hyperkalemic periodic paralysis, 247 California-LaCrosse encephalitis, 251t Calleja, islets of, 11 Callosal alien hand syndrome, 10 Caloric testing in benign paroxysmal positional vertigo, 52 in Meniere’s disease, 53 Calpain-3, in limb-girdle muscular dystrophy, 241, 242t Campylobacter jejuni, 222 Canavan’s disease, 115, 194b diagnostic testing for, 115

pathophysiology of, 115 symptoms of, 115 treatment of, 115 Cannabis. See Marijuana Capgras syndrome, 162b Capping defect, with spinal tumor, 131 Capsaicin, intranasal, for cluster headache prophylaxis, 142 Carbamazepine, 102t for acquired epileptiform opercula syndrome, 96 for bipolar disorder, 174 for complex regional pain syndrome, 150 for neuromyotonia, 246 for pediatric seizures, 99 for schizophrenia, 172 for SUNCT syndrome, 143 for trigeminal neuralgia, 148 Carbamyl phosphate synthetase deficiency, 282 Carbatrol. See Carbamazepine Carboplatin, for juvenile pilocytic astrocytoma, 121 Carcinomatous meningitis, 131–132 diagnostic testing for, 132 lumbar puncture in, 132 magnetic resonance imaging of, 132 pathophysiology of, 131 prognosis of, 132 symptoms of, 131–132 treatment of, 132 Cardiac valve(s), abnormalities of, and ischemic stroke, 56 Cardiobacterium, 69 Cardiomyopathy hypertension and, 296 muscular dystrophy and, 237–238 Cardiovascular procedures, stroke risk with, 55b Carnitine for isovaleric acidemia, 281 for Leigh’s disease, 47 for methylmalonic aciduria, 281 for multiple sclerosis, 109 for propionic acidemia, 281 Carnitine palmitoyl transferase deficiency, 243 Carotid artery dissection, 70–71 angiography of, 70, 71f magnetic resonance imaging of, 70, 71f treatment of, 71 Carotid artery ligation, 71 Carotid endarterectomy candidates, identification of, 57 for ischemic stroke, 59 for stroke prevention, 62, 62b Carotid stenosis diagnostic testing for, 57, 59f and ischemic stroke, 55 treatment of, 62, 62b Carpal ligament release, transverse, 211 Carpal tunnel syndrome, 210–211 anatomical considerations of, 210f diagnostic testing for, 211 electromyography of, 211 nerve conduction studies of, 211 pathophysiology of, 210 preacher’s hand versus, 211f risk factors for, 210 serology of, 211 symptoms of, 210–211 treatment of, 211

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Cataplexy, 167–168 Catatonia, acute lethal, 202t Catatonic schizophrenia, 170b Cat-scratch disease, 251–252 Cauda equina syndrome, 32, 32t Caudal regression syndrome, 274 Caudal vermis syndrome, 20 Caudate, 10f, 11–12, 11f lesions of, 12 Causalgia, 150 Caveolin-3, in limb-girdle muscular dystrophy, 241, 242t Cavernous angioma/cavernoma/cavernous hemangioma, 79, 79f CD4 cell count, in HIV infection, 260t CDKN2A mutations and astrocytoma, 120, 120f and oligodendroglioma, 120b, 122, 122b Celexa (citalopram), 174t Celiac disease, 299, 299b Central amygdala, 8 Central cord syndrome, 31 Central core disease, 242 childhood, 242 congenital, 242 diagnostic testing for, 242 muscle biopsy in, 242, 243f pathophysiology of, 242, 247b prognosis of, 242 symptoms of, 242 treatment of, 242 Central disk herniation, 152, 152f Central nervous system tumors, 119–132. See also specific types Central neurocytoma, 129 diagnostic testing for, 129 histology of, 129 location of, 129 treatment of, 129 Central pontine myelinosis, 112–113, 178 histology of, 112f, 113 pathophysiology of, 112 symptoms of, 113 Central sleep apnea, 168 Centronuclear myopathy, 239–240 Centrotemporal epilepsy, 97 diagnostic testing in, 97 EEG findings in, 97, 97f pathophysiology of, 97 prognosis of, 97 subtypes of, 97 symptoms of, 97 treatment of, 97 Cephalosporin(s) for brain abscess, 251 for Lyme disease, 254 Cerebellar cognitive-affective syndrome, 20 Cerebellar degeneration, in paraneoplastic syndromes, 136t Cerebellar fits, 20 Cerebellar malformations, 271–273 Cerebellar peduncles, 20f, 21b Cerebellar relay nuclei, 18–19 Cerebellar tonsil, 20f Cerebellum, 18–20 efferents of from deep cerebellar nuclei, 19 from direct projections, 19 general afferent fibers of, 18–19 granular layer of, 18, 19f

modulatory inputs to, 19 molecular layer of, 18, 19f neuron types of, 18, 19f pathophysiology in, 19–20 sensory inputs to, 19 subdivisions based on function, 19, 20f vascular supply of, 19, 21f visual motor regulation by, 45 Cerebral artery dissections, idiopathic, 70 Cerebral cortex, 1–8 afferents of, 1 Brodmann areas of, 1, 1f chemoanatomy of, 1 efferents of, 1 gyri and lobes of, 1, 1f language areas of, 5–7 malformations of, 269–271 motor systems of, 2–3 somatosensory systems of, 3–4 subtypes of, 1–2 cytoarchitectonic, 1–2 general functional, 2 visual motor regulation by, 45–46 Cerebral infarction arterial territories in, 57f computed tomography of, 57, 58f diagnostic testing for, 57 hemorrhagic conversion of, 57 magnetic resonance imaging of, 57, 58f patterns of, 71f Cerebral palsy, 287–288 choreoathetotic, 288 diagnostic testing for, 288 hemiplegic, 288 paraplegic, 288 pathophysiology of, 288 quadriplegic, 288 subtypes of, 288 symptoms of, 288 Cerebral salt wasting syndrome, 16t Cerebrospinal fluid (CSF), 35–36 abnormalities of, 271 analysis of in acute disseminated encephalomyelitis, 111 in acute inflammatory demyelinating polyneuropathy, 222 in acute motor axonal neuropathy, 223 in acute motor-sensory axonal neuropathy, 223 in acute necrotizing hemorrhagic encephalomyelitis, 112 in acute panautonomic neuropathy, 223 in Aicardi-Goutieres syndrome, 116 in Alzheimer’s disease, 158 in bacterial meningitis, 249 in carcinomatous meningitis, 132 in chronic headache, 146 in chronic inflammatory demyelinating polyneuropathy, 224 in Devic’s disease, 110 in febrile seizures, 91 in HIV encephalitis, 261 in Lyme disease, 254 in Marburg’s variant of multiple sclerosis, 111 in multiple sclerosis, 108 in normal pressure hydrocephalus, 36, 163 in paraneoplastic syndromes, 135 in pseudotumor cerebri, 147 in sarcoidosis, 299 in spontaneous intracranial hypotension, 147

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in syphilis, 254 in tonic-clonic seizures, 88 in tuberculoid meningitis, 252 in variant Creutzfeldt-Jakob disease, 266 pathophysiology in, 35–36 Cerebrotendinous xanthomatosis, 297t Cerebrovascular malformations, 77–79 Cerebyx. See Fosphenytoin Cervical collar, for greater occipital neuralgia, 149 Cervical dystonia, 191–192 Cervical plexus, 207 anatomy of, 207 lesions of, symptoms of, 207 pathophysiology in, 207 Cervical spine disease, versus tension-type headache, 141b Cervical vertigo, 54t Chancre, in syphilis, 254 Channelopathies, of muscle, 246–248 Charcot-Marie-Tooth neuropathies, 218–220 diagnostic testing for, 218–220 nerve biopsy in, 206, 220, 220f subtypes of, 218, 219t symptoms of, 218, 219f Charcot’s joints, 293 Chemotherapy for astrocytoma, 121 for choroid plexus papilloma, 128 for gliomatosis cerebri, 123 for medulloblastoma, 126 for metastasis, 131 for oligodendroglioma, 122 Cherry-red spots, diseases with, 283b Chiari malformations, 271–272, 273f Chickenpox, 111, 257 Chicken wire appearance, in oligodendroglioma, 122 Childhood ataxia with central nervous system hypomyelination, 115–116 Chiro-oral syndrome, 14 Chlamydia pneumoniae, and multiple sclerosis, 104 Chloramphenicol, for brain abscess, 251 Chloride channel(s), diseases of, 248 Chlorpromazine, 172t Cholestyramine, for stroke prevention, 62 Choline, in vanishing white matter disease, 116 Chorda tympani, 32f Chordoid meningioma, 124 Chordoma, 130 histology of, 130 location of, 130 prognosis of, 130 treatment of, 130 Choreoathetosis lesions causing, 12 paroxysmal nonkinesigenic, 190t paroxysmal with spasticity and ataxia, 190t Choreoathetotic cerebral palsy, 288 Choroid artery, 38 Choroid plexus papilloma, 128 computed tomography of, 128 diagnostic testing for, 128 versus ependymoma, 127–128, 128b, 128t epidemiology of, 128 histology of, 128 location of, 127b, 128 magnetic resonance imaging of, 128 treatment of, 128

Chromatopsia, 42 Chronic fatigue syndrome, 151 diagnostic testing in, 151 epidemiology of, 151 pathophysiology of, 151 prognosis of, 151 psychological factors in, 151 symptoms of, 151 treatment of, 151 Chronic headaches, 143–146 adjunctive therapy for, 146 cluster, 144–146 conditions associated with, 144 definition of, 143 diagnostic testing in, 146 epidemiology of, 144 genetics of, 144 medication detoxification for, 146, 146b medication overuse and, 144 migraine, 143–144, 146 neuroimaging of, 146 pathophysiology of, 143–144 patient education on, 146 primary, 144–145 prognosis of, 146 secondary, 143, 143b tension-type, 144–146 treatment of, 146 Chronic inflammatory demyelinating polyneuropathy (CIDP), 224–225 CSF analysis in, 224 diagnostic requirements for, 224, 224b diagnostic testing for, 224 epidemiology of, 224 histology of, 224 nerve biopsy in, 206, 224 nerve conduction study of, 224 neuroimaging of, 224 pathophysiology of, 224 prognosis of, 225 symptoms of, 224 treatment of, 224–225, 224b Cidofovir, for cytomegalovirus, 258 Cigarette smoking, and ischemic stroke, 56 Ciguatoxin, 267t Ciliary ganglion, 33t Ciliospinal reflex, 25t Cingulate cortex, as focus of complex partial seizures, 86 Cingulate gyrus, 10f Cingulum, 9, 9f Circadian rhythm(s), 17, 164 Circadian rhythm disorders, 169–170 and cluster headache, 142 in major depressive disorder, 173 pathophysiology of, 169 subtypes of, 169 treatment of, 170 Circle of Willis, 39f, 79 Circle of Zinn-Haller, 38 Circuit of Papez, 7, 7f Cisternography in normal pressure hydrocephalus, 36, 163 in spontaneous intracranial hypotension, 147 Citalopram, 174t Cladribine, for multiple sclerosis, 109

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Clarke’s column, 30f, 31 “Clasp knife” spasticity, 2 Claude’s syndrome, 22, 22f, 23b Claustrum, 10f, 11 Clear cell ependymoma, 127 Clear cell meningioma, 124 Climbing fibers, 18 Clindamycin, for toxoplasmosis, 261, 264 Clofazimine, for leprosy, 253 Clofibrate, for stroke prevention, 62 Clomipramine, 174t Clonazepam, 102t for dystonia, 192 for epileptic pseudoataxia, 93b for gelastic seizures, 84b for multiple sclerosis, 109 for parasomnias, 170 for startle seizures, 88 for tic disorders, 193 for trigeminal neuralgia, 148 Clonic seizures focal, neonatal, 90 multifocal, neonatal, 90 Clonidine for complex regional pain syndrome, 150 contraindicated in ischemic stroke, 59 for opioid dependence, 181 for stiff man’s syndrome, 201 for tic disorders, 193 Clopidogrel, for stroke prevention, 61 Clorazepate, 102t Clostridium botulinum, 267t Clostridium tetani, 267t Clozapine, 172t as alternative in drug-induced parkinsonism, 202 for Alzheimer’s disease, 158 for Lewy body dementia, 163 for Parkinson’s disease, 186 Clozaril. See Clozapine Clumsy hand-dysarthria syndrome, 25 Cluster headache, 141–142 chronic, 144–146 epidemiology of, 142 pathophysiology of, 142 phenotype of, 141b prophylactic treatment for, 142 symptoms of, 141–142 treatment of, 142 Coagulation disorders inherited, 71–72 subtypes of, 71–72 symptoms of, 72 treatment of, 72 and intracranial hemorrhage, 66 in ischemic stroke risk, 58 and subarachnoid hemorrhage, 64 Coat’s syndrome, 241 Cocaine, 180 acute intoxication, 180 biochemical effects of, 180 chronic use of, 180 and dystonia, 191 and intracranial hemorrhage, 66 in schizophrenia, 171 and subarachnoid hemorrhage, 63

treatment for dependence, 180 and vasospasm-like reaction, 77 withdrawal from, 180 Coccidioides, 263 Coccygeal nerve, 209f Cochlea, 49, 49f injury of, 51, 51b Cochlear duct, 49f Cochlear nucleus, 26 Cockayne’s syndrome, 200, 286 diagnostic testing for, 286 histology of, 286 nerve conduction study of, 286 neuroimaging of, 286, 286f pathophysiology of, 286 symptoms of, 286 treatment of, 286 type II/infantile-onset, 286 type I/juvenile-onset, 286 Codeine abuse of, 181 for tension-type headache, 141 Coenzyme Q10 for Leigh’s disease, 47 for MELAS syndrome, 69 for migraine prophylaxis, 141 Cogentin. See Benztropine Cognitive-behavioral therapy, for insomnia, 167 Cognitive impairment. See also Dementia(s) mild, 154 Collet-Sicard syndrome, 34t Collier’s sign, 45 Colloid cyst, 128–129 diagnostic testing for, 128 histology of, 128 location of, 128 symptoms of, 128 treatment of, 129 Coloboma, 272 Colorado tick fever, 251t Color vision, disorders of, 42 Coma, diabetic and hypoglycemic, 295t Commissure(s), 10. See also specific types Common peroneal nerve, 209f, 229t anatomy of, 218f compression syndromes of, 218, 218b, 218f conduction studies of, 205, 218 Complement membrane attack complexes, in myasthenia gravis, 234 Complex febrile seizures, 91 Complex partial seizures, 85–86 versus absence seizures, 85t diagnostic testing for, 86 EEG findings of, 86 with frontal lobe focus, 86 with mesial temporal cortex focus, 85–86 with neocortical temporal focus, 86 pathophysiology of, 85 pediatric, 98–99 subtypes of, 98–99 symptoms of, 98 treatment of, 99 symptoms of, 85 Complex regional pain syndrome, 149–150 diagnostic testing for, 150 dystonia in, 191

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subtypes of, 149–150 symptoms of, 150 treatment of, 150 Complex repetitive discharges, on EMG, 233 Compound muscle action potential (CMAP), 204, 206, 215 Compression neuropathies, 210–218. See also specific nerves histology of, 210 of lower extremities, 217–218 pathophysiology of, 210 Computed tomography (CT) of Alzheimer’s disease, 158 of cerebral infarction, 57, 58f of choroid plexus papilloma, 128 of chronic headache, 146 of Cockayne’s syndrome, 286 of colloid cyst, 129 of ependymoma, 127 of Sturge-Weber syndrome, 278 of subarachnoid hemorrhage, 63 of tuberous sclerosis, 277 of venous infarction, 75, 75f Computed tomography angiography (CTA) of carotid stenosis, 57 of infectious endocarditis, 69 COMT inhibitors, for Parkinson’s disease, 186t Concussion, vestibular, vertigo with, 54t Conditioning, 154b Conduction aphasia lesions causing, 6, 9 symptoms of, 6 Conductive hearing loss, 50 Confusional migraine, 138 Congenital fibrosis of extraocular muscles, 248t Congestive heart failure, and ischemic stroke, 55 Constipation, in Parkinson’s disease, 185 Constructional apraxia, lesions causing, 5 Continuous positive airway pressure (CPAP), for sleep breathing disorders, 169 Contraction, muscle, 230, 230f Contractures in Duchenne’s muscular dystrophy, 237–238 in Emery-Dreifuss muscular dystrophy, 238 Contrast-enhancing tumors, 136t Conus medullaris syndrome, 32, 32t Conversion disorder, 176–177 pathophysiology of, 176 prognosis of, 177 symptoms of, 177 treatment of, 177 Copaxone (glatiramer acetate), for multiple sclerosis, 109 Copper abnormal levels of, 301t in Wilson’s disease, 194–195 Corneal reflex, 25t Corneomandibular reflex, 25t Corona radiata/corona semiovale, 8–9 lesions of, 8–9, 8f pathophysiology in, 8 Coronary artery bypass graft, stroke risk with, 55b Corpus callosotomy, for seizure control, 102 Corpus callosum, 10 agenesis of, 10, 271–272 pathophysiology in, 10 transection of, 10

Corti, organ of, 33t, 49 Cortical auditory hallucinosis, 51 Cortical-based ganglionic degeneration, 188 diagnostic testing for, 188 genetics of, 188 pathophysiology of, 188 prognosis of, 188 symptoms of, 188 Cortical dementia, versus subcortical, 154, 155t Cortical gyri, important, 1, 1f Cortical malformations, 269–271 Cortical neurons, types of, 1, 2f Cortical relay nuclei, thalamic, 13 Cortical resection, focal, for seizure control, 102 Corticobulbar tract, 3, 23, 29 Corticocortical fibers, 1 Corticomedial amygdala, 8 Corticopontine tract, 18 Corticospinal tract, 3, 29 anterior, 29, 30f components of, 3 decussation of, 3 lateral, 30, 30f Corticotropin-releasing hormone (CRH), 17t in chronic fatigue syndrome, 151 in seizures/epilepsy, 82 Cortisol, in chronic fatigue syndrome, 151 Corynebacterium diphtheriae, 267t Coumadin for antiphospholipid antibody syndrome, 73 for arterial dissection, 71 versus aspirin, 61, 61t for inherited coagulation disorders, 72 side effects of, 61 for stroke prevention, 61, 61t Cowdry type A inclusions, 256, 256f, 257 Cranial nerve(s), 32–34. See also specific nerves anatomy of, 32 disorders of, 32–34 ganglia of, 32, 33t ocular motor, 43, 43f syndromes of, 34, 34t Craniopharyngioma, 133 location of, 133 pathophysiology of, 133 prognosis of, 133 symptoms of, 133 treatment of, 133 Craniosynostosis syndromes, 271 Crank (drug), 180–181 Crank case oil, 133 C-reactive protein in ischemic stroke risk, 58 in temporal arteritis, 76 Creatinine, in vanishing white matter disease, 116 Creutzfeldt-Jakob disease versus Alzheimer’s disease, 159t EEG findings in, 265, 265f inherited, 266 sporadic, 265–266 variant, 266 Cri du chat, 289 Crouzon’s syndrome, 271 CRPS. See Complex regional pain syndrome Cruciate paralysis, 28

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Cryoglobulinemia(s), 226–228 diagnostic testing for, 228 nerve biopsy in, 228 nerve conduction study of, 228 serology in, 228 subtypes of, 226 symptoms of, 226 treatment of, 228 type I, 226 type II, 226 type III, 226 Cryptococcus, 262–263, 263f CSF. See Cerebrospinal fluid CT. See Computed tomography Cushing reflex, 296 Cutaneous sensory terminals, 205t Cyanotic breath-holding spells, 99 Cyclobenzaprine, for dystonia, 192 Cyclooxygenase deficiency, 47 Cyclophosphamide for acute disseminated encephalomyelitis, 112 for chronic inflammatory demyelinating polyneuropathy, 225 for Devic’s disease, 110 for Marburg’s variant of multiple sclerosis, 111 for multifocal motor neuropathy, 225 for multiple sclerosis, 110 for paraneoplastic syndromes, 135 Cyclosporine, for myasthenia gravis, 235 Cyclothymia, 173b Cymbalta (duloxetine), 174t Cyst(s) colloid, 128–129 Rathke’s pouch, 133b Cystathionine -synthase, 73f Cystathionine -synthase deficiency, 72–73 Cysticercosis, 264, 264f Cytarabine, for carcinomatous meningitis, 132 Cytomegalovirus (CMV), 257–258 histology of, 257 with HIV infection, 257–258, 262 in immunosuppressed, 257–258 intrauterine infection, 290 simian, and multiple sclerosis, 104 treatment for, 258 types of infection, 257–258 in utero, 257 D Dandy-Walker malformation, 272–274 associated abnormalities with, 272 pathophysiology of, 272, 272b, 273f symptoms of, 274 treatment of, 274 Dantrolene, for multiple sclerosis, 109 Dapsone for leprosy, 253 prophylactic, for cancer patients, 132 Darkschewitsch, nucleus of, 44 Darvon (propoxyphene) abuse, 181 Daytime sleepiness, 167b excessive, disorders of, 167–169 Decerebrate posturing, 289 Declarative memory, 154b Decorticate posturing, 289

316

Deep brain stimulation for dystonia, 192 for Parkinson’s disease, 187 Deep cerebellar nuclei, 19 Deep peroneal nerve, 227f Deep vein thrombosis (DVT), prevention of, 60 Dejerine-Roussy syndrome, 15 lesions causing, 15, 15b symptoms of, 15 treatment of, 15 Dejerine’s syndrome, 28 Delayed sleep phase syndrome, 169 Delirium, lupus, 298 Delirium tremens, 179 Delta frequency, in EEG, 80b, 81–82, 82f in schizophrenia, 171 in tonic seizures, 88 Deltoid muscle, medial, 229t Delusions in Alzheimer’s disease, 157 in Lewy body dementia, 162, 162b in schizophrenia, 171 in schizophreniform disorder, 172 Dementia(s), 154–163. See also specific types in acute disseminated encephalomyelitis, 112 in adrenoleukodystrophy, 117 in Alexander’s disease, 115 in ALS, 196 Alzheimer’s, 155–159 in Cockayne’s syndrome, 286 in cortical-based ganglionic degeneration, 188 cortical versus subcortical, 154, 155t definition of, 154 drug-induced, 155 epidemiology of major disorders, 155f frontotemporal, 161 HIV-related, 260–261 in Huntington’s disease, 159t, 194 Lewy body, 161–163 in multiple sclerosis, therapy for, 109 in neuronal ceroid lipofuscinosis, 284 in normal pressure hydrocephalus, 36, 155, 163 in Parkinson’s disease, 159t, 185 progression of mild cognitive impairment to, 154 reversible causes of, 154–155 semantic, 161 subtypes of, 154 toxin-induced, 155 vascular (multi-infarct), 159–160 Demerol. See Meperidine Demyelinating disorders, 104–113. See also specific disorders nutrition- and electrolyte-related, 112–113 Demyelinating nerve conduction study, 205b Denervation, EMG findings of, 232 Dentate gyrus, 7 Dentate nucleus, 19 Dentatorubropallidoluysian atrophy (DRPLA), 191, 199 diagnostic testing for, 199 epidemiology of, 199 histology of, 199 pathophysiology of, 199 symptoms of, 199 Depacon. See Valproate Depakote. See Valproate

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Deprenyl. See Selegiline Depression. See also Major depressive disorder in Alzheimer’s disease, 157–158 with cognitive disturbances, versus Alzheimer’s disease, 159t in complex regional pain syndrome, 150 in migraine sufferers, 139 in multiple sclerosis, therapy for, 109 in Parkinson’s disease, 185 in schizophrenia, 171 Dermacentor, 251b, 251t, 255, 255b Dermatomes, 227f–228f Dermatomyositis, 244–245 adult, 244 childhood, 244 diagnostic testing for, 245 muscle biopsy in, 245, 245f pathophysiology of, 244 prodrome for, 244 prognosis of, 245 serology in, 245 subtypes of, 244 symptoms of, 244–245 treatment of, 245 Desipramine, 174t Desmopressin acetate, for orthostatic hypotension, 185 Detoxification, for chronic headache, 146, 146b Development abnormal, 287–292 normal, milestones of, 288t Developmental delay, 287–292 global, 289–292 language, 287 motor, 287–289 Developmental disease, 269–278. See also specific types Devic’s disease, 110–111 diagnostic testing for, 110 histology of, 110 prognosis of, 111 symptoms of, 110 treatment of, 110 Dexamethasone, 118t for bacterial meningitis, 249 Dexamethasone suppression test, in major depressive disorder, 173 Dextroamphetamine abuse, 180–181 Diabetes insipidus, central type, 16t Diabetes mellitus, 293–295 and ischemic stroke, 56 secondary, 293 subtypes of, 293 type 1/insulin-dependent, 293 type 2/noninsulin-dependent, 293 Diabetic amyotrophy, 294–295 Diabetic coma, 295t Diabetic mononeuropathy, 294 Diabetic myopathy, 294–295 Diabetic neuropathies, 293–294 acute painful, 294 asymmetric and focal, 294 autonomic, 293–294 chronic sensorimotor, 293 treatment of, 294 Diabetic plexopathy, proximal, 206, 294 Diaminopyridine, for Lambert-Eaton myasthenia, 237 Diastat. See Diazepam

Diazepam for glycine encephalopathy, 280 for status epilepticus, 89t Diazoxide, contraindicated in ischemic stroke, 59 Didanosine, for HIV infection, 260 Diencephalic autonomic seizures, 20 Dietary supplements, for migraine prophylaxis, 141 Diffuse plaque, in Alzheimer’s disease, 156 Diffusion-weighted imaging (DWI), of cerebral infarction, 57, 58f DiGeorge syndrome, 274 Digoxin, for pseudotumor cerebri, 147 Dihydroergotamine for cluster headache, 142 for migraine, 140 Dihydroxyphenylalanine decarboxylase deficiency, 280 Dilantin. See Phenytoin Dilaudid (hydromorphone) abuse, 181 Diltiazem, and parkinsonism, 202 Diphtheria, 267t Diplacusis, 51 Diplopia in Lambert-Eaton myasthenia, 237 monocular, 43b in multiple sclerosis, 106 Dipyridamole, for stroke prevention, 60–61 Disinhibition, lesions causing, 12 Diskectomy, 153 Disk herniation, 152, 152f, 153 Disomy 15, 289b Disorganized schizophrenia, 170b Distal sensory polyneuropathy, in HIV infection, 261, 261b Disulfiram, for alcohol dependence, 179 Ditropan. See Oxybutynin Diuretics and central pontine myelinosis, 112 for Meniere’s disease, 53 for pseudotumor cerebri, 147 Dix-Hallpike maneuver, 52 DNA repair disorders, 285–287 Domoate, 267t Donepezil for Alzheimer’s disease, 158 in multiple sclerosis, 109 DOPA decarboxylase deficiency, 280 Dopamine, 17t amphetamines and, 180 in basal ganglia, 11 in Parkinson’s disease, 183, 184f Dopamine agonists and dystonia, 191 for Lewy body dementia, 163 for Parkinson’s disease, 186, 186t for periodic limb movement disorder, 169 for restless legs syndrome, 169 and tics, 193 Dopaminergic nuclei, 22 Dopaminergic pathway(s) mesocortical, 22 mesolimbic, 22 DOPA-responsive dystonia, 190b, 190t, 192 Dorello’s canal, 43f Dorsal digital nerve, 227f Dorsal horn, 30 Dorsal mesencephalon syndromes, 23 Dorsal motor nucleus of vagus, 26

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Dorsal pontine syndromes, 24f, 25 Dorsal raphe nucleus, 28 Dorsal scapular nerve, 207f Dorsal spinocerebellar tract, 30 Dorsolateral frontal cortex, as focus of complex partial seizures, 86 Dorsolateral medullary syndrome, 28 Dorsolateral prefrontal cortex, as focus of simple partial seizures, 84 Dorsolateral tract, 30f Dorsomedial nucleus, 14f, 15, 16f lesions of, 15 in Wernicke-Korsakoff syndrome, 15b Doublecortin gene mutations, 269b Double lumen sign, in carotid dissection, 72f Down’s syndrome, 289 Alzheimer’s disease in, 156 germinoma in, 129 Downward gaze, 44 Doxepin, for chronic headache, 144 Doxycycline for Lyme disease, 254 for Rocky Mountain spotted fever, 256 Dreams, 166 Dressing apraxia, lesions causing, 5 Drop attack, 88 Drug abuse, 177–182. See also specific drugs and intracranial hemorrhage, 66 in schizophrenia, 171 and subarachnoid hemorrhage, 63 and vasculitis, 77 Duane’s syndrome, 248t Duchenne’s muscular dystrophy, 237–238 diagnostic testing for, 237 muscle biopsy in, 237, 237f pathophysiology of, 237 symptoms of, 237 treatment of, 237–238 Duloxetine, 174t Dural enhancement, unexpected causes of, 267b Dural tails, meningioma with, 124, 124f Dutch-type amyloid angiopathy, 66 Dwarfism, in Cockayne’s syndrome, 286 Dynorphin, in spiny neurons, 11 Dysarthria in central pontine myelinosis, 113 in Huntington’s disease, 194 hypophonic, 12 in multiple sclerosis, 106 in progressive supranuclear palsy, 187 in Wilson’s disease, 195 Dysembryoplastic neuroepithelial tumor, 129 Dysesthesia(s), in restless legs syndrome, 169 Dysferlin, in limb-girdle muscular dystrophy, 241, 242t Dysgeusia, 4 Dyskinesia, in Parkinson’s disease, 185–186 Dyslipidemia(s), 297–301, 297t and ischemic stroke, 56, 56b management, for stroke prevention, 62 Dysmyelinating disorders, 113–118, 113b. See also s pecific types Dysphagia in Canavan’s disease, 115 in central pontine myelinosis, 113 in Huntington’s disease, 194 in Parkinson’s disease, 185

Dysphonia in rheumatoid arthritis, 297 spastic, 191 Dyssomnia(s), 166–170. See also specific types Dysthymia, 173b in migraine sufferers, 139 Dystonia(s), 189–192 adult-onset, 191 autoimmune, 191 causes of, 189–190 cervical, 191–192 childhood, 191 deep brain stimulation for, 192 diagnostic testing in, 192 DOPA-responsive, 190b, 190t, 192 drug-induced, 191 early-onset, 190t, 192 facial/oromandibular, 191 focal, 191 generalized, 191, 191b genetics of, 190t, 192 iatrogenic, 191 lesions causing, 13–14 limb, 191 multifocal, 191 myoclonic, 190b, 190t in Parkinson’s disease, 185–186, 190, 190t pathophysiology of, 189 primary, 190, 190t rapid-onset, 190t secondary, 190–191 segmental, 191 subtypes of, 191 surgery for, 192 symptoms of, 191 treatment of, 192 Dystrophin(s), sarcoglycans and, 242f Dystrophin gene, 237–238 E Eastern equine encephalitis, 251t Echinococcosis, 265 Echinococcus, 265 Echocardiography, 58 of infectious endocarditis, 69 transesophageal, 58 Echolalia, in frontotemporal dementia, 161 Ecstasy (drug), 180–181 Edinger-Westphal nucleus, 43, 43f Edrophonium test, in myasthenia gravis, 235 EEG. See Electroencephalogram Efferent(s) cerebellar from deep cerebellar nuclei, 19 from direct projections, 19 cortical, 1 hypothalamic, 18f reticular formation, 29 Effexor. See Venlafaxine Ehlers-Danlos syndrome, 77 arterial dissection in, 70 Eikenella, 69 Ejaculation, 34 Elavil. See Amitriptyline

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Elbow extension, 229t Elbow flexion, 229t Elbow pain, in ulnar nerve entrapment, 213 Elderly, electromyography in, 234 Electrode(s) for EEG, 80 nasopharyngeal, 80 sphenoid, 80 Electrodecremental response, in tonic seizures, 88, 88f Electroencephalogram (EEG) in acquired epileptiform opercula syndrome, 96 in Alzheimer’s disease, 158 amplitude asymmetries in, 80–81 in Creutzfeldt-Jakob disease, 265, 265f electrodes for, 80 frequencies (waves) of, 80b frequency asymmetries in, 81 in giant axonal neuropathy, 221 in glycine encephalopathy, 280 in hypertensive encephalopathy, 296 hyperventilation response in, 80, 95, 95f in juvenile rheumatoid arthritis, 297 in Lennox-Gastaut syndrome, 93, 93f in mesial temporal sclerosis, 86 in migraine, 139 periodic lateralizing epileptiform discharges in, 81f, 82 photic stimulation in, 80 polymorphic delta activity in, 81 in Rasmussen’s syndrome, 98 rhythmic delta activity in, 82, 82f in schizophrenia, 171 in seizures/epilepsy, 80–82 abnormalities consistent with foci, 80–82, 81f–82f in absence seizures, 95, 95f in benign myoclonic epilepsy, 94 in benign occipital epilepsy, 97 in febrile seizures, 92 in infantile spasms, 88f, 92, 92f in juvenile myoclonic epilepsy, 94, 94f in partial seizures, 86 in rolandic epilepsy, 97, 97f in severe myoclonic epilepsy, 94 in status epilepticus, 90 in tonic-clonic seizures, 87–88, 87f, 88b in tonic seizures, 88, 88b, 88f sharp waves in, 80 sleep, waking, and sleep deprivation in, 80, 164–166, 165f–166f spike-and-wave discharge in, 81f in subacute sclerosing panencephalitis, 260, 260f in transient global amnesia, 8 Electrolyte abnormalities, 301t Electrolyte-related demyelinating disorders, 112–113 Electromyography (EMG), 204, 232–234 abnormal, 233, 233f in acute inflammatory demyelinated polyneuropathy, 222 of acute motor axonal neuropathy, 223 of acute motor-sensory axonal neuropathy, 223 in ALS, 196 of anterior interosseous syndrome, 212 of brachial plexopathy, 209 of carpal tunnel syndrome, 211 complex repetitive discharges on, 233 in elderly, 234 fasciculation potentials in, 233, 233b of femoral nerve syndromes, 218

fibrillation potentials in, 232–233 insertional activity on, 233 irritability on, 233 of Lambert-Eaton myasthenia, 237 of lumbosacral plexopathy, 210 in McArdle’s disease, 243 of Miller-Fisher syndrome, 223 of multifocal motor neuropathy, 225 myokymic discharges on, 233 myopathic changes on, 232 of myotonia congenita, 248 myotonic discharges on, 233, 233b of myotonic dystrophy, 239 in neonates, 233 of neuromyotonia, 246 neuromyotonic discharges on, 233 neuropathic changes on, 232–233 normal, 233f of paramyotonia congenita, 247 of peroneal nerve syndromes, 218 in polymyositis, 245 of posterior interosseous nerve syndrome, 216 of radial nerve injury in brachium, 216 sharp waves on, 233 technical considerations for, 233–234 of ulnar nerve entrapment at elbow, 213 Electrophoresis, in monoclonal gammopathy, 226 Electroretinogram, 38 Eletriptan, 140t Embolism, paradoxical, 58 Embryogenesis, disorders of, 269–278 Emery-Dreifuss muscular dystrophy, 238 diagnostic testing for, 238 subtypes of, 238 symptoms of, 238 treatment of, 238 type 1, 238 type 2, 219b, 238 EMG. See Electromyography Empty sella syndrome, 132b Empyema, 249 Encephalitis bacterial, 251–252 herpes, 256 HIV, 260–261 measles, 259 viral, 251t, 258 Encephalocele, 274b Encephalomyelitis, in paraneoplastic syndromes, 136t Encephalopathy. See specific types Endarterectomy, carotid candidates for, identification of, 57 for ischemic stroke, 59 for stroke prevention, 62, 62b Endocarditis, 69 infectious, 69–70 marantic, 69 Endocrine disorders, and dementia, 155 Endolymphatic duct, 49f Endovascular clot removal, for venous infarction, 75 Endovascular stenting, for arterial dissection, 71 En plaque meningioma, 125 Entacapone, for Parkinson’s disease, 186t Entamoeba, 264 Enterobacteriaceae, and brain abscess, 250

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Enterococcus, 69 Entrapment neuropathies, 210–218. See also specific nerves histology of, 210 of lower extremities, 217–218 pathophysiology of, 210 Ependymoma, 127–128 versus choroid plexus papilloma, 127–128, 128b, 128t classic, 127 clear cell, 127 computed tomography of, 127 diagnostic testing for, 127–128 epidemiology of, 127 histology of, 127, 127f infratentorial, 127 location of, 127 magnetic resonance imaging of, 128 myxopapillary, 127 papillary, 127 pseudorosettes in, 127, 127f subtypes of, 127 Ephaptic transmission, 148, 148b Ephedrine, for orthostatic hypotension, 185 Ephedrine abuse, 180 Epidermal growth factor (EGF) and astrocytoma, 119, 120f and oligodendroglioma, 122 Epidural blood patching, for spontaneous intracranial hypotension, 148 Epilepsia partialis continua, 89b Epilepsy, 80–102 autosomal dominant partial, with auditory features, 98, 98b, 120b benign myoclonic, 93–94 benign occipital, 96–97 diagnostic testing for, 80–82 electroencephalogram in, 80–82, 81f–82f with ischemic stroke, 57 juvenile myoclonic, 94 with multiple sclerosis, 106 prolactin level in, 82 rolandic/centrotemporal, 97 seizures in. See also specific types nonsyndromal generalized, 86–89 partial, 82–86 prolonged (status epilepticus), 89–90 severe myoclonic, 94 treatment of medical, 101, 101f, 102t–103t surgical, 102 Epileptic pseudoataxia, 93b Episodic ataxia(s) type I inherited, 200 type II inherited, 200–201 Episodic headaches lasting less than four hours, 141–143 lasting more than four hours, 137–141 Episodic memory, 154b Epley maneuver, 52 Epstein-Barr virus (EBV), and multiple sclerosis, 104 Erection, 34 in REM sleep, 166 Ergot(s) for cluster headache, 142 for migraine, 140 overuse of, and chronic headache, 144 for Parkinson’s disease, 186t

Ergotamine, for migraine, 140 Erythrocyte sedimentation rate (ESR) in ischemic stroke risk, 58 in temporal arteritis, 58, 76 Erythropoietin, for orthostatic hypotension, 185 Escherichia coli, and meningitis, 250t Escitalopram, 174t Essential hypertension, 295 Essential tremor, 201 diagnostic testing for, 201 pathophysiology of, 201 risk factors for, 201, 201b symptoms of, 201, 201b treatment of, 201 Estrogen use and ischemic stroke, 56 and subarachnoid hemorrhage, 63 Ethambutol, for tuberculosis, 252 Ethosuximide, 102t for absence seizures, 95 Eustachian tube, 49f Evoked potential(s) brainstem auditory, 49, 49f in multiple sclerosis, 108 somatosensory, 205 in hereditary spastic paraplegia, 198 in multiple sclerosis, 108, 108f in schizophrenia, 172 trigeminal, 148 visual, 41–42, 41f in multiple sclerosis, 42, 108 Excitatory amino acid transporter (EAAT-2), in ALS, 196 Executive impairment, in Alzheimer’s disease, 157 Exelon (rivastigmine), for Alzheimer’s disease, 158 Extensor carpi radialis, 216 Extensor carpi radialis longus, 216f Extensor carpi ulnaris, 216f Extensor digiti quinti, 216f Extensor digitorum communis, 216f Extensor indicis, 216f Extensor pollicis brevis, 216, 216f Extensor pollicis longus, 216 Extraocular muscles, congenital fibrosis of, 248t Extreme lateral disk herniation, 152, 152f Eyelid myoclonus with absence seizures, 95b Eye movement(s) in Huntington’s disease, 194 in progressive supranuclear palsy, 187 regulation of, 21, 44–47 F Fabry’s disease, 285t Facial nerve (CN VII), 24f, 32, 32f ganglia of, 32f, 33t palsy of (Bell’s palsy), 32–34 Facial nucleus, 23, 26f Facial/oromandibular dystonia, 191 Facial synkinesis, 34 Facioscapulohumeral muscular dystrophy, 240–241 diagnostic testing for, 241 muscle biopsy in, 241, 241f pathophysiology of, 240 prognosis of, 241 symptoms of, 240–241 treatment of, 241 Factitious disorders, 42, 176–177

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Factor V Leiden mutation, 72 Famcyclovir for Bell’s palsy, 34 for herpes zoster virus, 257 Farber’s lipogranulomatosis, 285t Fasciculation potentials, on EMG, 233, 233b Fasciculus cuneatus, 30, 30f Fasciculus gracilis, 30, 30f Fastigial nucleus, 19, 29 Fast-twitch motor units, 232 Fast-twitch muscle fibers, 231, 231f Fatal familial insomnia, 266 Fatigable fast-twitch motor units, 232 Fatigue chronic, syndrome of, 151 in fibromyalgia, 151 in multiple sclerosis, 106, 109 Fatigue-resistant motor units fast-twitch, 232 slow-twitch, 232 Fatty acid supplementation, for adrenoleukodystrophy, 117 Febrile seizures, 91–92 complex, 91 CSF analysis in, 91 diagnostic testing in, 91–92 EEG findings in, 92 pathophysiology of, 91 simple, 91 subtypes of, 91 treatment of, 92 vaccine-induced, 91 Feeding behavior, hypothalamic regulation of, 16–17 Felbamate, 103t Femoral nerve, 209f, 227f, 229t anatomy of, 217f compression syndromes of, 217–218 diagnostic testing for, 218 electromyography of, 218 nerve conduction study of, 218 pathophysiology of, 217 symptoms of, 217–218 treatment of, 218 Fibrillary astrocytoma, 119–121 epidemiology of, 120 genetics of, 119–120, 120f grading of, 119, 119b, 119t infratentorial, 120 location of, 120 MIB-1 antibody labeling of, 119, 119b nuclear atypia in, 119, 120f prognosis of, 121 supratentorial, 120 treatment of, 121 Fibrillation potentials, in EMG, 232–233 Fibroma(s), ungual, in tuberous sclerosis, 276, 277f Fibromuscular dysplasia, 70 angiography of, 70, 70f arterial dissection in, 70 diagnostic testing for, 70 epidemiology of, 70 pathophysiology of, 70 symptoms of, 70 treatment of, 70 Fibromyalgia, 150–151 diagnostic testing for, 151 epidemiology of, 151

pathophysiology of, 150 prognosis of, 151 psychological factors in, 150 symptoms of, 151 treatment of, 151 Fibrous meningioma, 123, 124f Finger flexion, distal, 229t Flaccid bladder, 36t Flame sign, in carotid dissection, 72f Flexor carpi radialis, 210f, 229t Flexor carpi radialis tendons, 210f Flexor carpi ulnaris, 213f–214f, 229t Flexor digitorum profundus, 211, 213f–214f, 229t Flexor digitorum superficialis, 210f Flexor pollicis brevis, 210f, 213f, 229t Flexor pollicis longus, 211, 229t Flexor retinaculum, 210f Flocculonodular lobe, 20f Florid plaques, in prion disease, 266 Fludrocortisone, 118t for orthostatic hypotension, in Parkinson’s disease, 185 Fluid therapy, for spontaneous intracranial hypotension, 148 Fluoxetine, 174t for cataplexy, 168 for chronic headache, 144 for migraine prophylaxis, 140 Focal cortical dysplasia, 269 Focal cortical resection, for seizure control, 102 Foix-Alajouanine syndrome, 252, 252b Foix syndrome, 34t Folate deficiency of, 301t for MHTR deficiency, 73 for spina bifida prevention, 274 for toxoplasmosis, 261 Follicle-stimulating hormone (FSH), adenoma and, 133 Foot dorsiflexion, 229t Foot drop in ALS, 196 in peroneal nerve syndromes, 218 Foot eversion, 229t in Charcot-Marie-Tooth neuropathies, 219f Foot inversion, 229t Foot plantar flexion, 229t Forebrain, basal, 10f, 11 Formed hallucinations, 4b Fornix (pl. fornices), 11f Foscarnet, for cytomegalovirus, 258 Fosphenytoin, 103t for status epilepticus, 89t Fourth ventricle, tumors of, 128b Foville’s syndrome, 24f, 25 Fragile X syndrome, 290 Freezing episodes, in Parkinson’s disease, 185 Frequency asymmetries, in EEG, 81 Fried egg appearance, in oligodendroglioma, 122 Friedreich’s ataxia, 199–200 diagnostic testing for, 200 histology of, 199 pathophysiology of, 199 prognosis of, 200 symptoms of, 200, 200b treatment of, 200 Froehlich’s syndrome, 17b Frohse, arcade of, 216, 217f Froment’s sign, 213, 215f

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Frontal eye field, 45 as focus of simple partial seizures, 84 Frontal horn, in adult hydrocephalus, 35 Frontal horn ballooning (“Mickey Mouse” ventricles), 35 Frontal intermittent rhythmic delta activity (FIDA), 82, 82f Frontal lobe, as focus of complex partial seizures, 86 Frontal lobe release reflexes, in Alzheimer’s disease, 158, 158b Frontal lobe syndromes, 5, 5t Frontal operculum as focus of complex partial seizures, 86 as focus of simple partial seizures, 84 Frontopolar cortex, as focus of complex partial seizures, 86 Frontotemporal dementia, 161 Frontotemporal lobar degeneration, 160–161 versus Alzheimer’s disease, 159t diagnostic testing in, 161 epidemiology of, 155f genetics of, 161 histology of, 160–161, 160f neuroimaging in, 161, 161f pathophysiology of, 161 subtypes of, 161 treatment of, 161 Frovatriptan, 140t Fukutin gene, 243 Fukutin protein, 243 Fukuyama congenital myopathy, 242–243 diagnostic testing for, 243 pathophysiology of, 243 prognosis of, 243 symptoms of, 243 Fungal infection, 262–263. See also specific types diagnosis of, 263 pathophysiology of, 262 symptoms of, 262–263 Fungal meningitis, 77t, 262–263 Furosemide, for pseudotumor cerebri, 147 Fusiform aneurysm, 78 Fusiform neurons, 1 F waves in acute inflammatory demyelinated polyneuropathy, 222 in nerve conduction studies, 206 G GABA in arousal/sleep, 164 in aspiny neurons, 11 barbiturates and, 179 in spiny neurons, 11 Gabapentin, 102t for dystonia, 192 for migraine prophylaxis, 140 for multiple sclerosis, 109 for restless legs syndrome, 169 for trigeminal neuralgia, 148 GABA receptor agonists, for insomnia, 167 Gabitril. See Tiagabine Gait in Duchenne’s muscular dystrophy, 237 in MASA syndrome, 271 in normal pressure hydrocephalus, 36, 163 Gait ataxia in adrenoleukodystrophy, 117 in caudal vermis syndrome, 20 in rostral vermis syndrome, 19

322

Galactosylceramidase, in Krabbe’s disease, 117–118 Galantamine, for Alzheimer’s disease, 158 Galen, vein of, malformations of, 78, 274–275 Gamma aminobutyric acid. See GABA Gamma-knife radiosurgery for chronic cluster headache, 145 for Parkinson’s disease, 186 Ganciclovir, for cytomegalovirus, 258 Ganglia, cranial nerve, 32, 33t Gangliocytoma/ganglioglioma, 129 epidemiology of, 129 histology of, 129 location of, 129 prognosis of, 129 treatment of, 129 Ganglionic degeneration, cortical-based, 188 diagnostic testing for, 188 genetics of, 188 pathophysiology of, 188 prognosis of, 188 symptoms of, 188 Gangliosidosis GM1, 284b, 285t GM2, 285t Gasserian ganglion, 33t microvascular decompression of, 142 Gastrocnemius muscle, 229t, 231f Gaucher’s disease, 285t Gaze in Huntington’s disease, 194 in progressive supranuclear palsy, 187 regulation of, 44–46 Gaze centers, cortical, 45–46 Gaze deviation, 46 Gelastic seizures, 84b Gemfibrozil, for stroke prevention, 62 Generalized anxiety disorder, 175 Generalized seizures atonic, 89 myoclonic, 89 nonsyndromal, 86–89 tonic, 88 tonic-clonic, 86–88 treatment of, 101f Geniculate ganglion, 32f, 33t Genitofemoral nerve, 209f, 227f Gennari, band of, 2 Gentamicin, intratympanic, for Meniere’s disease, 53 Geodon. See Ziprasidone Geography, and multiple sclerosis, 104 Germinoma, 129–130 diagnostic testing for, 130 genetics of, 129 histology of, 130 location of, 130 pathophysiology of, 129–130 prognosis of, 130 treatment of, 130 Gerstmann’s syndrome, 5, 188 Gerstmann-Straussler-Scheinker disease, 266, 266b Ghost plaque, in Alzheimer’s disease, 156 Giant axonal neuropathy, 221 diagnostic testing for, 221 EEG findings in, 221 histology of, 221, 221f

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nerve conduction studies of, 221 neuroimaging of, 221 pathophysiology of, 221 prognosis of, 221 symptoms of, 221 Giant cell arteritis, 75–76 Giant cell (temporal) arteritis, 75–76 diagnostic testing for, 58, 76 epidemiology of, 76 erythrocyte sedimentation rate in, 58, 76 pathophysiology of, 75 prognosis of, 76 and stroke, 58, 76 symptoms of, 76 treatment of, 76 Giant cell neuropathy. See Phenylketonuria Glabellar reflex, 25t Glatiramer acetate, for multiple sclerosis, 109 Glaucoma in Sturge-Weber syndrome, 278 visual evoked potentials in, 42b Glial fibrillary acidic protein (GFAP) in Alexander’s disease, 114 in ependymoma, 127 in oligodendroglioma, 122 in pleomorphic xanthoastrocytoma, 121 tumors positive for, 127b Glioblastoma multiforme, 120f, 121 Gliomatosis cerebri, 123 diagnostic testing for, 123 histology of, 123 prognosis of, 123 symptoms of, 123 treatment of, 123 Gliosis in cortical-based ganglionic degeneration, 188 in HIV infection, 260 in progressive supranuclear palsy, 187 in Wilson’s disease, 194 Global akinesia, lesions causing, 3 Global developmental delay, 289–292 Global hypoxia, 70 Globoid cell leukodystrophy (Krabbe’s disease), 117–118 Globus pallidus, 10f, 12 lesions of, 12 neurons of, 12 output projections from, 13 in Parkinson’s disease, 184f Globus pallidus stimulation, for Parkinson’s disease, 187 Glossopharyngeal nerve disorders/syndromes of, 34t ganglia of, 33t Glossopharyngeal neuralgia, 32, 149 diagnostic testing in, 149 pathophysiology of, 149 symptoms of, 149 treatment of, 149 Glucocorticoid(s), 118t for acute disseminated encephalomyelitis, 112 for adrenoleukodystrophy, 117 for anterior interosseous syndrome, 212 anti-inflammatory potency of, 118t for antiphospholipid antibody syndrome, 73 for brain abscess, 251 for brain tumors, 132

for chronic fatigue syndrome, 151 for chronic inflammatory demyelinating polyneuropathy, 224 for cluster headache prophylaxis, 142 for complex regional pain syndrome, 150 complications of, 118t for cryoglobulinemia, 228 for Devic’s disease, 110 for Duchenne’s muscular dystrophy, 238 for greater occipital neuralgia, 149 for hearing loss, 50 for herpes zoster virus, 257 for idiopathic hypertrophic pachymeningitis, 267 for juvenile rheumatoid arthritis, 297 for Landau-Kleffner syndrome, 96 for Marburg’s variant of multiple sclerosis, 111 for metastasis, 131 mineralocorticoid potency of, 118t for multifocal motor neuropathy, 225 for multiple sclerosis, 109 for myasthenia gravis, 235 for paraneoplastic syndromes, 135 for posterior interosseous nerve syndrome, 216 for pseudotumor cerebri, 147 for sarcoidosis, 299 for spontaneous intracranial hypotension, 148 for status migrainosus, 141 for tuberculosis, 253 for Vogt-Koyanagi-Harada syndrome, 268 Glucose abnormalities of blood vessels, 295t for carnitine palmitoyl transferase deficiency, 243 for hyperkalemic periodic paralysis, 247 in vanishing white matter disease, 116 Glutamate, in ALS, 196 Glutamate decarboxylase, in stiff man’s syndrome, 201 Gluten-sensitive enteropathy, 299 Gluteus maximus, 229t Gluteus minimus, 229t Glycine encephalopathy, 280 Glycine supplementation, for isovaleric acidemia, 281 Golgi neurons, 18 Gonadotropin-releasing hormone (GnRH), 17t Gottron’s papules, in dermatomyositis, 245 Gower’s sign, in Duchenne’s muscular dystrophy, 237 Gradenigo syndrome, 34t Granular cells, 1, 18, 19f Gray matter somatotopic organization of, 31, 31f spinal cord, 30 Greater auricular nerve, 149f Greater occipital nerve, 149f Greater occipital nerve neuralgia, 149 Greater petrosal nerve, 32f Great radicular artery, 31f Growth hormone-releasing hormone (GHRH), 17t adenoma secreting, 133 GSPT1 gene, and adenoma, 133 Guillain-Barre syndrome, 221–224 conditions preceding, 222 epidemiology of, 222 nerve biopsy in, 206 pathophysiology of, 221–222 subtypes without pronounced weakness, 223 subtypes with pronounced weakness, 222–223 treatment of, 223–224

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Gummas, 255 Gustatory hallucinations, 4b Guyon’s tunnel, 213, 215f lesions of, 213–216 surgical transection of, 216 Gyri, important cortical, 1, 1f

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H HAART therapy, 260–261 HACEK organisms, 69 Haemophilus, 69 Haemophilus influenzae, 250t Haemophilus influenzae vaccine, 249 Hakim-Adams syndrome, 35–36, 163 Hallucination(s) in Alzheimer’s disease, 157 auditory, 4b formed, 4b gustatory, 4b hypnagogic, 168 hypnopompic, 168 in Lewy body dementia, 162 olfactory, 4 in Parkinson’s disease, 186 in schizophrenia, 171 in schizophreniform disorder, 172 tactile, 4 in temporal lobe seizures, 85 types of, 4b unformed, 4b visual, 4b, 22 Hallucinosis cortical auditory, 51 peduncular, 22–23 pontine auditory, 51b Haloperidol (Haldol), 172t for autism, 291 for tic disorders, 193 Hamartoma, in tuberous sclerosis, 276 Hammertoes, in Charcot-Marie-Tooth neuropathies, 219f Hamstrings, 229t Hartnup’s disease, 280 Headache, 137–149. See also specific types with adenoma, 133 with brain abscess, 250 chronic, 143–146 cluster, 141–142 episodic lasting less than four hours, 141–143 lasting more than four hours, 137–141 with gliomatosis cerebri, 123 hypnic, 143 idiopathic stabbing, 143 with intracranial hemorrhage, 66 with ischemic stroke, 56, 56b migraine, 137–141 rebound, 144 special disorders of, 146–149 with subarachnoid hemorrhage, 63 with temporal arteritis, 76 tension-type, 141 Head drop, 196, 196b Head trauma, vertigo with, 54t Hearing aids, 50–51 Hearing loss, 50 in adrenoleukodystrophy, 117

conductive, 50 and language delay, 287 with neurofibromatosis type 2, 275 sensorineural, 50 treatment of, 50 Heart disease, and ischemic stroke, 55–56 Heat, and multiple sclerosis, 106b Heerfordt syndrome, 298b Heimann-Bielschowsky phenomenon, 46f–47f Helicotrema, 49f Heliotrope rash, in dermatomyositis, 244 Hemangioblastoma, 130 histology of, 130 treatment of, 130 in von Hippel-Lindau syndrome, 278 Hemangioma, cavernous, 79, 79f Hematoma, intramural, with arterial dissection, 70, 71f Hemiachromatopsia, 42 Hemianopsia adenoma and, 133 optic chiasm lesions and, 40 Hemiataxia lesions causing, 13–14 in multiple sclerosis, 106 Hemiballismus, 12–13 Hemicrania, paroxysmal, 142–143 chronic, 145 Hemicrania continua, 145 Hemidystonia, 191 lesions causing, 12 Hemifacial spasm, 32 in multiple sclerosis, 106 Hemimedullary syndrome, 28 Hemiparesis, in striatocapsular syndrome, 9 Hemiparkinsonism, lesions causing, 12 Hemiplegia, 25 Hemiplegia cruciata, 28 Hemiplegic cerebral palsy, 288 Hemiplegic migraine, 138 associated with benign familial infantile convulsions, 138 familial, 138, 138b Hemisection syndrome, 32 Hemispherectomy for Rasmussen’s syndrome, 98 for seizure control, 102 Hemispheric syndrome, 20 Hemorrhagic dementia, 159 Hemorrhagic stroke, sickle cell disease and, 74 Hemorrhagic tumors, 136t Heparin for arterial dissection, 71 for inherited coagulation disorders, 72 for ischemic stroke, 59 side effects of, 61 for stroke prevention, 61 for subarachnoid hemorrhage, 64 Heparin-induced thrombocytopenia (HIT), 61 Hepatitis B vaccine, and dermatomyositis, 244 Hepatolenticular degeneration, 194–195. See also Wilson’s disease Hereditary hemorrhagic telangiectasia, 250b Hereditary neuropathy(ies), 218–221 with predilection to pressure palsies (HNPP), 220–221 diagnostic testing for, 220 histology of, 220, 220f

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prognosis of, 221 subtypes of, 220 treatment of, 220 Hereditary spastic paraplegia(s), 197–198 diagnostic testing for, 198 genetics of, 198, 198b, 198t, 271b pathophysiology of, 197 somatosensory evoked potentials in, 198 subtypes of, 198, 198t symptoms of, 197 Heroin, 77, 181 Herpes 6 virus, and multiple sclerosis, 104 Herpes encephalitis, 256 Herpes simplex virus, 256–257 diagnostic testing for, 256 HSV-1, 256 HSV-2, 256 and multiple sclerosis, 104 pathophysiology of, 256, 256f prognosis of, 257 symptoms of, 256 treatment for, 256 Herpes virus(es), 77t, 256–258 Herpes zoster, 257 Herpes zoster ophthalmicus, 257 HESX-1 gene mutations, 270b Heteromodal association areas, 2, 4–5 frontal (prefrontal cortex), 4–5 parietal, 5 Heterotopia, 269 genetics of, 269b laminar, 269 periventricular, 269, 269f Heterotypical isocortex, 1–2 High-density lipoprotein (HDL), 56 High seeding potential, tumors with, 120b Hip abduction, 229t Hip adduction, 229t Hip extension, 229t Hip flexion, 229t Hippocampal commissure, 10 Hippocampal connections, intrinsic, 7, 8f Hippocampal formation, 7 components of, 7 functions of, 7 pathophysiology in, 7 Hippocampal sclerosis, 85–86 bilateral, and language delay, 287 Hippocampus, 7 in REM sleep, 166 Hirano bodies, in Alzheimer’s disease, 156, 156f Histoplasma, 263 HIV. See Human immunodeficiency virus HMG-CoA reductase inhibitors, 62 Hodgkin’s disease, vasculitis with, 76–77 Holoprosencephaly, 269–270 alobar, 270 genetics of, 270 subtypes of, 270 Homer-Wright rosettes, in medulloblastoma, 126, 126f Homocysteine elevated levels of, 72–73 in ischemic stroke, 56, 62 metabolic pathway of, 73f reduction of, 62 in vascular dementia, 160

Homocystinuria/homocystinemia, 72–73 pathophysiology of, 72 subtypes of, 72–73 Homotypical isocortex, 1 Homunculi, sensory and motor, 2, 3f, 4 Horizontal cells of Cajal, 1 Hormonal/parvocellular nuclei, 17 Hormone(s) hypothalamic, 17, 17t pituitary, 17, 17t Hormone replacement therapy and Alzheimer’s disease, 158 and ischemic stroke, 56 Horner’s syndrome, 71, 126, 208 Hot-cross bun sign, in multiple system atrophy, 189, 189f H reflex, in nerve conduction studies, 206 Huebner, recurrent artery of, 18, 39f Human immunodeficiency virus (HIV), 260–262 brain lesions with, 261b cytomegalovirus with, 257–258, 262 dementia with, 260–261 diagnostic testing for, 260 direct effects of, 260–261 encephalitis with, 260–261 histology of, 260, 260t intrauterine and neonatal, 290 lymphoma with, 262 meningitis with, 262 myopathy with, 261 neuromyotonia with, 246 neuropathy with, 261, 261b opportunistic infections with, 261–262 pathophysiology of, 260 stroke with, 261 toxoplasmosis with, 261, 261b treatment of, 260 vacuolar myelopathy with, 261 vasculitis with, 76–77, 77t Hunter’s syndrome, 271, 284t Huntingtin gene, 193 Huntington’s disease, 193–194 dementia in, 194 versus Alzheimer’s disease, 159t diagnostic testing for, 194 dystonia in, 191 histology of, 194 neuroimaging of, 194, 194f pathophysiology of, 193–194 prognosis of, 194 symptoms of, 194, 194b treatment of, 194 Hurler’s syndrome, 271, 284t Hydatid disease, 265 Hydralazine, 296 Hydranencephaly, 270–271 Hydrocephalus, 271 acquired pediatric, 271 adult, 35 communicating, 271 and cortical malformation, 270 with craniopharyngioma, 133 with Dandy-Walker malformation, 272 diagnosis of, 271 noncommunicating, 271 normal pressure, 35–36, 163 pathophysiology of, 271

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Hydrocephalus (Continued) pediatric, 35 with Sturge-Weber syndrome, 277 with subarachnoid hemorrhage, 63, 63b, 64–65 symptoms of, 271 syndromal, 271 treatment of, 65 X-linked, 271 Hydrocephalus ex vacuo, 36 in Rasmussen’s syndrome, 98 Hydrocodone, for restless legs syndrome, 169 Hydromorphone abuse, 181 Hydroxyurea, for sickle cell disease, 74 Hyperacusis, 51, 51b Hyperammonemia, diseases with, 279b Hyperekplexia, 88, 88b Hyperglycemia, management, in ischemic stroke, 60, 62 Hyperkalemic periodic paralysis, 246–247 diagnostic testing for, 246 pathophysiology of, 246 symptoms of, 246 treatment of, 247 Hyperpathia, 149–150 Hyperperfusion, and intracranial hemorrhage, 66 Hyperphagia, in Kluver-Bucy syndrome, 7 Hypersexuality, in Kluver-Bucy syndrome, 7 Hypertension, 295–297 causes of, 295–296 definitions of, 295 and ischemic stroke, 55, 59, 61–62 pathophysiology of, 295 primary/essential, 295 secondary, 295–296 symptoms of, 296 treatment of, 296 Hypertensive angiopathy, 65 Hypertensive emergencies, 295–296 Hypertensive encephalopathy, 296 Hypertensive urgency, 295–296 Hyperthyroidism with adenoma, 133 and hypokalemic periodic paralysis, 247 Hyperventilation, EEG response to, 80, 95, 95f Hypervolemic–hypertensive–hemodilution (triple H) therapy, 65 Hypnagogic hallucinations, 168 Hypnic headache, 143 Hypnopompic hallucinations, 168 Hypocalcemia, neonatal seizures with, 91 Hypochondriasis, 177 epidemiology of, 177 pathophysiology of, 177 prognosis of, 177 symptoms of, 177 treatment of, 177 Hypofrontality, in schizophrenia, 171 Hypoglossal nerve (CN XII), 26, 26f disorders/syndromes of, 34t Hypoglossal nucleus, 26 Hypoglycemia definition of, 91 neonatal seizures with, 91 Hypoglycemic coma, 295t Hypokalemic periodic paralysis, 247–248 diagnostic testing for, 247 symptoms of, 247 treatment of, 247–248

Hypomania, in bipolar disorder, 173 Hyponatremia and central pontine myelinosis, 112–113 with subarachnoid hemorrhage, 65 Hypophonia, in progressive supranuclear palsy, 187 Hypophonic dysarthria, lesions causing, 12 Hypopnea, definition of, 168 Hypothalamic hormones, 17, 17t Hypothalamic-pituitary-adrenal axis, in major depressive disorder, 173 Hypothalamus, 16–18 in arousal/sleep, 17, 164 autonomic regulation by, 16, 16b connections of, 18, 18f functions of, 16 lateral, 16, 16f medial, 16–18, 16f projections from, 1 subdivisions of, 16–18, 16f vascular anatomy of, 18 Hypothermia, malignant, 202t, 242, 242b, 247b Hypotonia in central core disease, 242 in Fukuyama congenital myopathy, 243 in Lesch-Nyhan disease, 287 lesions causing, 12 neonatal, in Canavan’s disease, 115 in urea metabolism disorders, 281 Hypotonic bladder, in multiple sclerosis, 109 Hypotonic disorders lower motoneuron, 289 neuromuscular junction, 289 peripheral nerve, 289 upper motoneuron, 289 Hypotonic motor delays, 288–289 Hypoxanthine-guanine phosphoribosyl transferase (HGPRT) enzyme, 286 Hypoxia, global, 70 Hypoxic encephalopathy, neonatal seizures with, 90–91 Hypoxic-ischemic encephalopathy, 159 I Icelandic-type amyloid angiopathy, 66, 95b Ice-pick headache, 143 ICH. See Intracranial hemorrhage Ichthyosis, in Refsum’s disease, 283 Ictal nystagmus, 46f–47f Ideomotor apraxia lesions causing, 3, 5 somatotopic, 5 Idiopathic hypertrophic pachymeningitis, 267 Idiopathic stabbing headache, 143 Iliacus muscle, 217f–218f Iliohypogastric nerve, 209f, 227f Ilioinguinal nerve, 209f, 227f Iliopsoas muscle, 229t Imipramine, in multiple sclerosis, 109 Immediate/working memory, 154b Immunoglobulin, intravenous. See Intravenous immunoglobulin Immunoglobulin disorders, 225–228. See also specific types Immunoglobulin G (IgG), in multiple sclerosis, 108 Immunosuppressant(s). See also specific types for antiphospholipid antibody syndrome, 73 for cryoglobulinemia, 228 for dermatomyositis, 245

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for Lambert-Eaton myasthenia, 237 for myasthenia gravis, 235 for paraneoplastic syndromes, 135 for sarcoidosis, 299 Impersistence, lesions causing, 5 Inattention, lesions causing, 5 Inclusion body myositis, 244 diagnostic testing for, 244 muscle biopsy in, 244, 244f nerve conduction studies of, 244 pathophysiology of, 244 prognosis of, 244 symptoms of, 244 treatment of, 244 Incomplete spinal cord injury, 31–32 Incus, 49f Indomethacin for hemicrania continua, 145 for idiopathic stabbing headache, 143 for paroxysmal hemicrania, 143, 145 Infantile epileptic encephalopathy, 94b Infantile spasms, 92–93 diagnostic testing in, 92 EEG findings in, 88f, 92, 92f and mental retardation, 92, 92b pathophysiology of, 92 prognosis of, 93 symptoms of, 92 treatment of, 93 Infarction(s). See also specific types cerebral arterial territories in, 57f computed tomography of, 57, 58f diagnostic testing for, 57 hemorrhagic conversion of, 57 magnetic resonance imaging of, 57, 58f patterns of, 71f migrainous, 138 venous, 74–75 Infection(s), 249–267. See also specific types fungal, 262–263 intrauterine, 290 parasitic, 264–265 viral, 256–262 Infection-like conditions, idiopathic, 267–268 Infectious endocarditis, 69–70 causative organisms of, 69 diagnostic testing for, 69 prognosis of, 70 risk factors for, 69 symptoms of, 69 treatment of, 69 Infectious hypothesis, of multiple sclerosis, 104 Infectious vasculitis, 77, 77t Inferior cerebellar peduncle, 21b, 24f, 26f Inferior colliculus, 11f, 22, 48f brachium of, 48f commissure of, 48f Inferior ganglion, 33t Inferior gluteal nerve, 209f, 228f, 229t Inferior longitudinal fasciculus, 9f, 10 Inferior occipitofrontal fasciculus, 9f, 10 Inferior olivary complex, 18, 26f, 27 Inferior vermis, 20f Infundibular nucleus, 16f Inguinal ligament, 217, 218f

Inner ear, 49, 49f Insertional activity, on EMG, 233 Insomnia, 166–167 in Alzheimer’s disease, 158 antidepressants for, 167 benzodiazepines for, 167, 167b chronic, 167 definition of, 166 fatal familial, 266 hypnotics for, 167 subtypes of, 166–167 symptoms of, 167 transient, 167 treatment of, 167 Insular cortex, 7 as focus of simple partial seizures, 84 Insulin-dependent diabetes mellitus (IDDM), 293 Intention tremor, lesions causing, 13–14, 21 Interferon(s) in Aicardi-Goutieres syndrome, 116 for arboviruses, 258 for chronic inflammatory demyelinating polyneuropathy, 225 for cryoglobulinemia, 228 for Devic’s disease, 110 for multiple sclerosis, 109–110 for subacute sclerosing panencephalitis, 260 Intermediate cutaneous nerve of thigh, biopsy of, 206 Intermediate disk herniation, 152, 152f Intermediate nerve, 32f Intermediate zone, of spinal cord, 30–31 Intermediolateral cell column, 30, 30f, 34 Internal acoustic porus, 32f Internal capsule, 9, 9f–10f pathophysiology in, 9 Internal carotid artery, 15f, 43f Interneurons cerebellar, 18 cortical, 1 Ia (reciprocal), 31 Ib, 31 spinal cord, 31 Internuclear ophthalmoplegia, 25, 44 Interossei nerve, 214f Interposed nuclei, 19 Interstitial nucleus of Cajal, 44 Intracranial hypotension, spontaneous, 147–148 Intracranial pressure, 35 brain abscess and, 250b in ischemic stroke, 60 in pseudotumor cerebri, 147 in subarachnoid hemorrhage, 64 Intralaminar thalamic nuclei (ITN), 15 Intramural hematoma, with arterial dissection, 70, 71f Intrauterine infections, 290 Intravenous immunoglobulin for acute disseminated encephalomyelitis, 112 for chronic inflammatory demyelinating polyneuropathy, 225 for dermatomyositis, 245 for Devic’s disease, 110 for Guillain-Barre syndrome, 223–224 for Lambert-Eaton myasthenia, 237 for Marburg’s variant of multiple sclerosis, 111 for multifocal motor neuropathy, 225 for multiple sclerosis, 109 for myasthenia gravis, 235

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Intravenous immunoglobulin (Continued) for paraneoplastic syndromes, 135 for stiff man’s syndrome, 201 Intrinsic hippocampal connections, 7, 8f Iron deficiency, and restless legs syndrome, 169 Irritability, on EMG, 233 Isaac’s syndrome, 136t, 245–246 Ischemic stroke, 55–62 age and, 55 diagnostic testing for, 57–58 epidemiology of, 55 prevention of, 60–62 race and, 55 risk factors for, 55–56 sex and, 55 sickle cell disease and, 74 subtypes of, 55 symptoms of, 56–57 thrombolytic therapy for, 58–59 treatment of, 58–62 in acute setting, 58–60 in subacute or chronic setting, 60–62 Islets of Calleja, 11 Isocortex, 1–2 heterotypical, 1–2 homotypical, 1 Isolated CNS vasculitis, 76–77 Isoniazid, for tuberculosis, 252 Isovaleric acidemia, 280–281, 280b Isovaleryl-CoA dehydrogenase deficiency, 280–281 IVIG. See Intravenous immunoglobulin Ixodes, 253, 253b, 267t J Jacksonian march, 84 Jactatio capitis nocturna, 170–171 Janeway lesions, 69 Jaw jerk reflex, 25 JC virus, 259, 262 Jeavon’s syndrome, 95b Jitteriness, in children, 99 Jugular ganglion, 33t Junctional scotoma, 39, 39f Juvenile myoclonic epilepsy, 94 diagnostic testing in, 94 EEG findings in, 94, 94f pathophysiology of, 94 symptoms of, 94 treatment of, 94 Juvenile pilocytic astrocytoma, 121 epidemiology of, 121 grading of, 121 histology of, 121, 121f location of, 121 treatment of, 121 Juvenile rheumatoid arthritis, 297 diagnostic testing in, 297 symptoms of, 297 treatment of, 297 Juxtarestiform body, 19

328

K Kayser-Fleischer rings in dystonia, 192 in Wilson’s disease, 195, 195b, 195f K complexes, in EEG of sleep, 165f, 166

Kearns-Sayre syndrome, 46–47 diagnostic testing for, 47 pathophysiology of, 46 symptoms of, 47 treatment of, 47 Kennedy’s disease, 197t Keppra. See Levetiracetam Ketamine abuse and dependence, 181–182 acute intoxication, 182 biochemical effects of, 181 withdrawal from, 182 Ketogenic diet, for Lennox-Gastaut syndrome, 93 Ketorolac, for status migrainosus, 141 Ki-67 nuclear antigen in astrocytoma, 119, 119b in meningioma, 123 Kinesia(s). See also specific types lesions causing, 6 Kinetopsia, 42 Kingella, 69 Klebsiella, and meningitis, 250t Klein-Levin syndrome, 15 lesions causing, 15 symptoms of, 15 treatment of, 15 Klinefelter’s syndrome, germinoma in, 129 Klumpke’s palsy, 208 Kluver-Bucy syndrome, 7 dementia in, 161 lesions causing, 7 symptoms of, 7, 7b Knee extension, 229t Knee flexion, 229t Korsakoff’s syndrome, 300 lesions causing, 13 Krabbe’s disease, 117–118 diagnostic testing for, 118 histology of, 118 infantile, 118 juvenile, 118 pathophysiology of, 117 symptoms of, 118 treatment of, 118 Krebs cycle defects, 287 Kugelberg-Welander disease, 197t Kuru, 266b L L1CAM gene mutations, 271, 271b La belle indifference, 177 Labetalol, 296 Labyrinthectomy, for Meniere’s disease, 53 Labyrinthitis, 53–54 diagnostic testing for, 54 pathophysiology of, 53 symptoms of, 54 treatment of, 54 LaCrosse encephalitis, 251t Lactate, in vanishing white matter disease, 116 Lactic acidosis, 287 Lafora disease, 95t Lambert-Eaton myasthenia, 236–237 with associated cancer, 236 autonomic dysfunction with, 237, 237b diagnostic testing for, 237

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electromyography of, 237 paraneoplastic, 135, 136t, 236 pathophysiology of, 236 subtypes of, 236 symptoms of, 236–237 treatment of, 237 without associated cancer, 236 Lamictal. See Lamotrigine Lamin A/C mutations, 219b, 219t, 238, 238b, 241, 242t Laminar heterotopia, 269 Laminectomy, for low back pain, 153 Lamotrigine, 102t for bipolar disorder, 174 for gelastic seizures, 84b Landau-Kleffner syndrome, 95–96 diagnostic testing in, 96 EEG findings in, 96 pathophysiology of, 95 prognosis of, 96 symptoms of, 95–96 treatment of, 96 Language area(s), 5–7 dominant hemisphere, 5–6 nondominant hemisphere, 6–7 secondary, 6 Language delay, 287 Language impairment, in Alzheimer’s disease, 157 Large infarct dementia, 159 Lateral cord injury, 209 Lateral corticospinal tract, 30, 30f Lateral cutaneous nerve of calf, 227f–228f Lateral cutaneous nerve of thigh. See Lateral femoral cutaneous nerve Lateral femoral cutaneous nerve, 209f, 218f, 227f–228f anatomy of, 218f compression syndrome of, 218 Lateral funiculus, 30 Lateral geniculate nucleus, 14, 14f, 40 blood supply of, 40 magnocellular pathway of, 40 parvocellular pathway of, 40 pathophysiology in, 40 projections of, 40–41 subdivisions of, 40 Lateral hypothalamus, 16, 16f Lateral lemniscus, 24f, 48f nucleus of, 48f Lateral medullary syndrome, 26f Lateral pectoral nerve, 207f Lateral plantar nerve, 227f Lateral pontine syndrome, 24f Lateral preoptic nucleus, 17 Lateral reticular nucleus, 29, 29b Lateral reticulospinal tract, 29 Lateral spinothalamic tract, 24f, 26f Lateral ventricle, tumors of, 128b Lateral vestibulospinal tract, 49, 50t Laterocollis, 191 Latissimus dorsi, 229t Latrotoxin, 267t Leigh’s disease, 47, 287 diagnostic testing for, 47 histology of, 47 subtypes of, 47 symptoms of, 47 treatment of, 47

Lennox-Gastaut syndrome, 93 diagnostic testing in, 93 EEG findings in, 93, 93f pathophysiology of, 93 prognosis of, 93 symptoms of, 93 treatment of, 93 Lenticular fascicle, 13 Leonine face, and cluster headache, 141b Lepromin skin test, 253 Leprosy, 253 diagnostic testing for, 253 indeterminate, 253 lepromatous, 253 pathophysiology of, 253 symptoms of, 253 treatment of, 253 tuberculous, 253 Lesch-Nyhan disease, 286–287 pathophysiology of, 286 symptoms of, 286–287 Lesser occipital nerve, 149f Leucine, for isovaleric acidemia, 281 Leucine-rich glioma-inactivated (LGI-1) protein, 120, 120b Leukemia, monoclonal gammopathy in, 226 Leukoariosis, 8–9 histology of, 8–9 irregular white matter abnormalities in, 8 lesions causing, 8–9, 8f periventricular white matter caps and halos in, 9 in vascular dementia, 160 Leukocytosis, in multiple sclerosis, 108 Levetiracetam, 102t Levodopa-carbidopa for dystonia testing, 192 for dystonia treatment, 192 for Parkinson’s disease, 186, 186t Lewis-Sumner syndrome, 224 Lewy body(ies), 156, 162, 162f Lewy body dementia, 161–163 versus Alzheimer’s disease, 159t delusions in, 162, 162b diagnostic testing for, 162–163 epidemiology of, 155f histology of, 161, 162f inclusions (Lewy bodies) in, 162, 162f parkinsonism in, 162–163, 186b pathophysiology of, 162 symptoms of, 162, 162b treatment of, 163 Lewy neurites, 162 Lexapro (escitalopram), 174t Lhermitte’s sign, in multiple sclerosis, 106 Libman-Sacks vegetations, 298 Lidocaine for complex regional pain syndrome, 150 intranasal, for cluster headache, 142, 145 Lifestyle factors, in ischemic stroke, 56 Li-Fraumeni syndrome, 121, 126 Light therapy, for circadian rhythm disorders, 170 Limb ataxia, in rostral vermis syndrome, 19 Limb dystonia, 191 Limb-girdle muscular dystrophy types 1A-E, 241 diagnostic testing for, 241 subtypes of, 241, 242t

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Limb-girdle muscular dystrophy (Continued) symptoms of, 241 types 2A-H, 241–242 diagnostic testing for, 242 subtypes of, 241–242, 242t Limbic areas, 2, 7–8 Limbic encephalitis, in paraneoplastic syndromes, 136t Limb temperature and electromyography, 233 and nerve conduction studies, 206 Line of Baillarger, 2, 2f Lingula, 20f Lipid metabolism disorders, 297–301, 297t Lipoprotein(s) levels of, and ischemic stroke, 56, 62 reduction of, 62 LIS-1 gene mutations, 269b Lisch nodules, 274f, 275 Lissauer’s tract, 30f Lissencephaly, 269 Listeria monocytogenes in HIV infection, 262 and meningitis, 250t Lithium for alcohol dependence, 179 for bipolar disorder, 174 for chronic headache, 145 for cluster headache prophylaxis, 142 for hypnic headache, 143 for Klein-Levin syndrome, 15 for major depressive disorder, 173 and parkinsonism, 202 and restless legs syndrome, 169 for schizophrenia, 172 side effects of, 174 Little’s disease, 288 Liver failure, and central pontine myelinosis, 112 Lobar prosencephaly, 270 Lobe(s), important cortical, 1, 1f Locked-in syndrome mesencephalic, 23 pontine, 24f, 25, 113 Locus coeruleus, 19, 25, 28, 164 Lomustine, for oligodendroglioma, 122 Long association fibers, 9–10, 9f Long-term/remote memory, 154b Long thoracic nerve, 207f Long tracts, of spinal cord, 29–30, 30f Lorazepam, for status epilepticus, 89t Lorenzo’s oil, 117 Loss of heterozygosity (LOH) and astrocytoma, 120, 120f and oligodendroglioma, 122 Low back pain, 151–153 diagnostic testing in, 152 pathophysiology of, 151–152 prognosis of, 153 treatment of, 153 Low-density lipoprotein (LDL), 56 Lower extremity(ies) compression neuropathies of, 217–218 movements, muscles, nerves, and roots of, 229t Lower motoneuron hypotonic disorders, 289 Lubag syndrome, 190t Luckenschadel, 272f

Lumbar artery, 31f Lumbar puncture in carcinomatous meningitis, 132 in chronic headache, 146 in febrile seizures, 91 in normal pressure hydrocephalus, 36, 163 in paraneoplastic syndromes, 135 in pseudotumor cerebri, 147 in spontaneous intracranial hypotension, 147 traumatic, 35 Lumbar radiculopathies, 152, 152b, 152t Lumbar spinal fusion, 153 Lumboperitoneal shunt for normal pressure hydrocephalus, 163 for pseudotumor cerebri, 147 Lumbosacral plexus, 209–210 anatomy of, 209f lesions of, 209–210 diagnostic testing for, 210 electromyography of, 210 magnetic resonance imaging of, 210 symptoms of, 209–210 pathophysiology in, 209 tumor compression or invasion of, 209, 209b Lumbrical muscle, 210f, 213f Lundberg waves, 35 A waves, 35 B waves, 35 C waves, 35 in carcinomatous meningitis, 132 in normal pressure hydrocephalus, 36, 163 in pseudotumor cerebri, 147 Lupus anticoagulant antibody, 73 Lupus delirium, 298 Lupus erythematosus, systemic, 298 Luteinizing hormone (LH) adenoma and, 133 in seizures/epilepsy, 82 Lyme disease, 253–254 acute, 254 chronic, 254 diagnostic testing for, 254 epidemiology of, 254 pathophysiology of, 253–254 symptoms of, 254 treatment of, 254 vasculitis with, 77t Lyme disease vaccine, 254 Lymphocyte-rich meningioma, 123 Lymphoma(s) HIV-related, 262 Hodgkin’s, vasculitis with, 76–77 monoclonal gammopathy in, 226 Lysosomal storage diseases, 282–285. See also specific types M Machado-Joseph’s disease, 191, 199t Macroadenoma, 133 Macrocephaly in Canavan’s disease, 115 in megaloencephalic leukoencephalopathy with subcortical cysts, 116 Macula, 41–42 Mad cow disease, 266

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Magnesium abnormal levels of, 301t in chronic fatigue syndrome, 151 and tension-type headache, 141 Magnetic resonance angiography (MRA) of carotid stenosis, 57 of infectious endocarditis, 69 of Sturge-Weber syndrome, 278 of subarachnoid hemorrhage, 63 Magnetic resonance imaging (MRI) of acute disseminated encephalomyelitis, 112, 112f of adrenoleukodystrophy, 117 of Alzheimer’s disease, 158, 158f of arterial dissection, 70, 71f of arteriovenous malformations, 78f of brachial plexopathy, 209 of CADASIL syndrome, 67 of carcinomatous meningitis, 132 of cavernoma, 79f of cerebral infarction, 57, 58f of choroid plexus papilloma, 128 of chronic headache, 146 of Cockayne’s syndrome, 286, 286f of colloid cyst, 129 of ependymoma, 128 of glossopharyngeal neuralgia, 149 of hereditary spastic paraplegia, 198 of HIV encephalitis, 261 of Huntington’s disease, 194f of hypertensive encephalopathy, 296 of intracranial hemorrhage, 66, 66f of lumbosacral plexopathy, 210 of megaloencephalic leukoencephalopathy with subcortical cysts, 116 of migraine, 139 of multiple sclerosis, 105f, 108 of multiple system atrophy, 189f of neurofibromatosis type 1, 275, 276f of normal pressure hydrocephalus, 36, 163 of palatal myoclonus, 22 of Pelizaeus-Merzbacher disease, 114f of semantic dementia, 161f of spinal cord tumor, primary, 131, 131f of Sturge-Weber syndrome, 278 of systemic lupus erythematosus, 298 of transient global amnesia, 8 of trigeminal neuralgia, 148 of tuberous sclerosis, 277, 278f of vanishing white matter disease, 116 of vascular dementia, 160 of venous infarction, 75, 75f Magnetic resonance spectroscopy (MRS) of Canavan’s disease, 115 of vanishing white matter disease, 116 Magnetic resonance venography (MRV) of chronic headache, 146 of pseudotumor cerebri, 147 Magnocellular nucleus, 17 Magnocellular pathway, 40 Major depressive disorder, 173 biological pathophysiology of, 173 genetics of, 173 prognosis of, 173 psychosocial pathophysiology of, 173

symptoms of, 173, 173b treatment of, 173 Malaria, 264 cerebral, 264 diagnostic testing for, 264 prognosis of, 264 symptoms of, 264 treatment of, 264 Male sexual function, 34 Malformations, 269–275. See also specific types Malignant hypothermia, 202t, 242, 242b, 247b Malignant peripheral nerve sheath tumor, 135 histology of, 135 pathophysiology of, 135 prognosis of, 135 symptoms of, 135 treatment of, 135 Malignant psoas syndrome, 209b Malleus, 49f Malnutrition, alcohol abuse and, 178 Mammillary body(ies), 16f, 17 Mammillary region, 17–18 Mammillotegmental tract, 18f Mammillothalamic fasciculus, 18f Manganese, abnormal levels of, 301t Mania, in bipolar disorder, 173 Maple syrup urine disease, 279 diagnostic testing for, 279 infant onset of, 279 neonatal onset of, 279 pathophysiology of, 279 symptoms of, 279 treatment of, 279 Marantic endocarditis, 69 Marburg’s variant of multiple sclerosis, 111 diagnostic testing for, 111 histology of, 111 pathophysiology of, 111 prognosis of, 111 symptoms of, 111 treatment of, 111 Marché à petit pas of Dejerine, lesions causing, 5 Marchiafava-Bignami disease, 113, 178 histology of, 113 pathophysiology of, 113 prognosis of, 113 symptoms of, 113 treatment of, 113 Marcus-Gunn pupil, 106 Marfan’s syndrome, 70, 77 Marie-Foix syndrome, 24f, 25 Marijuana, 181 acute intoxication, 181 biochemical effects of, 181 in schizophrenia, 171 symptoms of use, 181 withdrawal from, 181 Martin-Gruber anastomosis, 212, 212f Mastoidectomy, for labyrinthitis, 54 McArdle’s disease, 243 McDonald criteria, for multiple sclerosis, 107t MDM2 protein, and astrocytoma, 119, 120f Measles, 259–260 and acute disseminated encephalomyelitis, 111 diagnosis of, 260

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Measles (Continued) and multiple sclerosis, 104 pathophysiology of, 259 treatment of, 260 types of infection, 259–260 Measles inclusion body encephalitis, 259 Measles-mumps-rubella (MMR) vaccine, 260 febrile seizures induced by, 91 Meclizine for Meniere’s disease, 53 for vertigo, 52 for vestibular neuronitis, 53 MECP2 mutations, 291, 291b Medial cord injury, 209 Medial cutaneous nerve of arm, 227f–228f Medial cutaneous nerve of forearm, 227f–228f Medial deltoid muscle, 229t Medial geniculate, 14, 14f Medial geniculate body, 48f Medial gluteal nerve, 228f Medial hypothalamus, 16–18, 16f Medial lemniscus, 24f, 26f Medial longitudinal fasciculus, 29 rostral interstitial nucleus of, 44 Medial pectoral nerve, 207f Medial plantar nerve, 227f–228f Medial preoptic nucleus, 17 Medial vestibulospinal tract, 49, 50t Median nerve, 207f, 214f, 227f, 229t anatomy of, 210f compression syndromes of, 210–212 preacher’s hand position in, 211f stimulation, in multiple sclerosis, 108, 108f Median preoptic nucleus, 16 Medulla, 26–28, 26f in arousal/sleep, 164 motor output centers of, 26 pathophysiology in, 28 sensory input centers of, 26 Medullary accessory ocular motor nuclei, 44–45 Medullary raphe nuclei, 19 Medullary reticular formation, 26f, 29, 164 Medullary syndromes, 28 Medulloblastoma, 126 diagnostic testing for, 126 epidemiology of, 126 histology of, 126, 126f Homer-Wright rosettes in, 126, 126f location of, 126 treatment of, 126 Megaloencephalic leukoencephalopathy with subcortical cysts, 116 diagnostic testing for, 116 histology of, 116 pathophysiology of, 116 symptoms of, 116 Meige’s syndrome, 191 Meissner’s corpuscle, 205t MELAS syndrome, 67–69 diagnostic testing for, 68f, 69 pathophysiology of, 67 ragged red fibers in, 68f, 69 symptoms of, 67 treatment of, 69 Melatonin in arousal/sleep, 164 biosynthesis of, 165f

for circadian rhythm disorders, 170 and cluster headache, 142 Melatonin therapy, for cluster headache prophylaxis, 142 Memantine for Alzheimer’s disease, 158 for vascular dementia, 160 Memory putamen lesions and, 12 types of by duration, 154b by subject, 154b Memory loss. See also specific disorders of age-related, 154 in Alzheimer’s disease, 157 Meniere’s disease, 52–53 diagnostic testing for, 53 pathophysiology of, 52–53 prognosis of, 53 symptoms of, 53 chronic, 53 episodic, 53 treatment of, 53 Meningioma(s), 123–125 anaplastic/malignant, 124 angiomatous, 123 atypical, 124 chordoid, 124 clear cell, 124 diagnostic testing for, 124–125 with dural tails, 124, 124f en plaque, 125 fibrous, 123, 124f genetics of, 124, 275b location of, 124 lymphocyte-rich, 123 meningothelial, 123, 124f MIB-1 antibody labeling of, 123 neuroimaging of, 124–125, 124f prognosis of, 125 psammomatous, 123, 124f receptor on, 123b secretory, 123 transitional, 123, 124f treatment of, 125 WHO grade III subtype of, 124 WHO grade II subtypes of, 124 WHO grade I subtypes of, 123 Meningitis bacterial, 249 vasculitis with, 77t carcinomatous, 131–132 fungal, 262–263 vasculitis with, 77t HIV-related, 262 Mollaret’s, 268 petechial rash with, 255b in sarcoidosis, 298 in syphilis, 254 in tuberculosis, 252 Meningitis vaccines, 249 Meningocele, 274 Meningothelial meningioma, 123, 124f Menopausal migraine, 138 Menstrual migraine, 138 Mental retardation Aicardi-Goutieres syndrome and, 116

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aphasia, shuffling gait, adducted thumbs (MASA) disorder, 271 autism and, 291 cortical malformations and, 269 infantile spasms and, 92, 92b megaloencephalic leukoencephalopathy with subcortical cysts and, 116 muscular dystrophy and, 238, 241 neurofibromatosis type 1 and, 275 phenylketonuria and, 279 sphingolipidoses and, 283 Sturge-Weber syndrome and, 277 tuberous sclerosis and, 276 Meperidine abuse of, 181 and parkinsonism, 202 Merkel’s cell, 205t Mesencephalic accessory ocular motor nuclei, 44 Mesencephalic raphe nuclei, 164 Mesencephalic reticular formation, 22, 28, 164 Mesencephalic trigeminal nucleus, 25 Mesencephalon, 21–23 in arousal/sleep, 164 motor output centers of, 21–22 pathophysiology in, 21–23 Mesial temporal cortex, as focus of complex partial seizures, 85–86 Mesial temporal sclerosis, 85–86 classic, 85, 85b diagnostic testing for, 86 histology of, 85 minimal, 85 pathophysiology of, 86 subtypes of, 85 total, 85 Mesocortex, 2 Mesocortical dopaminergic pathway, 22 Mesolimbic dopaminergic pathway, 22 Mestinon. See Pyridostigmine Metabolic disorders, 279–292. See also specific types and dementia, 154 and dystonia, 191 Metachromatic leukodystrophy, 117 adult, 117 diagnostic testing for, 117 histology of, 117 infantile, 117 juvenile, 117 pathophysiology of, 117, 117b symptoms of, 117 treatment of, 117 Metastasis, 130–131 epidemiology of, 130 pathophysiology of, 130 subtypes of, 130 treatment of, 131 Metazoan infection, 264–265 Methadone for opioid dependence, 181 for restless legs syndrome, 169 Methamphetamine abuse, 180–181 Methaqualone abuse, 179 Methimazole, for adenoma, 133 Methotrexate for carcinomatous meningitis, 132 for dermatomyositis, 245 for multiple sclerosis, 109

Methylenedoxy methamphetamine (MDMA), 180–181 Methylenetetrahydrofolate, 279b Methylenetetrahydrofolate reductase (MHTR), 73f Methylenetetrahydrofolate reductase (MHTR) deficiency, 73 Methylmalonic aciduria, 281 Methylmalonyl-CoA, 281, 281f Methylmalonyl-CoA reductase, 281 Methylphenidate, for orthostatic hypotension, 185 Methylphenidate abuse, 180–181 Methylprednisolone, 118t for multiple sclerosis, 108–110 Methysergide for chronic headache, 145 for cluster headache prophylaxis, 142 for migraine prophylaxis, 140 Metoclopramide and parkinsonism, 202 for status migrainosus, 141 and tardive dyskinesia, 201 Metronidazole, for brain abscess, 251 Mexiletine for complex regional pain syndrome, 150 for myotonia congenita, 248 for myotonic dystrophy, 239 Meyer’s loop, 40–41 Meynert, nucleus basilis of, 1, 11 Meynert’s bundle, 18f Mi2 antibody, in dermatomyositis, 244–245 MIB-1 antibody labeling of astrocytoma, 119, 119b of meningioma, 123 “Mickey Mouse” ventricles, 35 Microadenoma, 133 Microangiopathic/small artery infarction, 71f Microcephaly, in Aicardi-Goutieres syndrome, 116 Midazolam, for status epilepticus, 89t Midbrain locked-in syndrome, 23 Middle cerebellar peduncle, 21b, 24f Middle cerebral artery, 15f, 39–40, 57f Middle ear, 49f Midline cerebellar degeneration, 178 Midodrine, for orthostatic hypotension, 185 Migraine, 137–141 abdominal, 138 acephalgic, 138 antiemetics for, 140 with aura (classic), 137–138 aura phase of, 137 basilar, 138 and benign occipital epilepsy, 96 chronic, 143–144, 146 complicated, 138 confusional, 138 diagnostic testing for, 139 EEG findings in, 139 epidemiology of, 139 ergots for, 140 genetics of, 139 headache phase of, 137 hemiplegic, 138 magnetic resonance imaging of, 139 menstrual/menopausal, 138 nonsteroidal antiinflammatory drugs for, 140

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Migraine (Continued) ophthalmoplegic, 138 opioids for, 140 pathophysiology of, 139 postdrome phase of, 137 in pregnancy, 139, 141 prodrome phase of, 137 with prolonged aura, 138 prophylactic treatment of, 140–141 psychiatric comorbidity with, 139 risk factors for, 139 subtypes of, 137–139 symptoms of, 137 transformed, 143–144 treatment of, 139–141 acute, 139–140 triggers for, 139 triptans for, 139–140, 140t variants of, 138 vertigo with, 54t without aura (common), 137–138 Migraine equivalent, 138 Migrainous infarction, 138 Mild cognitive impairment (MCI), 154 amnestic, 154 definition of, 154 with impairment in multiple domains, 154 with impairment in nonmemory domain, 154, 154b progression of, 154, 154b subtypes of, 154 Millard-Gruber syndrome, 24f, 25 Miller-Fisher syndrome, 223 diagnostic testing for, 223 prognosis of, 223 symptoms of, 223 Mini-mental status exam (MMSE), in dementia, 154 Mirapex. See Pramipexole Mirtazapine, 174t Mitochondrial respiratory chain complex I, 47 Mitoxantrone for Marburg’s variant of multiple sclerosis, 111 for multiple sclerosis, 109 Mixed neuronal-glial tumors, 129 Mobius syndrome, 248t Modafinil for multiple sclerosis, 109 for narcolepsy, 168 Molecular mimicry, 104 Mollaret, triangle of, 21, 21b Mollaret’s cells, 268 Mollaret’s meningitis, 268 Monoamine oxidase (MOA) inhibitors, 174t Monoclonal gammopathy(ies), 225–226 diagnostic testing for, 226 inclusion body myositis with, 244 pathophysiology of, 225 serum protein electrophoresis in, 226 of undetermined significance (MGUS), 224–226 urine protein electrophoresis in, 226 Monocular diplopia, 43b Monomodal auditory association area, 48f Monomodal motor association areas, 2 Monomodal sensory association areas, 2 Mononeuritis multiplex, 226, 226b, 297 Mononeuropathy, diabetic, 294 Monosomy, 5p, 289

Mood disorder(s), 173–174. See also specific types Morphine abuse, 181 Morquio’s syndrome, 284t Mosquito, as vector of disease, 251t Mossy fibers, 18b, 19f Motoneuron(s), 231 , 31 -I, 31 -II, 31 somatotopic arrangement of, 31, 31f upper and lower, in hypotonic disorders, 289 Motor delay, developmental, 287–289 Motor homunculi, 2, 3f Motor nerve conduction studies, 204–205, 205f Motor-sensory neuropathies, hereditary, 218–220 Motor systems, 2–3 Motor tics, 192 Motor trigeminal nucleus, 23 Motor unit(s), 231–232 fatigable fast-twitch, 232 fatigue-resistant fast-twitch, 232 fatigue-resistant slow-twitch, 232 types of, 232, 232f Motor unit potentials (MUPs), 232–234 complex repetitive discharges and, 233 in elderly, 234 myopathic changes in, 232 in neonates, 233 neuropathic changes in, 232–233 normal, 232f reinnervation changes in, 232–233 Movement disorder(s), 183–202. See also specific types iatrogenic, 201–202 Moyamoya disease, 79 angiography of, 79, 79f diagnostic testing for, 79 epidemiology of, 79 M protein, in monoclonal gammopathy, 225 MRA. See Magnetic resonance angiography M response, in nerve conduction studies, 206 MRI. See Magnetic resonance imaging MS. See Multiple sclerosis Mucopolysaccharidoses, 283, 284t Multifocal motor neuropathy, 225 diagnostic testing for, 225 electromyography of, 225 epidemiology of, 225 nerve conduction studies of, 225 pathophysiology of, 225 prognosis of, 225 serology in, 225 symptoms of, 225 treatment of, 225 Multi-infarct dementia, 159–160. See also Vascular dementia Multiple myeloma, monoclonal gammopathy in, 226 Multiple sclerosis, 104–111 versus acute disseminated encephalomyelitis, 110 age and, 104 autoimmune hypothesis of, 104 brainstem auditory evoked potentials in, 108 clinically isolated, 107 CSF analysis in, 108 dementia in, therapy for, 109 depression in, therapy for, 109 diagnostic criteria for Barkhof MRI, 108

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McDonald, 107t Poser, 107t, 110 diagnostic testing for, 107–108 electrophysiological testing in, 108, 108f epidemiology of, 104–105 etiological hypotheses of, 104 genetics of, 104 geography and, 104 histology of, 105, 105f infectious hypothesis of, 104 magnetic resonance imaging of, 105f, 108 Marburg’s variant of, 111 monophasic brainstem or cerebellar syndromes in, 107 neuroimaging of, 107–108 normal appearing white matter (NAWM) in, 105 optic neuritis in, 106–107, 110 pathophysiology of, 104, 244b pediatric/early-onset, 110 diagnostic testing for, 110 pathophysiology of, 110 symptoms of, 110 treatment of, 110 plaques in, 105 acute/active, 105, 105f chronic, 105, 105f shadow, 105 in pregnancy, 106b, 109, 109b primary progressive, 107 progressive relapsing, 107 progressive types, therapy for, 109 race and, 105 relapsing-remitting, 105f, 106 preventive therapy for acute attacks in, 109 therapy for, 108–109 secondary progressive, 106 sensory abnormalities in, 106 serology in, 108 sex and, 105 somatosensory evoked potentials in, 108, 108f subtypes of, 106–107 symptoms of, 106 acute, 106 chronic, 106, 109 conditions exacerbating, 106b paroxysmal, 106, 109 transverse myelitis in, 107 treatment of, 108–109 variants of, 110–111 vision loss in, 106 visual evoked potentials in, 42, 108 Multiple sclerosis-associated retrovirus, 104 Multiple sleep latency test, in narcolepsy, 168 Multiple subpial transections, for seizure control, 102 Multiple system atrophy (MSA), 188–189 classification of new scheme for, 188–189 old scheme for, 188 histology of, 188 OPCD form of, 189 with predominant cerebellar features, 189 with predominant parkinsonian features, 188–189, 189b, 189f striatonigral degeneration form of, 188–189 Multivitamin supplementation, for Kearns-Sayre syndrome, 47 Mumps and acute dissemination encephalomyelitis, 111 and multiple sclerosis, 104

MUPs. See Motor unit potentials Muscle(s), 229t. See also specific muscles contraction of, 230, 230f diagnostic testing of, 232–234 diseases of, 230–248. See also specific types absent muscle, 248t acquired, 244–246 with autoimmune disease, 244b autosomal dominant, 238–241 autosomal recessive, 241–243 channelopathies, 246–248 congenital, 237–243 diabetic, 294–295 HIV-related, 261 inherited metabolic, 243 X-linked, 237–238 physiology of, 230–232 recruitment principle of, 232 Muscle biopsy, 234 in Becker’s muscular dystrophy, 238 in central core disease, 242, 243f contraindicated by rhabdomyolysis, 234 in dermatomyositis, 245, 245f in Duchenne’s muscular dystrophy, 237, 237f in facioscapulohumeral muscular dystrophy, 241, 241f in Fukuyama congenital myopathy, 243 in hyperkalemic periodic paralysis, 246 in hypokalemic periodic paralysis, 247 in inclusion body myositis, 244, 244f in myasthenia gravis, 235 in myotonic dystrophy, 239, 239f in myotubular myopathy, 240, 240f in nemaline rod myopathy, 240, 241f in neuromyotonia, 246 open, 234 in paramyotonia congenita, 247 in polymyositis, 245, 246f technical limitations of, 234 Muscle fiber(s), 230–231 fast-twitch/type II, 231, 231f pacemaker, 233 slow-twitch/type I, 231, 231b super-fast, 231 tonic, 231 Muscle relaxants for dystonia, 192 for fibromyalgia, 151 for greater occipital neuralgia, 149 for low back pain, 153 Muscle specific tyrosine kinase (MuSK), in myasthenia gravis, 235 Muscular dystrophy. See also specific types Becker’s, 238 Duchenne’s, 237–238 Emery-Dreifuss, 238 facioscapulohumeral, 240–241 limb-girdle, 241–242 Musculocutaneous nerve, 207f, 227f–228f, 229t Musicogenic seizures, 86 Mutism, in frontotemporal dementia, 161 Myalgia paresthetica, 218 Myasthenia(s) congenital, 236 familial infantile, 236 Lambert-Eaton, 135, 136t, 236–237 transitory neonatal, 236

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Myasthenia crisis, 235b Myasthenia gravis, 234–236 autoimmune, 234 diagnostic testing for, 235 edrophonium test in, 235 electromyography of, 235 epidemiology of, 234 muscle biopsy in, 235 nerve conduction studies of, 235, 235f paraneoplastic, 135, 136t, 234 pathophysiology of, 234 prognosis of, 236 serum antibodies in, 235 symptoms of, 234–235 with thymoma, 234–236 treatment of, 235–236 Myasthenic syndromes, 234–237. See also specific types pediatric, 236 MYCN gene, and neuroblastoma, 126 Mycobacteria, 252–253 Mycobacterium leprae, 253. See also Leprosy Mycobacterium tuberculosis, 252–253. See also Tuberculosis Mycophenolate for myasthenia gravis, 235 for paraneoplastic syndromes, 135 Mycoplasma pneumoniae, 111–112, 222 Myelin-associated glycoprotein (MAG), 206, 225, 225b Myelination disorders, 104–118. See also specific types Myelin basic protein, in multiple sclerosis, 108 Myelin onion bulbs, 220, 220f, 282 Myelitis, transverse, 107 Myelomeningocele, 274 Myelopathia centralis diffusa, 115–116 Myocardial infarction, and ischemic stroke, 55 Myoclonic dystonia, 190b, 190t Myoclonic epilepsy benign, 93–94 juvenile, 94 severe, 94 Myoclonic epilepsy with ragged red fibers (MERRF), 95t Myoclonic seizure(s), 89 neonatal, 90 Myoclonic seizure syndromes, 95, 95t Myoclonus in Alzheimer’s disease, 158 in cortical-based ganglionic degeneration, 188 eyelid, with absence seizures, 95b palatal, 21–22 in paraneoplastic syndromes, 136t Myokymic discharges, on EMG, 233 Myopathy. See Muscle(s), diseases of; specific types Myotilin, in limb-girdle muscular dystrophy, 241, 242t Myotonia congenita, 248 differential diagnosis of, 248t Myotonic conditions, comparison of, 248t Myotonic discharges, on EMG, 233, 233b Myotonic dystrophy, 238–239 adult-onset, 239 congenital-onset, 239 diagnostic testing for, 239 differential diagnosis of, 248t electromyography of, 239 muscle biopsy in, 239, 239f prognosis of, 239 subtypes of, 238 symptoms of, 239, 239f

treatment of, 239 type I, 238 type II, 238 Myotubularin mutations, 219b, 219t, 240, 240b Myotubular myopathy, 239–240 autosomal dominant, 239 autosomal recessive, 239 diagnostic testing for, 240 muscle biopsy in, 240, 240f prognosis of, 240 subtypes of, 239–240 symptoms of, 240 X-linked, 240 Myringotomy, for labyrinthitis, 54 Mysoline. See Primidone Myxopapillary ependymoma, 127 N Nabumetone, for chronic headache, 144 N-acetylaspartate (NAA) in Canavan’s disease, 115 in vanishing white matter disease, 116 Naegleria, 264 Naloxone, for opioid dependence, 181 Naltrexone for alcohol dependence, 179 for opioid dependence, 181 Naproxen, for chronic headache, 144 Naratriptan, 140t Narcan (naloxone), for opioid dependence, 181 Narcolepsy, 167–168 diagnostic testing in, 168 hallucinations in, 168 pathophysiology of, 167 symptoms of, 167–168 treatment of, 168 Nasal bundle, 38f injury of, 38, 38f Nasal step of Ronne, 38, 38f Nasopharyngeal electrodes, 80 Nausea, with subarachnoid hemorrhage, 63 Near triad reflex, 44, 44b Neck pain, 153f in brachial plexopathy, 208 in C6 radiculopathy, 211b Negative seizure phenomena, 84 Neglect contralateral tactile, 5 in striatocapsular syndrome, 9 tactile, 5, 15 visual, 42–43 Neisseria meningitidis, 249, 250t Nemaline rod myopathy, 240 muscle biopsy in, 240, 241f pathophysiology of, 240 prognosis of, 240 symptoms of, 240 Nembutal. See Pentobarbital Neocortical temporal foci, of complex partial seizures, 86 Neonatal convulsions, benign familial, 98 hemiplegic migraine with, 138 Neonatal-infantile convulsions, benign familial, 98–99 Neonatal seizures, 90–91 causes of, 90–91, 90t focal clonic, 90 multifocal clonic, 90

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myoclonic, 90 “subtle,” 90 subtypes of, 90 tonic, 90 Nerve(s), 229t. See also specific nerves diagnostic testing of, 204–207 disorders of, 203–228. See also specific types physiology of, 203–204 Nerve biopsy, 206–207 in Charcot-Marie-Tooth neuropathies, 206, 220, 220f in chronic inflammatory demyelinating polyneuropathy, 224 in cryoglobulinemia, 228 diagnostic applications of, 206 in giant axonal neuropathy, 221f procedure for, 206–207 sites for, 206 supportive uses of, 206 tissue preparation for, 207 Nerve conduction studies, 204–206 of acute inflammatory demyelinating polyneuropathy, 222 of acute motor axonal neuropathy, 223 of acute motor-sensory axonal neuropathy, 223 of anterior interosseous syndrome, 212 axonopathic, 205b of brachial plexopathy, 209 of carpal tunnel syndrome, 211 of chronic inflammatory demyelinating polyneuropathy, 224 of Cockayne’s syndrome, 286 of complex regional pain syndrome, 150 of cryoglobulinemia, 228 demyelinating, 205b of femoral nerve syndromes, 218 of giant axonal neuropathy, 221 of hereditary neuropathy with predilection to pressure palsies, 220–221 of inclusion body myositis, 244 involving spinal cord, 206 of Miller-Fisher syndrome, 223 motor, 204–205, 205f of multifocal motor neuropathy, 225 of myasthenia gravis, 235, 235f of neuromyotonia, 246 of peroneal nerve syndromes, 218 of posterior interosseous nerve syndrome, 216 of radial nerve injury in brachium, 216 sensory, 205–206 technical considerations in, 206 of ulnar nerve entrapment at elbow, 213 of ulnar nerve entrapment at wrist, 215 Nerve growth factor, and neuroblastoma, 126 Nerve root(s), 229t compression of, 152 noncompressive, painful diseases of, 152b Nervi erigentes, 34 Neuralgia, post-herpetic, 257, 257b Neurasthenia, 151 Neuritic plaque, in Alzheimer’s disease, 155–156 Neuroacanthocytosis, 191, 193 Neuroanatomy, 1–54. See also specific anatomical structures Neuroblastoma, 125–126 genetics of, 126 histology of, 125–126 location of, 125 pediatric, 125b, 126 prognosis of, 126 symptoms of, 126

Neurocutaneous syndromes, 275–278. See also specific types Neurocysticercosis, 264, 264f Neurocytoma, central, 129 Neurofibrillary tangles in Alzheimer’s disease, 155, 155f in herpes simplex virus infection, 256 Neurofibroma, 134–135 diffuse, 135 histology of, 134, 135f location of, 134 multiple, 134 plexiform, 135 solitary, 134 subtypes of, 134–135 symptoms of, 135 treatment of, 135 Neurofibromatosis type 1, 275 café au lait spots in, 275, 275f diagnostic criteria of, 275b diagnostic testing for, 275 magnetic resonance imaging of, 275, 276f pathophysiology of, 275 symptoms of, 275 type 2, 275–276 diagnostic criteria for, 275b diagnostic testing for, 276 histology of, 275 pathophysiology of, 275 symptoms of, 275 Neurofibromatosis 1 gene (NF-1), 275 Neurofibromatosis 2 gene (NF-2), 275 and meningioma, 124, 275b Neurogenic syndromes of water imbalance, 16t Neurohormonal/magnocellular nuclei, 17 Neurohypophysis, 16f, 18f Neuroimaging. See specific modalities and disorders Neuroleptic malignant syndrome, 202t Neurologic thoracic outlet syndrome, 208b Neuromuscular junction hypotonic disorders, 289 Neuromuscular transmission, 230, 231f Neuromyelitis optica (Devic’s disease), 110–111 Neuromyotonia (Isaac’s syndrome), 245–246 diagnostic testing for, 246 HIV-related, 246 paraneoplastic, 136t, 245 subtypes of, 245 symptoms of, 246 treatment of, 246 Neuromyotonic discharges, on EMG, 233 Neuron(s) cerebellar, types of, 18, 19f cortical, types of, 1, 2f spiny, 11 Neuronal ceroid lipofuscinosis, 95t, 284–285 adult, 285 diagnostic testing for, 285 early-infantile, 285 histology of, 284 intrauterine, 290 juvenile, 285 late-infantile, 285 subtypes of, 285 symptoms of, 284 Neuronal spreading depression, 139 Neurontin. See Gabapentin

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Neuroophthalmology, 37–47 Neuropathy(ies). See also specific nerves acquired, 221–228 alcoholic, 178, 178b diabetic, 293–294 hereditary, 218–221 with a predilection to pressure palsies, 220–221 HIV-related, 261, 261b in paraneoplastic syndromes, 136t traumatic and compression, 210–218 Neuropeptide Y, in aspiny neurons, 11 Neuropil thread, in Alzheimer’s disease, 155 Neurosyphilis, 255 meningovascular, 255 parenchymatous, 255 Neurotology, 49–54 anatomy in, 48f, 49–50, 49f pathophysiology in, 50–54 Neurotoxins, 267t Niacin for fibromyalgia, 151 for MELAS syndrome, 69 for stroke prevention, 62 Niacin deficiency, 113, 301t Nicotinamide adenine dinucleotide (NADH) ubiquinone oxidoreductase flavoprotein-1, in Alexander’s disease, 114 Nicotinic acid deficiency, 301t Niemann-Pick disease, 285t, 297t Nimodipine, for vasospasm, 65 Nipride, 296 N-methyl-D-aspartate (NMDA), in Huntington’s disease, 193 Nocturnal eating/drinking behavior, 170 Nodose ganglion, 33t Noninsulin-dependent diabetes mellitus (NIDDM), 293 Non-REM parasomnias, 170 Non-REM sleep, 165, 165b, 165f, 166 Nonsteroidal antiinflammatory drugs (NSAIDs) for Alzheimer’s disease prevention, 158 for anterior interosseous syndrome, 212 for carpal tunnel syndrome, 211 for chronic fatigue syndrome, 151 for chronic headache, 144–145 detoxification, in chronic headache, 146 for greater occipital neuralgia, 149 for low back pain, 153 for migraine, 140 side effects of, 140 for tension-type headache, 141 for ulnar nerve entrapment, 213, 216 Norepinephrine in complex regional pain syndrome, 150 from locus coeruleus, 28 Normal pressure hydrocephalus, 35–36, 163 dementia in, 36, 155, 163 diagnostic testing for, 36, 163 epidemiology of, 35, 163 mechanisms of, 35 pathophysiology of, 163 prognosis of, 36, 163 symptoms of, 36, 163 treatment of, 36, 163 Nortriptyline, 174t Notch 3 protein, in CADASIL syndrome, 67 Nothnagel’s syndrome, 23, 23b Nucleoside metabolism disorders, 285–287 Nucleus accumbens, 11–12

Nucleus ambiguus, 26, 26f Nucleus basilis of Meynert, 1, 11 Nucleus cuneatus, 26, 26f Nucleus gracilis, 26, 26f Nucleus interpositus, 45 Nucleus of Darkschewitsch, 44 Nucleus of diagonal band of Broca, 11 Nucleus of Roller, 45 Nucleus proprius, 30 Nucleus proprius hypoglossi, 45 Nucleus raphe magnus, 29 Nucleus reticularis pontis, 29, 44, 164 Nutritional disorders, 299–301. See also specific types Nutrition-related demyelinating disorders, 112–113 Nystagmus Bruns’, 46f–47f ictal, 46f–47f localized syndromes of, 46, 46f–47f with palatal myoclonus, 22 in Parinaud’s syndrome, 45 retraction, 23 seesaw, 46f–47f O Obersteiner-Redlich zone, ephaptic transmission at, 148, 148b Obstructive sleep apnea, 166, 168 Obturator nerve, 209f, 227f, 229t Occipital epilepsy, benign, 96–97 Occipital intermittent rhythmic delta activity (OIRDA), 82 Occipital nerves, 149f damage to, 149 Occipito-parieto-temporal junction, as focus of simple partial seizures, 84 Ocular apraxia, in Balint’s syndrome, 43 Ocular ataxia, in Balint’s syndrome, 43 Ocular motor cranial nerves, 43, 43f. See also specific nerves Ocular motor system, 43–47 inherited disorders of, 46–47 Ocular sensory system, 37–43 Oculomotor artery, 39f Oculomotor nerve (CN III), 32, 43, 43f disorders/syndromes of, 34t ganglion of, 33t palsy of, 43–44 Oculomotor nucleus, 21, 43–44, 43f pathophysiology in, 44 Ohtahara’s syndrome, 94b Olanzapine, 172t as alternative in drug-induced parkinsonism, 202 for Alzheimer’s disease, 158 for Lewy body dementia, 163 Olfaction, 4 Olfactory cortex, 10f Olfactory hallucinations, 4 in temporal lobe seizures, 85 Olfactory tract, 39f Oligoastrocytoma, 123 Oligoclonal bands, in multiple sclerosis, 108 Oligoclonal gammopathy, 225 Oligodendroglioma(s), 122–123 anaplastic, 122–123 benign, 123 calcifications in, 122, 122f diagnostic testing for, 122 epidemiology of, 122 genetics of, 120b, 122, 122b grading of, 122

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histology of, 122, 122f location of, 122 prognosis of, 123 treatment of, 122 Olivopontocerebellar degeneration (OPCD), 188–189 Olivospinal tract, 30f Ondansetron, for multiple sclerosis, 109 Ondine’s curse, 167b One-and-a-half syndrome, 23, 25, 44–45 Opalski cells, 194, 195f Ophthalmic artery, 39, 43f Ophthalmodynia, 143 Ophthalmologic syndromes, 23 Ophthalmoplegia in Miller-Fisher syndrome, 223 in myotubular myopathy, 240 in sarcoidosis, 298 Ophthalmoplegic migraine, 138 Opioids abuse and dependence, 181 symptoms of, 181 treatment of, 181 acute intoxication, 181 biochemical effects of, 181 and dementia, 155 detoxification, in chronic headache, 146 for migraine, 140 overuse of, and chronic headache, 144 for restless legs syndrome, 169 withdrawal from, 181 Oppenheim, useless hand sign of, 106 Opponens digiti quinti, 213f Opponens pollicis, 210f, 229t in carpal tunnel syndrome, 211 Opportunistic infections, in HIV infection, 261–262 Opsoclonus, in paraneoplastic syndromes, 136t Optic chiasm, 38f, 39–40, 39f anterior lesions of, 39, 39f blood supply of, 39 body lesions of, 39 decussation of, 39 lateral lesions of, 40 pathophysiology in, 39–40 Optic disk, 38–39 blood supply of, 38 pathophysiology in, 38–39 Optic nerve (CN II), 32, 39, 43f blood supply of, 39, 39f intracanalicular segment of, 39 intracranial segment of, 39, 39f intraocular segment of, 39 intraorbital segment of, 39 pathophysiology in, 39 subdivisions of, 39 Optic nerve atrophy in Canavan’s disease, 115 in vanishing white matter disease, 115 Optic nerve sheath fenestration, for pseudotumor cerebri, 147 Optic neuritis, 39 in Devic’s disease, 110 in multiple sclerosis, 106–107, 110 retrobulbar, 106–107 visual evoked potentials in, 41f Optic neuritis ischemic optic neuropathy, 32 Optic neuropathy anterior ischemic, 38–39 visual evoked potentials in, 42

Optic radiations, 40–41 pathophysiology in, 41 Optic tracts, 16f, 38f, 40 blood supply of, 40 nongeniculate projections of, 40 pathophysiology in, 40 Oral appliances, for sleep breathing disorders, 169 Oral contraceptives and ischemic stroke, 56 and subarachnoid hemorrhage, 63 Orbitofrontal cortex, 7 as focus of complex partial seizures, 86 Organ failure, and dementia, 154 Organic acid disorders, 279b Organ of Corti, 33t, 49 Ornithine transcarbamylase deficiency, 281–282 Orthostatic hypotension in Parkinson’s disease, 185 treatment of, 185 Osler-Weber-Rendu syndrome, 250b Osteogenesis imperfecta, arterial dissection in, 70 Otic ganglion, 33t Otic zoster, 257 Otoacoustic emissions, 50b Oval window, 49f Oxaprozin, for chronic headache, 144 Oxcarbazepine, 102t Oxidative phosphorylation disorders, 287 Oxybutynin, for bladder dysfunction, in multiple sclerosis, 109 Oxygen inhalation, for cluster headache, 142, 145 Oxytocin, 17t P p53 gene and astrocytoma, 119, 120f and oligodendroglioma, 122 Pacchionian corpuscle, 205t Pacemaker muscle fiber, 233 Pachygyria, 269 Pachymeningitis, idiopathic hypertrophic, 267 Pain disorders, 137–153. See also specific types Paint brush appearance, of spinal tumor, 131 Palatal myoclonus, 21–22 diagnostic testing for, 22 symptoms of, 22 Pallid breath-holding spells, 99 Pallidotomy for dystonia, 192 for Parkinson’s disease, 187 Palmaris longus, 210f, 214f Palmaris longus tendons, 210f Pancerebellar syndrome, 20 Pancoast’s tumor, 208 Pancreatitis, in von Hippel-Lindau syndrome, 278 PANDAS infection syndrome, 191, 193 Panic attacks, 175 Papez, circuit of, 7, 7f Papillary ependymoma, 127 Papilledema, 38 with pseudotumor cerebri, 147 Papillitis, in multiple sclerosis, 106 Papillomacular bundle, 38f injury of, 37, 37b, 38f Paracusis, 51 Paradoxical embolism, 58 Paraflocculus, 20f

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Parahippocampal gyrus, 7 Paralimbic cortex, 2, 7 Paralysis. See specific types Paramedian pontine reticular formation, 29, 29b, 44–45 Paramedian raphe, 24f Paramyotonia congenita, 246b, 247, 248t Paraneoplastic syndromes, 135–136 diagnostic testing for, 135 epidemiology of, 135 Lambert-Eaton myasthenia in, 135, 136t, 236 myasthenia gravis in, 135, 136t, 234 with neuroblastoma, 126 neuromyotonia in, 136t, 245 pathophysiology of, 135 prognosis of, 136 subtypes of, 136, 136t thymoma, 234b treatment of, 135 Paranoid schizophrenia, 170b Paraplegia(s), spastic conditions with, 197b hereditary, 197–198, 271b Paraplegic cerebral palsy, 288 Paraproteinemic neuropathies, 225–228 Parasitic infection, 264–265. See also specific types Parasomnia(s), 170–171 non-REM, 170 REM, 170 transitional, 170–171 Parasympathetic regulation, by hypothalamus, 16b Paraventricular nucleus, 16f, 17, 18f Paresis, general, 255 Paresthesia(s) in carpal tunnel syndrome, 211 in femoral nerve syndromes, 218 in multiple sclerosis, 106 in restless legs syndrome, 169 in ulnar nerve entrapment, 213, 215 Parietal eye field, 46 Parietal heteromodal association areas, 5 dominant-sided lesions of, 5, 5b nondominant-sided lesions of, 5 Parietal lobe, as focus of simple partial seizures, 84 Parinaud’s syndrome, 22f, 23, 44–45, 271 Parkin gene, 183 Parkinsonism, 190t in cortical-based ganglionic degeneration, 188 drug-induced, 202 in Huntington’s disease, 194 lesions causing, 12 in Lewy body dementia, 162–163, 186b in multiple system atrophy, 189, 189b, 189f treatment of, 163 Parkinson’s disease, 183–186 autonomic dysfunction in, 186 deep brain stimulation for, 187 dementia in, 161, 185 versus Alzheimer’s disease, 159t dyskinesia in, 185–186 dystonia in, 185–186, 190, 190t epidemiology of, 183 familial, 184t genetics of, 183, 184t histology of, 183 pathophysiology of, 183, 184f restless legs syndrome in, 169, 185

risk factors for, 183 side effects of medications in, management of, 186–187 surgery for, 186–187 symptoms of, 185 treatment-induced hallucinations in, 186 treatment of, 185–187, 186t wearing-off/freezing phenomenon in, 185 Parosmia, 4 Paroxetine, 174t Paroxysmal choreoathetosis nonkinesigenic, 190t with spasticity and ataxia, 190t Paroxysmal disorders, nonseizure, in children, 99 Paroxysmal hemicrania, 142–143 chronic, 145 pathophysiology of, 143 symptoms of, 142–143 treatment of, 143 Pars compacta, 12 in Parkinson’s disease, 183, 184f Pars opercularis, 5, 5b Pars reticulata, 12, 22 Pars triangularis, 5 Partial seizures, 82–86 complex, 85–86 versus absence seizures, 85t with frontal lobe focus, 86 with mesial temporal cortex focus, 85–86 with neocortical temporal focus, 86 pathophysiology of, 85 pediatric, 98–99 symptoms of, 85 diagnostic testing for, 86 EEG findings in, 86 pediatric, 95–99 simple, 82–85 with dorsolateral prefrontal cortex focus, 84 with frontal operculum focus, 84 with insula cortex focus, 84 motor, 82–84 with occipito-parieto-temporal junction focus, 84 with parietal lobe focus, 84 pediatric, 95–98 with premotor cortex focus, 84 with primary motor cortex focus, 84 with primary visual cortex focus, 84 sensory, 84–86 with supplementary motor area focus, 84 symptomatic manifestations of, 83f with temporal lobe focus, 84–85 treatment of, 101f Parvocellular nuclei, 17 Parvocellular pathway, 40 Patent foramen ovale, and ischemic stroke, 56 Paxil (paroxetine), 174t Pectineus muscle, 217f Pediatric hydrocephalus, 35 Pediatric seizures, 91–99 Peduncular hallucinosis, 22–23 Pedunculopontine tegmental nucleus, 19, 28, 164 Pelizaeus-Merzbacher disease, 113–114, 198, 198b diagnostic testing for, 114 histology of, 114, 114f pathophysiology of, 113–114 prognosis of, 114 symptoms of, 114, 114t treatment of, 114

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Pellagra (niacin deficiency), and Marchiafava-Bignami disease, 113 Pemoline, for multiple sclerosis, 109 Penicillamine, for Wilson’s disease, 195 Penicillin(s), for syphilis, 254 Penicillin G, for syphilis, 255 Penile erection, 34 in REM sleep, 166 Pentobarbital abuse, 179 Pentobarbital drip, for status epilepticus, 89t Pergolide, for Parkinson’s disease, 186t Perihypoglossal nuclei, 28, 45 Perilymphatic duct, 49f Perimesencephalic hemorrhage, 62 Periodic breathing, 99 Periodic lateralizing epileptiform discharges (PLEDs), 81f, 82 Periodic limb movement disorder, 169 pathophysiology of, 169 symptoms of, 169 treatment of, 169 Peripheral nerve(s), organization of, 204f Peripheral nerve hypotonic disorders, 289 Peripheral nervous system tumors, 134–135. See also specific types Peripheral sensory dermatomes, 227f–228f Periventricular heterotopia, 269, 269f Permax. See Pergolide Peroneal nerve, 227f, 229t anatomy of, 218f compression syndromes of, 218, 218b conduction studies of, 205, 218 Peroneus brevis, 229t Peroneus longus, 229t Peroxins, 283 Peroxisomal phytanoyl-CoA deficiency, 282–283 Peroxisome(s), disorders of, 282–283 Peroxisome ghosts, 283 Perphenazine, and tardive dyskinesia, 201 Perseverative automatism, 85 Perseverative behavior, in frontotemporal dementia, 161 PET. See Positron emission tomography Petechial rash, 255b Phakomatoses, 275–278. See also specific types subependymal giant cell astrocytoma with, 121 Phencyclidine (PCP), 181–182 acute intoxication, 182 biochemical effects of, 181 treatment for dependence, 182 Phencyclidine, withdrawal from, 182 Phenelzine, 174t Phenobarbital, 102t detoxification, in chronic headache, 146 for status epilepticus, 89t Phenylacetate, for urea metabolism disorders, 282 Phenylalanine hydroxylase deficiency, 279 Phenylalanine-restricted diet, 279 Phenylbutazone, for chronic headache, 144 Phenylketonuria, 279 diagnostic testing for, 279 pathophysiology of, 279 prognosis of, 279 symptoms of, 279 treatment of, 279 Phenytoin, 103t for myotonia congenita, 248 for neuromyotonia, 246 for pediatric seizures, 99 for status epilepticus, 89t

Pheochromocytoma, in von Hippel-Lindau syndrome, 278 Phobia(s), 175 social, 175 specific, 175 treatment of, 175 Phonic tics, 192 Phosphate, abnormal levels of, 301t Phosphofructokinase deficiency, 243 Photic stimulation, in electroencephalogram, 80 Photomyoclonic response, in EEG, 80 Photoparoxysmal response, in EEG, 80 Photoreception, 37, 37f Phrenic nerve, 207f Phytanic acid, in Refsum’s disease, 282–283 Pial arterial network, 38 Pick body(ies), 160–161, 160f Pick cells, 160–161 Pick’s disease, 160–161. See also Frontotemporal lobar degeneration “Pie in the sky” visual defects, 41 Pimozide for tic disorders, 193 for trigeminal neuralgia, 148 Pineal gland, 11f in arousal/sleep, 164 Pineal tumors, 125 histology of, 125 pediatric, by occurrence, 125b Pineoblastoma, 125 epidemiology of, 125 genetics of, 125 histology of, 125 prognosis of, 125 treatment of, 125 Pineocytoma, 125 histology of (rosettes), 125, 125f prognosis of, 125 treatment of, 125 PINK1 gene, in Parkinson’s disease, 183 Piroxicam, for chronic headache, 144 Pituitary apoplexy, 133 Pituitary hormones, 17, 17t Pituitary stalk, 39f Pituitary tumor(s), 132–133. See also specific types Plantar digital nerve, 227f Planum temporale, 6 Plaques, in Alzheimer’s disease, 155–156 Plasmacytoma(s), monoclonal gammopathy with, 226 Plasmapheresis for acute disseminated encephalomyelitis, 112 for chronic inflammatory demyelinating polyneuropathy, 225 for cryoglobulinemia, 228 for Devic’s disease, 110 for Guillain-Barre syndrome, 223–224 for Marburg’s variant of multiple sclerosis, 111 for multiple sclerosis, 109 for neuromyotonia, 246 for Refsum’s disease, 283 Plasmodium falciparum, 264 Platelet-derived growth factor- and astrocytoma, 119, 120f and oligodendroglioma, 122 Plavix. See Clopidogrel Pleomorphic xanthoastrocytoma, 121 epidemiology of, 121 histology of, 121 location of, 121 treatment of, 121

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Plexopathies, 207–210. See also specific types proximal diabetic, 206, 294 Pneumocystis carinii prophylaxis, with glucocorticoid therapy, 132 POEMS syndrome, 226 Poland syndrome, 248t Polio, 259 Polio-related syndromes, 259 Poliosis, in Vogt-Koyanagi-Harada syndrome, 268 Polyarteritis nodosa, 76, 226b Polydipsia, psychogenic, 16t Polymicrogyria, 269 Polymorphic delta activity, in EEG, 81 Polymyalgia rheumatica, 76, 76b Polymyositis, 245 diagnostic testing for, 245 muscle biopsy in, 245, 246f pathophysiology of, 245 symptoms of, 245 treatment of, 245 Polysomnography in chronic fatigue syndrome, 151 in fatal familial insomnia, 266 in fibromyalgia, 151 in Lewy body dementia, 162 in narcolepsy, 168 in REM sleep behavior disorder, 170 Pons, 23–25, 24f motor output centers of, 23 pathophysiology in, 25 sensory input centers of, 23–25 Pontine accessory ocular motor nuclei, 44–45 Pontine auditory hallucinosis, 51b Pontine fibers, loss in multiple system atrophy, 189, 189f Pontine locked-in syndrome, 24f, 25, 113 Pontine nuclei, 18, 18b, 24f Pontine reticular formation, 24f, 28–29, 164 Pontine tracts, 24f Pontocerebellum, 19 Ponto-geniculo-occipital (PGO) spikes, 164, 166 Porencephaly, 269 Port-wine stain, 278, 278f Poser criteria, for multiple sclerosis, 107t, 110 Positron emission tomography (PET) in Alzheimer’s disease, 158 in fibromyalgia, 150 in frontotemporal lobar degeneration, 161 in Huntington’s disease, 194 in Rasmussen’s syndrome, 98 Postcentral gyrus, 11f Posterior acoustic stria, 48f Posterior auricular nerve, 32f Posterior cerebral artery, 15f, 18, 21f, 39f, 40–41, 43f, 57f Posterior choroidal artery, 15f Posterior ciliary artery, 38 Posterior cingulate gyrus, 7 Posterior cochlear nucleus, 48f Posterior commissure, 10 nucleus of, 44 Posterior communicating artery, 15f, 18, 39f, 43f aneurysm of, 43 Posterior cord injury, 209 Posterior cord syndrome, 32 Posterior cutaneous nerve of thigh, 209f, 228f Posterior funiculus, 30, 30f Posterior inferior cerebellar artery, 21f

Posterior interosseous nerve syndrome, 216 diagnostic testing for, 216 electromyography of, 216 nerve conduction study of, 216 pathophysiology of, 216 symptoms of, 216 treatment of, 216 Posterior nucleus of the hypothalamus, 17 Posterior reversible leukoencephalopathy, 296, 296b Posterior spinal artery, 31f Posterior spinocerebellar tract, 30f Posterior tibial nerve, conduction studies of, 205 Posterolateral nucleus of the hypothalamus, 18 Posteromedial central arteries, 39f Postpolio syndrome, 259 Posttraumatic stress disorder, 175–176 Potassium channel(s), diseases of, 200, 200b, 245, 245b Potassium supplementation, for hypokalemic periodic paralysis, 247 Pouch sign, in carotid dissection, 72f Prader-Willi syndrome, 289 Pramipexole for Parkinson’s disease, 186t for restless legs syndrome, 169 Praziquantel, for cysticercosis, 264 Preacher’s hand, 211f Precerebellar nuclei of reticular formation, 29b Prednisolone, 118t Prednisone, 118t for Bell’s palsy, 34 for chronic inflammatory demyelinating polyneuropathy, 224 for dermatomyositis, 245 for Devic’s disease, 110 for hearing loss, 50 for multiple sclerosis, 108, 110 for myasthenia gravis, 235 for stiff man’s syndrome, 201 Prefrontal cortex, 4–5 bilateral damage to, effects of, 5t lesions of, 5, 5t projections to and from, 4 unilateral damage to, effects of, 5t Pregnancy migraine in, 139, 141 multiple sclerosis in, 106b, 109, 109b Preictal pseudosleep, 100 Premotor area, 2 Premotor cortex, as focus of simple partial seizures, 84 Preoptic nucleus, 16–17, 16f Preoptic region, 16–17 Presenilin 1, in Alzheimer’s disease, 156, 157b Presenilin 2, in Alzheimer’s disease, 157 Pressure palsies, hereditary neuropathy with predilection to, 220–221 Pretectal nucleus, 44 Primary lateral sclerosis, 197t Primary motor area(s), 2 Primary motor cortex, 1–2 as focus of simple partial seizures, 84 lesions of, 2 somatotopic organization of, 2, 3f stimulation of, 2 Primary progressive aphasia, 161 Primary sensory area(s), 2 subdivision by sensory modality, 3–4 Primary sensory cortex, 3–4 lesions of, 4 stimulation of, 4

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Primary visual cortex, 2, 41–42 blood supply of, 41 diagnostic testing of, 41–42, 41f as focus of simple partial seizures, 84 pathophysiology in, 41 representation of visual fields on, 41 Primidone, 103t for essential tremor, 201 for pediatric seizures, 99 Primitive neuroepidermal tumors (PNETs), 125–126 histology of, 125 Principal trigeminal nucleus, 23, 24f Prion diseases, 265–266 dementia in, versus Alzheimer’s disease, 159t familial/inherited, 266 histology of, 265, 265f iatrogenic, 266 idiopathic, 265–266 infectious, 266 pathophysiology of, 265 types of, 265–266 Prion protein, 265 Procarbazine, for oligodendroglioma, 122 Procedural memory, 154b Prochlorperazine for status migrainosus, 141 and tardive dyskinesia, 201 Prodrome phase, of migraine, 137 Progressive bulbar palsy, 197t Progressive multifocal leukoencephalopathy (PML), 259, 262 Progressive muscular atrophy, 197t Progressive prosopagnosia, 161 Progressive supranuclear palsy (PSP), 187 diagnostic testing for, 187 genetics of, 187 histology of, 187 pathophysiology of, 187 prognosis of, 187 symptoms of, 187 Projection neurons, 1 Prolactin levels in pseudoseizures, 100 in seizures/epilepsy, 82 Prolactin-secreting adenoma, 133 Pronation, upper extremity, 229t Pronator quadratus, 210f in anterior interosseous syndrome, 211 Pronator teres, 210f, 214f, 229t Propanolamine abuse, 180 Propantheline, for bladder dysfunction, in multiple sclerosis, 109 Propionic acidemia, 280b, 281 Propofol drip, for status epilepticus, 89t Propositional prosody, 6 Propoxyphene abuse, 181 Propranolol for essential tremor, 201 for multiple sclerosis, 109 Proprioception loss of, lesions causing, 4 in multiple sclerosis, 106 ventral posterior nuclei in, 14 Propylthiouracil, for adenoma, 133 Prosencephaly lobar, 270 semilobar, 270

Prosody affective, 6 lesions affecting, 6 propositional, 6 Prosopagnosia, 42 progressive, 161 Prostaglandins, in migraine, 140 Protein C deficiency, 71–72 Protein S deficiency, 71–72 Proteolipid protein (PLP) abnormalities, 113–114, 113b, 114t Prothrombin G20210A resistance, 72 Protozoan infection, 264 Prourokinase, intracranial, 59 Provigil. See Modafinil Proximal diabetic plexopathy, 206, 294 Prozac. See Fluoxetine Psammomatous meningioma, 123, 124f Pseudoataxia, epileptic, 93b Pseudobulbar palsy, 25 Pseudodementia, versus Alzheimer’s disease, 159t Pseudoephedrine, for orthostatic hypotension, 185 Pseudo-pseudoseizures, 99b Pseudoseizures, 99–101 in conversion disorder, 177 developmental, 100 diagnostic testing in, 100 epidemiology of, 100 pathophysiology of, 99–100 posttraumatic, 99 prognosis of, 100 risk factors of, 100 symptoms of, 100 treatment of, 100 Pseudosleep, preictal, 100 Pseudotumor cerebri, 146–147 diagnostic testing for, 147 pathophysiology of, 146–147 risk factors for, 146 symptoms of, 147 treatment of, 147 vision disorders with, 147 Psoas muscle, 217f–218f femoral nerve entrapment in, 217 Psoas syndrome, malignant, 209b Psychiatry, 154–182. See also specific disorders and therapies Psychogenic polydipsia, 16t Psychosis, 171–172 PTEN tumor suppressor gene, 120 Pterygopalatine ganglion, 33t Pudendal nerve, 209f, 227f Puff of smoke sign, in Moyamoya disease, 79, 79f Pulvinar, 14f, 15, 45 Punishment center, posterior nucleus as, 17 Pure motor syndrome, 9 Pure sensory neuropathy, 223 Pure word deafness, 51 Purkinje neurons, 18, 19f Putamen, 10f, 11–12, 11f lesions of, 12 Pyramidal neurons, 1, 2f Pyramidal signs, in Alzheimer’s disease, 158 Pyramidal tract, 24f, 26f Pyrazinamide, for tuberculosis, 252 Pyridostigmine, for myasthenia gravis, 235 Pyridoxine. See Vitamin B6 Pyrimethamine, for toxoplasmosis, 261, 264 Pyruvate dehydrogenase deficiency, 47, 287

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Q Quaalude (methaqualone), 179 Quadriceps muscle, 229t Quadriplegic cerebral palsy, 288 Quetiapine, 172t as alternative in drug-induced parkinsonism, 202 for Alzheimer’s disease, 158 for Lewy body dementia, 163 for Parkinson’s disease, 186 Quinine for malaria, 264 for myotonia congenita, 248

344

R Rabies immunoglobulin, 258 Rabies virus, 258 diagnostic testing for, 258 histology of, 258, 258f pathophysiology of, 258 symptoms of, 258 treatment for, 258 Race and ischemic stroke, 55 and multiple sclerosis, 105 Radial nerve, 207f, 214f, 227f–228f, 229t anatomy of, 216f compression syndromes of, 216–217 Radial nerve injury in brachium, 216 diagnostic testing for, 216 electromyography of, 216 nerve conductions study of, 216 pathophysiology of, 216 symptoms of, 216 treatment of, 216 Radiation therapy for adenoma, 133 for astrocytoma, 121 for carcinomatous meningitis, 132 for chordoma, 130 for choroid plexus papilloma, 128 for germinoma, 130 for gliomatosis cerebri, 123 for malignant peripheral nerve sheath tumor, 135 for medulloblastoma, 126 for oligodendroglioma, 122 for pineoblastoma, 125 whole-brain, for metastasis, 131 Radicular artery, 31f Radiculopathy(ies), 152 C6, 211b L5, 218b lumbar, 152, 152b, 152t Radionuclide cisternography, in normal pressure hydrocephalus, 36, 163 Radiosurgery, stereotactic for chronic cluster headache, 145 for metastasis, 131 for Parkinson’s disease, 186 for trigeminal neuralgia, 149 Rage, lesions causing, 7, 17 Ragged red fibers in MELAS syndrome, 68f, 69 myoclonic epilepsy with, 95t Ramsay-Hunt syndrome, 257 Rapid eye movement (REM) sleep, 166, 166f Rasmussen’s syndrome, 97–98 diagnostic testing in, 98

EEG findings in, 98 neuroimaging in, 98 pathophysiology of, 97 symptoms of, 97 treatment of, 98 Rathke’s pouch, tumors and cysts of, 133, 133b Raymond-Gestan syndrome, 24f, 25 Raymond’s syndrome, 24f, 25 Reactive automatism, 85 Rebound headaches, 144 Reciprocal (Ia) interneurons, 31 Recruitment principle, 232 Rectus femoris muscle, 217f Recurrent artery of Huebner, 18, 39f Red nucleus, 21–22 connections of, 21, 21b pathophysiology in, 21–22 Reflex(es) near triad, 44, 44b trigeminal, 25, 25t Reflex seizures, 86, 86b Reflex sympathetic dystrophy, 149–150 pathophysiology of, 149 symptoms of, 149 Refsum’s disease, 282–283 diagnostic testing for, 283 histology of, 282 pathophysiology of, 282 symptoms of, 283 treatment of, 283 Reinnervation, EMG findings of, 232–233 Relaxation therapy for insomnia, 167 for migraine prophylaxis, 141 Remeron (mirtazapine), 174t Reminyl (galantamine), for Alzheimer’s disease, 158 Remote memory, 154b REM parasomnias, 170 REM sleep, 166, 166f REM sleep behavior disorder (RSBD), 162, 170 acute-onset, 170 diagnostic testing for, 170 epidemiology of, 170 insidious-onset, 170 pathophysiology of, 170 symptoms of, 170 Renshaw cells, 31 Repositioning maneuvers, for vertigo, 52 Requip. See Ropinirole Reserpine, for tardive dyskinesia, 202 Restless legs syndrome, 169, 185 diagnostic testing in, 169 iatrogenic, 169 idiopathic, 169 pathophysiology of, 169 secondary, 169 subtypes of, 169 treatment of, 169 Reticular formation, 26f, 28–29 afferents of, 29 anatomy of, 28 efferents of, 29 medullary, 26f, 29, 164 mesencephalic, 22, 28, 164 paramedian pontine, 29, 29b, 44–45 pontine, 24f, 28–29, 164

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precerebellar nuclei of, 29b subdivisions and key nuclei of, 28 Reticular thalamic nuclei (RTN), 15 Reticulospinal tracts, 29, 30f Retina, 37–38 diagnostic testing for, 38 fiber bundles of, subtypes of, 37, 38f fiber loss in, 37–38 hypertensive effects on, 296 macular, 41–42 pathophysiology in, 37–38 photoreception in, 37, 37f Retinoblastoma genetics of, 120b pineoblastoma with, 125 Retinoblastoma (RB) factor gene and astrocytoma, 120, 120f, 125b and pineoblastoma, 125 and retinoblastoma, 120b Retinopathy, in paraneoplastic syndromes, 136t Retraction nystagmus, 23 Retrobulbar optic neuritis, 106–107 Retrocollis, 191 Retroflex tract, 18f Rett’s syndrome, 291–292 histology of, 292 pathophysiology of, 291–292 prognosis of, 292 symptoms of, 292 Reward center, lateral hypothalamus as, 16 Reye syndrome, 243b versus acute disseminated encephalomyelitis, 112 Rhabdomyolysis, muscle biopsy contraindicated by, 234 Rheumatoid arthritis, 297 pathophysiology of, 297 symptoms of, 297 Rheumatoid factor, 297 Rheumatoid nodules, 297 juvenile, 297 Rhythmic delta activity, in EEG, 82, 82f Rhythmic movement disorder, 170–171 Ribavirin, for arboviruses, 258 Riboflavin, for migraine prophylaxis, 141 Rickettsia, 255–256 Rickettsia prowazekii, 256 Rickettsia rickettsia, 251b, 255–256 Rifampin for leprosy, 253 for tuberculosis, 252 Rigidity in Parkinson’s disease, 185, 186t in progressive supranuclear palsy, 187 Rinne test, 50 Risperdal. See Risperidone Risperidone, 172t for Alzheimer’s disease, 158 for autism, 291 for Lewy body dementia, 163 for tic disorders, 193 Ritonavir, for HIV infection, 260 Rivastigmine, for Alzheimer’s disease, 158 Rizatriptan, 140t Rocky Mountain spotted fever, 251b, 255–256 diagnostic testing for, 256 epidemiology of, 256 pathophysiology of, 255 prognosis of, 256

symptoms of, 256 treatment of, 256 Rolandic epilepsy, 97 diagnostic testing in, 97 EEG findings in, 97, 97f pathophysiology of, 97 prognosis of, 97 subtypes of, 97 symptoms of, 97 treatment of, 97 Roller, nucleus of, 45 Ronne, nasal step of, 38, 38f Ropinirole for Parkinson’s disease, 186t for restless legs syndrome, 169 Rosenthal fibers in Alexander’s disease, 114–115 in giant axonal neuropathy, 221 in juvenile pilocytic astrocytoma, 121 Rostral interstitial nucleus of medial longitudinal fasciculus (riMLF), 44 Rostral vermis syndrome, 19 etiology of, 19 symptoms of, 19 Round window, 49f Rubella and acute dissemination encephalomyelitis, 111 intrauterine infection, 290 and multiple sclerosis, 104 Rubrospinal tract, 30, 30f Ruffnian corpuscle, 205t Ryanodine calcium channel, 247b Ryanodine mutations, 242, 242b S Saccades, 45–46 in Huntington’s disease, 194 in progressive supranuclear palsy, 187 Saccular aneurysm, 78 Saccule, 49, 49f, 50t Sacral agenesis, 274 Saddle anesthesia, in multiple sclerosis, 106 SAH. See Subarachnoid hemorrhage St. Louis encephalitis, 251t Salt intake, restricted in Meniere’s disease, 53 in pseudotumor cerebri, 147 Salutary seizures, 3 Sanfilippo’s syndrome, 284t Saphenous nerve, 217f, 227f–228f Saposin B, in metachromatic leukodystrophy, 117 Sarcoglycans, in muscular dystrophy, 241, 242f, 242t Sarcoidosis, 298–299 diagnostic testing for, 299 pathophysiology of, 298 symptoms of, 298–299 treatment of, 299 Sartorius muscle, 217f Saturday night palsy, 216 Sawtooth waves, in REM sleep, 166 Saxitoxin, 267t Scalp electroencephalogram. See also Electroencephalogram in seizures/epilepsy, 80–82 Scapular winging, in brachial plexopathy, 208 Scaritoxin, 267t Scarpa’s ganglia, 33t, 49, 50t Scheie’s syndrome, 284t

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Schilder’s disease, 111b Schizencephaly, 269, 270f Schizophrenia antipsychotics for, 172, 172t catatonic, 170b diagnostic testing for, 171–172 disorganized, 170b EEG findings in, 171 genetics of, 171 mood and affect in, 172b paranoid, 170b pathophysiology of, 171 prognosis of, 172 prognostic signs in, 171b psychosocial factors in, 171 somatosensory evoked potentials in, 172 stress-diathesis model of, 171 subtypes of, 170b suicide risk in, 172 symptoms of, 171 treatment of, 172 Schizophreniform disorder, 172 pathophysiology of, 172 prognosis of, 172, 172b symptoms of, 172, 172b treatment of, 172 Schwannoma, 134 Antoni types A and B, 134, 134f histology of, 134, 134f location of, 134 in neurofibromatosis type 2, 275 symptoms of, 134 treatment of, 134 Verocay body with, 134, 134f Sciatic nerve, 209f, 229t Scimitar scotoma, 38 Scotoma(s), 37–39 from arcuate bundle injury, 37–38, 38f Bjerrum, 38, 38f centrocecal, in multiple sclerosis, 106 junctional, 39, 39f from nasal bundle injury, 38, 38f from papillomacular bundle injury, 37, 37b, 38f scimitar, 38 Seidel, 38, 38f Seamont maneuver, 52 Secobarbital abuse, 179 Secondary sensory cortex, 4 Secretory meningioma, 123 Sectoranopias, 40, 40f Sedative-hypnotic(s) abuse and dependence, 179 symptoms of, 179, 179b treatment of, 179–180 acute intoxication, 179 biochemical effects of, 179 for insomnia, 167 and vertigo, 54 withdrawal, 179 and REM sleep behavior disorder, 170 Seesaw nystagmus, 46f–47f Segawa syndrome, 190b, 190t, 280b Segmental dystonia, 191 Seidel scotoma, 38, 38f Seizure(s), 80–102 absence, 95

with acute disseminated encephalomyelitis, 112 with adrenoleukodystrophy, 117 with alcohol withdrawal, 179, 179b with Alexander’s disease, 114 with autism, 291 with Canavan’s disease, 115 with central pontine myelinosis, 113 diagnostic testing in, 80–82 diencephalic autonomic, 20 electroencephalogram in, 80–82, 81f–82f febrile, 91–92 gelastic, 84b generalized atonic, 89 myoclonic, 89 nonsyndromal, 86–89 tonic, 88 tonic-clonic, 86–88 with gliomatosis cerebri, 123 with glycine encephalopathy, 280 with herpes encephalitis, 256 inherited, 90–99 with intracranial hemorrhage, 66, 91 with ischemic stroke, 57, 60 with megaloencephalic leukoencephalopathy with subcortical cysts, 116 with metastasis, 131 with multiple sclerosis, 106 musicogenic, 86 neonatal, 90–91 with neurofibromatosis type 1, 275 nonepileptiform, 99–101 partial, 82–86 complex, 85–86, 98–99 simple, 82–85, 95–98 pediatric, 91–99 with phenylketonuria, 279 prolactin level and, 82 prolonged (status epilepticus), 89–90 recurrence of, risk of, 82b reflex, 86, 86b remission from, 101, 101b with Rett’s syndrome, 292 salutary, 3 sound-induced, 98–99 startle, 88, 88b with Sturge-Weber syndrome, 277 with subarachnoid hemorrhage, 63, 65, 91 treatment of, 101–102 medical, 101, 101f, 102t–103t medication failure in, management of, 101 surgical, 102 with tuberous sclerosis, 276, 276b version, 84 vertigo with, 54t, 84–85 with Zellweger’s syndrome, 283 Selective serotonin reuptake inhibitors (SSRIs), 174t for alcohol dependence, 179 for Alzheimer’s disease, 158 for autism, 291 benefits of, specific, 174t for frontotemporal lobar degeneration, 161 for generalized anxiety disorder, 175 for insomnia, 167 in multiple sclerosis, 109 for phobias, 175

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for posttraumatic stress disorder, 176 side effects of, 174t for tic disorders, 193 Selegiline, for Parkinson’s disease, 186, 186t Selenium, abnormal levels of, 301t Sella turcica, 43f Semantic dementia, 161 magnetic resonance imaging of, 161f Semantic memory, 154b Semicircular canals, 49, 49f, 50t Semilobar prosencephaly, 270 Senile plaque, in Alzheimer’s disease, 155–156 Sensorineural hearing loss, 50 Sensory homunculi, 2, 3f, 4 Sensory nerve conduction studies, 205–206 Sensory neuron(s), types of, 205t Sensory paralytic bladder, 36t Sensory testing, in complex regional pain syndrome, 150 Sentinel hemorrhage, 63 Septal nuclei, 11 Septo-optic dysplasia, 270, 270f Septum pellucidum, 10f–11f Seroquel. See Quetiapine Serotonin, biosynthesis of, 165f Serotonin-norepinephrine reuptake inhibitors, 174t for posttraumatic stress disorder, 176 Serotonin syndrome, 202t Serpentine aneurysm, 78 Sertraline, 174t Serum protein electrophoresis (SPEP), in monoclonal gammopathy, 226 Setting sun sign, 45 Severe myoclonic epilepsy, 94 diagnostic testing in, 94 EEG findings in, 94 pathophysiology of, 94 symptoms of, 94 treatment of, 94 Sex (gender) and ischemic stroke, 55 and multiple sclerosis, 105 Sexual function, 34 Sexuality in Alzheimer’s disease, 157 in frontotemporal dementia, 161 in Kluver-Bucy syndrome, 7 Shagreen patch, in tuberous sclerosis, 277, 277b, 277f Sharp waves on EEG, 80 on EMG, 233 Shawl sign, in dermatomyositis, 244 Shingles, 257 Short-lasting unilateral neuralgiform headaches with conjunctival injection and tearing (SUNCT) syndrome, 143 Short-term/anterograde memory, 154b Shoulder abduction, 229t Shoulder adduction, 229t Shoulder pain, 153f in brachial plexopathy, 208 Shunt(s) lumboperitoneal for normal pressure hydrocephalus, 163 for pseudotumor cerebri, 147 ventricular, for Dandy-Walker malformation, 274 ventriculoperitoneal, for normal pressure hydrocephalus, 36, 163 Shy-Drager syndrome, 188–189

Sialidosis type 1, 95t Sicca syndrome, 299 Sickle cell crisis, 74 Sickle cell disease, 73–74 diagnostic testing for, 74 epidemiology of, 74 pathophysiology of, 73–74 and stroke, 74 symptoms of, 74 treatment of, 74 Simian cytomegalovirus, and multiple sclerosis, 104 Simple febrile seizures, 91 Simple partial seizures, 82–85 motor, 82–84 with dorsolateral prefrontal cortex focus, 84 with frontal operculum focus, 84 with insula cortex focus, 84 with premotor cortex focus, 84 with primary motor cortex focus, 84 with supplementary motor area focus, 84 pediatric, 95–98 sensory, 84–85 with occipito-parieto-temporal junction focus, 84 with parietal lobe focus, 84 with primary visual cortex focus, 84 with temporal lobe focus, 84–85 symptomatic manifestations of, 83f Simultanagnosia, in Balint’s syndrome, 43 Sinemet. See Levodopa-carbidopa Singing, lesions affecting, 6 Single photon emission computed tomography (SPECT) of Alzheimer’s disease, 158 in conversion disorder, 176 in frontotemporal lobar degeneration, 161 in Lewy body dementia, 163 in Rasmussen’s syndrome, 98 Sjögren’s syndrome, 299 Skeletal muscle, 231, 231b Skew deviation, ocular, 45 Sleep in cluster headache, 142 electroencephalogram in, 80, 164–166, 165f–166f in fibromyalgia, 151 non-REM/slow-wave, 165, 165b, 165f, 166 normal, 164–166 physiology of, 164 REM (rapid eye movement), 166, 166f stages of, 165–166 distribution of, 166 stage 1, 165f, 166 stage 2, 165f, 166 stage 3, 166 Sleep apnea, 168–169 central, 168 definition of, 168 number of episodes, 168b obstructive, 166, 168 risk factors for, 168 Sleep attacks, 167 Sleep breathing disorders, 168–169 subtypes of, 168 symptoms of, 168 treatment of, 169 Sleep disorder(s), 164–171. See also specific types in Alzheimer’s disease, 158 in Lewy body dementia, 162

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Sleep hypopnea, 168 Sleep paralysis, 168 Sleep restriction therapy, 167 Sleep spindles, 165f, 166 Sleep terrors, 170 Sleep walking, 170 Slow-twitch motor units, 232 Slow-twitch muscle fibers, 231, 231b Slow-wave sleep, 165, 165b, 165f, 166 Small infarct dementia, 159 Smallpox, and acute dissemination encephalomyelitis, 111 Smith-Lemli-Opitz syndrome, 297t Smoking, and ischemic stroke, 56 Sneddon’s syndrome, 73 Social phobia, 175 Sodium, abnormal levels of, 301t Sodium channel(s), diseases of, 246–247, 246b Sodium chloride, for hyperkalemic periodic paralysis, 247 Sodium oxybate, for cataplexy, 168 Soleus muscle, 229t Solitary tract nucleus, 26, 26f Solumedrol, for dermatomyositis, 245 Somatic activity, in REM sleep, 166 Somatization disorder, 174, 174b, 176 pathophysiology of, 176 prognosis of, 176 symptoms of, 176, 176b treatment of, 176 Somatoform disorder(s), 176–177 Somatosensory evoked potentials, 205 in hereditary spastic paraplegia, 198 in multiple sclerosis, 108, 108f in schizophrenia, 172 Somatosensory systems, 3–4 Somatostatin, in aspiny neurons, 11 Somatotopic ideomotor apraxia, lesions causing, 5 Somatotopic organization of primary motor cortex, 2, 3f of primary sensory cortex, 3f, 4 of spinal cord gray matter, 31, 31f Somnambulism, 170 Somnogenic systems, 164 Sonata. See Zaleplon Sonic hedgehog gene, 270, 270b, 274 Sounds, seizures trigged by, 98–99 Spasms, infantile, 92–93 Spastic bladder, 36t in multiple sclerosis, 109, 109b in normal pressure hydrocephalus, 36, 163 Spastic dysphonia, 191 Spasticity in Alexander’s disease, 114–115 in Canavan’s disease, 115 “clasp knife,” 2 in multiple sclerosis, therapy for, 109 in paroxysmal choreoathetosis, 190t in vanishing white matter disease, 115 Spastic paraplegia(s) conditions with, 197b hereditary, 197–198, 271b Spatial disorientation, lesions causing, 5 Spatial inattention, lesions causing, 5 Special sensory systems, 4 SPECT. See Single photon emission computed tomography Speech prosody, lesions affecting, 6–7

Sphenoid electrodes, 80 Sphingolipid metabolic pathway, 283, 284f Sphingolipidoses, 283–284, 285t, 297t Spike-and-wave discharge, in EEG, 81f in tonic-clonic seizures, 88, 88b Spina bifida, 274, 301 Spina bifida occulta, 274 Spinal cord, 29–32 connections with reticular formation, 29 gray matter of, 30–31 somatotopic organization of, 31, 31f long tracts of, 29–30, 30f nerve conduction studies of, 206 pathophysiology in, 31–32 tethered, 274 vascular supply of, 31, 31f Spinal cord injury incomplete, 31–32 lateral, 209 medial, 209 in multiple sclerosis, 106 posterior, 209 Spinal cord tumors, primary, 131 extradural, 131, 131f extraparenchymal-intradural, 131 imaging characteristics of, 131, 131f intraparenchymal, 131, 131f location of, 131 types of, 131 Spinal malformations, 274 Spinal metastasis, 130 Spinal muscular atrophy(ies), 197t arrested infantile-onset, 197t distal, 198b infantile-onset, 197t juvenile-onset, 197t type IV, 197t Spinal trigeminal nucleus, 26 Spinocerebellar ataxia, 198–199 subtypes of, 199, 199t symptoms of, 199 Spinocerebellar tracts, 30, 30f Spinocerebellum, 19 Spino-olivary tract, 30f Spinoreticulothalamic tract, 29 Spinotectal tract, 30f Spinothalamic tract, 24f, 26f Spinothalamic tract/anterolateral system, 29, 30f Spinous process, 149f Spiny neurons, 11 dopaminergic inputs to, 11 nondopaminergic inputs to, 11 type I, 11 type II, 11 Spirochetes, 253–255. See also specific diseases caused by Spironolactone, for hypokalemic periodic paralysis, 248 Spongiform vacuolation, 265, 265f Spongy degeneration of infancy (Canavan’s disease), 115 Spontaneous intracranial hypotension, 147–148 diagnostic testing in, 147–148 pathophysiology of, 147 symptoms of, 147 treatment of, 148 SSRIs. See Selective serotonin reuptake inhibitors Stabbing headache, idiopathic, 143

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Stapedius acoustic reflex, 49 Stapedius nerve, 32f Stapes, 49f Staphylococcus, and brain abscess, 250 Staphylococcus aureus, 69, 250t Staphylococcus epidermidis, 250t STaRCH infections, 290 Staring spells, 95, 95b Startle seizures, 88, 88b Static confusional state/encephalopathy, lesions causing, 5 Static encephalopathy, 289–290 causes of, 289–290 genetics of, 289–290 subtypes of, 289 Statins, 62 Status dystonicus, 191b Status epilepticus, 89–90 causes of, 89 definition of, 89 prognosis of, 90 treatment of, 89–90, 89t Status migrainosus, 139, 141, 141b Stavudine, for HIV infection, 260 Stellate cells, 1 Stenting, endovascular, for arterial dissection, 71 Stereognosis, lesions causing, 4 Stereotactic radiosurgery for chronic cluster headache, 145 for metastasis, 131 for Parkinson’s disease, 186 for trigeminal neuralgia, 149 Stereotactic thalamotomy, for multiple sclerosis, 109 Stereotypies in autism, 291 in frontotemporal dementia, 161 in tardive dyskinesia, 201–202 Stiff man’s syndrome, 135, 136t, 201 diagnostic testing for, 201 pathophysiology of, 201 symptoms of, 201 treatment of, 201 Stokes-Adams attacks, 70 Strabismus, vertical, 45 Strategically placed infarct dementia, 159 Streptococcus, 191, 193 and brain abscess, 250 and meningitis, 250t Streptococcus pneumoniae, 250t Streptococcus viridans, 69 Streptomycin, for tuberculosis, 252 Stress-diathesis model, of schizophrenia, 171 Stress management, for tinnitus, 51 Stria medullaris, 18f Stria terminalis, 11f Striatocapsular syndrome, 9 differential diagnosis of, 9b lesions causing, 9 Striatonigral degeneration, 188–189 Striatum, 11–12, 11f lesions of, 12 neurons of, 11–12 in Parkinson’s disease, 183, 184f Stroke(s) intracranial hemorrhage (ICH), 65–67 subarachnoid hemorrhage, 62–65

Sturge-Weber syndrome, 277–278 diagnostic testing for, 278 histology of, 277 pathophysiology of, 277 port-wine stain in, 278, 278f symptoms of, 277–278 tram-track calcifications of, 278, 278f treatment of, 278 Stylomastoid foramen, 32f Subacute sclerosing panencephalitis, 259–260, 263f EEG findings in, 260, 260f intrauterine, 290 prognosis of, 260 symptoms of, 260 treatment of, 260 Subclavian nerve, 207f Subcortical afferents, 4 Subcortical aphasias, 13b Subcortical cysts, megaloencephalic leukoencephalopathy with, 116 Subcortical dementia, versus cortical, 154, 155t Subcortical malformations, 271 Subcortical projections, 3 Subcortical white matter, 8–10 Subependymal giant cell astrocytoma, 121 histology of, 121, 121f treatment of, 121 Subiculum, 7 Submandibular ganglion, 33t Subpial transections, multiple, for seizure control, 102 Subscapular nerve, 207f, 229t Substance abuse, 177–182. See also specific substances definition of, 177 epidemiology of, 177 Substance dependence, 177–182. See also specific substances definition of, 177 epidemiology of, 177 Substance P in fibromyalgia, 150 in migraine, 139 in spiny neurons, 11 Substantia gelatinosa, 30, 30f Substantia nigra, 12, 22 lesions of, 12 output projections from, 13 in Parkinson’s disease, 183, 184f subdivisions of, 12 Subthalamic nucleus, 12–13 lesions of, 12–13 Subthalamic stimulation, for Parkinson’s disease, 187 “Subtle” seizures, neonatal, 90 Suicide, in schizophrenia, 172 Sulfadiazine, for toxoplasmosis, 261, 264 Sulfatides, urinary, in metachromatic leukodystrophy, 117 Sumatriptan for cluster headache, 142 for migraine, 140t Super-fast muscle fibers, 231 Superficial peroneal nerve, 227f Superficial peroneal nerve biopsy, 206 Superficial radial nerve biopsy, 206 Superior cerebellar artery, 21f, 39f, 43f Superior cerebellar peduncle, 21b, 24f, 45 Superior cervical ganglia, 164 Superior colliculus, 11f, 45

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Superior ganglion, 33t Superior gluteal nerve, 209f, 228f, 229t Superior longitudinal fasciculus, 9, 9f Superior nuchal line, 149f Superior occipitofrontal fasciculus, 9f, 10 Superior olivary nucleus, 48f, 49 Superior temporal gyrus, 10f Supination, upper extremity, 229t Supinator muscle, 216f, 229t Supplementary motor area, 2–3, 46 as focus of complex partial seizures, 86 as focus of simple partial seizures, 84 lesions of, 2–3 stimulation of, 3 Suprachiasmatic nucleus, 17, 164 Supraclavicular nerve, 227f–228f Supramarginal gyrus, 4 Supraoptic hypophyseal tract, 18f Supraoptic nucleus, 16f, 17, 18f Supraoptic region, 17 Suprascapular nerve, 207f, 229t Supraspinatus muscle, 229t Sural nerve, 227f–228f Sural nerve biopsy, 206 Sydenham’s chorea, 193 Sylvian aqueduct, syndrome of, 23, 45 Sympathetic regulation, by hypothalamus, 16b Syndrome of inappropriate ADH secretion (SIADH), 16t -Synuclein disorders associated with, 183, 183b in Parkinson’s disease, 183 Syphilis, 254–255 diagnostic testing for, 254–255 in HIV infection, 262 intrauterine infection, 290 latent, 254f, 255 primary, 254, 254f secondary, 254, 254f tertiary, 77t, 254f, 255 treatment of, 254–255 Systemic diseases, 293–301. See also specific types Systemic lupus erythematosus (SLE), 298 diagnostic testing for, 298 histology of, 298 pathophysiology of, 298 symptoms of, 298 T Tacrine, for Alzheimer’s disease, 158 Tacrolimus, for paraneoplastic syndromes, 135 Tactile hallucinations, 4 Tactile neglect lesions causing, 5, 14–15 symptoms of, 15 Taenia solium, 264 Takayasu’s arteritis, 76 Tangier’s disease, 297t Tapeworm, 264 Tardive dyskinesia, 172, 201–202 pathophysiology of, 201 symptoms of, 201–202 treatment of, 202 Taste, 4 Taste perception, distorted, 4 Tau protein in Alzheimer’s disease, 155–156

disorders associated with, 187b in frontotemporal lobar degeneration, 161 haplotypes of, 161, 161b in progressive supranuclear palsy, 187 Tay-Sach disease, 285t Tectospinal tract, 30f Tegretol. See Carbamazepine Telethonin, in limb-girdle muscular dystrophy, 242, 242t Temodar. See Temozolomide Temozolomide for astrocytoma, 121 for oligodendroglioma, 122 Temporal arteritis, 75–76 diagnostic testing for, 58, 76 epidemiology of, 76 erythrocyte sedimentation rate in, 58, 76 pathophysiology of, 75 prognosis of, 76 and stroke, 58, 76 symptoms of, 76 treatment of, 76 Temporal artery biopsy, 76 Temporal horns, in adult hydrocephalus, 35 Temporal lobe, as focus of simple partial seizures, 84–85 Temporal lobectomy, for seizure control, 102 Temporal pole lesions, 7 Temporomandibular joint disease, versus tension-type headache, 141b Tensilon test, in myasthenia gravis, 235 Tension-type headache, 141 versus cervical spine disease, 141b chronic, 144–146 diagnostic testing for, 141 pathophysiology of, 141 symptoms of, 141 versus temporomandibular joint disease, 141b treatment of, 141 Tensor tympani acoustic reflex, 49 Teres major muscle, 229t Terson’s hemorrhage, 63 Tertiary syphilis, 77t, 254f, 255 Tetanus, 267t Tethered spinal cord, 274 Tetracycline(s), for Rocky Mountain spotted fever, 256 Tetrahydrobiopterin cofactor, 279 Tetrahydrocannabinol (THC), 181 Tetrathiomolybdate, for Wilson’s disease, 195 Tetrotoxin, 267t Thalamic fascicles, 13 Thalamic stimulation, for Parkinson’s disease, 187 Thalamocortical fibers, 1 Thalamogeniculate artery, 15f Thalamoperforate artery, 15f, 18 Thalamostriate vein, 11f Thalamotomy for dystonia, 192 for multiple sclerosis, 109 for Parkinson’s disease, 187 Thalamotuberal artery, 15f, 18 Thalamus, 11f, 13–15, 13f in arousal/sleep, 164 chemoanatomy of, 15 functional divisions of, 13–15, 14f vascular anatomy of, 15, 15f vestibular, 50 Thenar atrophy, in carpal tunnel syndrome, 211

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Theophylline, for spontaneous intracranial hypotension, 148 Thermoregulation, 17, 17b Theta frequency, in EEG, 80b in REM sleep, 166 in schizophrenia, 171 in tonic seizures, 88 Thiamine biochemical actions of, 299 deficiency of, 155, 178, 299–300 for maple syrup urine disease, 279 for status epilepticus, 90 Thiotepa, for carcinomatous meningitis, 132 Third occipital nerve, 149f Third ventricle, tumors of, 128b Thomson’s disease, 248 Thoracic aorta operation, stroke risk with, 55b Thoracic intercostal artery, 31f Thoracic outlet syndrome arterial, 208b neurologic, 208b venous, 208b Thoracodorsal nerve, 207f, 229t Thorazine (chlorpromazine), 172t Thrombectomy, for venous infarction, 75 Thrombocytopenia, heparin-induced, 61 Thromboembolic/large artery infarction, 71f Thrombolytic therapy for ischemic stroke, 58–59 for venous infarction, 75 Thumb abduction, 229t in carpal tunnel syndrome, 211 Thumb adduction, 229t in MASA syndrome, 271 Thumb flexion in anterior interosseous syndrome, 211 distal, 229t proximal, 229t Thumb opposition, 229t in carpal tunnel syndrome, 211 Thumb pronation, in anterior interosseous syndrome, 211 Thymectomy, for myasthenia gravis, 236 Thymoma, myasthenia gravis with, 234–236 Thymoma paraneoplastic syndromes, 234, 234b Thyroid-stimulating hormone (TSH), adenoma and, 133 Thyrotropin-releasing hormone (TRH), 17t Tiagabine, 103t Tibialis anterior muscle, 229t Tibialis posterior muscle, 229t Tibial nerve, 209f, 229t Tibial nerve stimulation, in multiple sclerosis, 108 Tic disorder(s), 192–193 drug-induced, 193 idiopathic, 192 pathophysiology of, 192 postinfectious, 193 posttraumatic, 193 prognosis of, 193 secondary, 193 subtypes of, 192 symptoms of, 193 treatment of, 193 Tic douloureux. See Trigeminal neuralgia Tick(s), 251b, 251t, 253, 253b, 255, 255b Tick paralysis, 267t Ticlopidine (Ticlid), for stroke prevention, 61 Tigroid leukodystrophy, 286, 286f

Tigroid myelination, 114, 114f Tinnitus, 50–51 in Meniere’s disease, 53 with neurofibromatosis type 2, 275 with pseudotumor cerebri, 147 treatment of, 51 Tissue plasminogen activator (tPA), 58 complications of, 58 exclusion criteria for, 58 Tizanidine for chronic headache, 144–145 for dystonia, 192 for multiple sclerosis, 109 Tobacco-alcohol nutritional amblyopia, 178 Tocainide, for complex regional pain syndrome, 150 Toe-walking in Charcot-Marie-Tooth neuropathies, 219f in Duchenne’s muscular dystrophy, 237 Tolosa-Hunt syndrome, 34t Tomaculae, 207, 220, 220f Tonic-clonic seizures, 86–88 cerebrospinal fluid analysis in, 88 clonic phase of, 87 diagnostic testing in, 87–88 EEG findings in, 87–88, 87f anticonvulsant effects on, 88, 88b ictal, 87 interictal, 88 spike-and-wave discharges, 88, 88b epidemiology of, 87 immediately pre-tonic-clonic phase of, 86–87 interictal abnormalities in, subtypes of, 88 post-ictal phase of, 87 premonition phase of, 86 symptoms of, 86 tonic phase of, 87 Tonic muscle fibers, 231 Tonic seizures, 88 diagnostic testing in, 88 EEG findings in, 88, 88b, 88f electrodecremental response in, 88, 88f neonatal, 90 symptoms of, 88 treatment of, 88 Tonic spasms, in multiple sclerosis, 106 Tonsillectomy, for sleep breathing disorders, 169 Topagnosia, lesions causing, 4 Topiramate (Topamax), 103t for alcohol dependence, 179 for chronic headache, 144–145 for cluster headache prophylaxis, 142 for migraine prophylaxis, 140 Top-o’-basilar syndrome, 23, 42 TORCH infections, 290 Torsin-A gene mutations, 190t, 192 Torticollis, 191 Tourette’s syndrome, 192–193 Toxin syndromes, 267t Toxoplasma carinii, 261, 264 Toxoplasmosis, 264 diagnostic testing for, 261, 264 epidemiology of, 261 HIV-related, 261, 261b prognosis of, 261 symptoms of, 261 treatment of, 261, 264

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Tracheostomy, for sleep breathing disorders, 169 Traction response, 288, 288b Tram-track calcifications, of Sturge-Weber syndrome, 278, 278f Transcortical aphasia lesions causing, 6 mixed, 6 motor, 6 sensory, 6 subtypes of, 6 Transesophageal echocardiography (TEE), 58 Transformed migraine, 143–144 Transient global amnesia, 7–8 diagnostic testing for, 7–8 epidemiology of, 7 lesions causing, 7 prognosis of, 8 symptoms of, 7 Transient insomnia, 167 Transient ischemic attack (TIA), 55 with arterial dissection, 71 diagnostic testing for, 57 Transitional meningioma, 123, 124f Transitional parasomnias, 170–171 Transmissible spongiform encephalopathy, 266 Transthyretin mutations, 66 Transverse carpal ligament release, 211 Transverse myelitis, 107 Tranylcypromine, 174t Traumatic neuropathy, 210–218. See also specific nerves Trazodone for Alzheimer’s disease, 158 for insomnia, 167 Tremor(s) with alcohol withdrawal, 179 in cortical-based ganglionic degeneration, 188 essential, 201 intention, 13–14, 21 in multiple sclerosis, therapy for, 109 in Parkinson’s disease, 185, 186t Treponema pallidum, 254–255. See also Syphilis Triamcinolone, 118t Triangle of Mollaret, 21, 21b Triceps brachii muscle, 214f, 216f, 229t Tricyclic antidepressants, 174t benefits of, specific, 174t for cataplexy, 168 for chronic fatigue syndrome, 151 for complex regional pain syndrome, 150 side effects of, 174t Trigeminal dysesthesia, 148, 148b Trigeminal evoked potentials, 148 Trigeminal nerve, 43, 43f disorders/syndromes of, 34t ganglion of, 33t, 43f microvascular decompression of, 142, 148 innervation by, onion-skin pattern of, 26, 27f Trigeminal nerve (CN V), 24f Trigeminal neuralgia, 32, 148–149 diagnostic testing in, 148 ephaptic transmission in, 148 in multiple sclerosis, 106 pathophysiology of, 148 symptoms of, 148 treatment of, 148–149 Trigeminal neuropathy, autoimmune sensory, 297b

Trigeminal nucleus mesencephalic, 25 motor, 23 principal, 23, 24f spinal, 26 Trigeminal reflexes, 25, 25t Trigeminal rhizotomy for cluster headache, 142, 145 percutaneous, for trigeminal neuralgia, 149 Trigeminocervical complex, 139 Triglycerides, 56 Trihexyphenidyl for drug-induced parkinsonism, 202 for dystonia, 192 for Parkinson’s disease, 186t Triiodothyronine, for major depressive disorder, 173 Trilateral retinoblastoma syndrome, 125 Trileptal. See Oxcarbazepine Triple H therapy, 65 Triptans for chronic headache, 144–145 for cluster headache, 142, 145 for migraine, 139–140, 140t overuse of, and chronic headache, 144 side effects of, 140 for tension-type headache, 141 Trisomy 18, 289 Trisomy 21. See Down’s syndrome Trochlear nerve (CN IV), 32, 43, 43f disorders/syndromes of, 34t palsy of, 43–44 Trochlear nucleus, 21, 44 Troponin mutations, 240 True apnea, in children, 99 TSC-1 gene, 276 TSC-2 gene, 276 Tuber(s), 276 Tuberal nuclei, 16f Tuberal region, 17 Tuberculoma, 252 Tuberculosis, 252–253 diagnostic testing for, 252 epidemiology of, 252 in HIV infection, 262 pathophysiology of, 252 prognosis of, 253 symptoms of, 252 treatment of, 252–253 vasculitis with, 77t Tuberculous leprosy, 253 Tuberohypophyseal tract, 18f Tuberous sclerosis, 276–277 angiography of, 277 computed tomography of, 277 diagnostic testing for, 277 genetics of, 276 histology of, 276 magnetic resonance imaging of, 277, 278f pathophysiology of, 276 seizures with, 276, 276b skin lesions with, 276–277, 276f–277f symptoms of, 276–277 Tumor(s), 119–136. See also specific types calcified, 136t central nervous system, 119–132 contrast-enhancing, 136t

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hemorrhagic, 136t with high seeding potential, 120b imaging characteristics of, 136t metastases from, 130–131 paraneoplastic syndromes with, 135–136 peripheral nervous system, 134–135 pituitary, 132–133 simple spread of, 249b spinal cord, primary, 131 Tumor necrosis factor (TNF), in migraine, 139 Turcot syndrome, 121, 126 Two-point discrimination, 4 Tympanic canal, 49f Tympanic membrane, 49f Typhus, 256 U Ubiquitin in Alzheimer’s disease, 155–156 in frontotemporal lobar degeneration, 161 in Parkinson’s disease, 183 “U” fibers, 9 Ulnar artery, 210f Ulnar nerve, 207f, 210f, 214f, 227f–228f, 229t anatomy of, 212f compression syndromes of, 212–216 Ulnar nerve entrapment at elbow, 212–213 diagnostic testing for, 213 differential diagnosis of, 214f electromyography of, 213 Froment’s sign in, 213, 215f nerve conduction study of, 213 pathophysiology of, 213 symptoms of, 213, 213b at wrist, 213–216 diagnostic testing for, 215 nerve conduction study of, 215 pathophysiology of, 213 symptoms of, 213–215 treatment of, 216 Ulnar wrist flexion, 229t Ultrasound in sickle cell disease, 74 of vasospasm, 65 Uncinate fasciculus, 9, 9f, 19 Uncinate fits, 85 Unformed hallucinations, 4b Ungual fibroma, in tuberous sclerosis, 276, 277f Unidentified bright objects (UBOs), in MRI, 275, 276f Unimodal somatosensory association area, 4 Unverricht-Lundborg disease, 95t Upper extremity(ies), movements, muscles, nerves, and roots of, 229t Upper motoneuron hypotonic disorders, 289 Upward gaze, 44 Urea cycle, 282f Urea metabolism disorders, 279b, 281–282 diagnostic testing for, 282 pathophysiology of, 281, 282f symptoms of, 281 treatment of, 282 Urinary incontinence, normal pressure hydrocephalus and, 36, 163 Urination, 34, 35f Urine acidification, for PCP/ketamine intoxication, 182

Urine protein electrophoresis, in monoclonal gammopathy, 226 Urokinase, 59 Useless hand sign of Oppenheim, 106 Uthoff’s syndrome, 106b Utricle, 49, 49f, 50t Uvulopalatopharyngoplasty (UPPP), for sleep breathing disorders, 169 V Vaccination(s) and acute dissemination encephalomyelitis, 111 and dermatomyositis, 244 and febrile seizures, 91 and polio, 259 VACTERL syndrome, 271, 271b Vacuolar myelopathy, in HIV infection, 261 Vacuolating leukoencephalopathy, 116 Vagal nerve stimulation, for seizure control, 102 Vagus nerve (CN X), 26, 26f in alcoholic neuropathy, 178 disorders/syndromes of, 34t ganglia of, 33t Valacyclovir, for herpes zoster virus, 257 Valium. See Diazepam Valproate, 103t for absence seizures, 95 for benign myoclonic epilepsy, 94 for bipolar disorder, 174 for chronic headache, 144–145 for cluster headache prophylaxis, 142 for epileptic pseudoataxia, 93b for juvenile myoclonic epilepsy, 94 for Klein-Levin syndrome, 15 for migraine prophylaxis, 140 for pediatric seizures, 99 for schizophrenia, 172 Valsalva maneuver, in labyrinthitis, 54 Valve abnormalities, and ischemic stroke, 56 Vancomycin, for brain abscess, 251 Vanishing white matter disease, 115–116 diagnostic testing for, 115–116 histology of, 115 magnetic resonance imaging of, 116 magnetic resonance spectroscopy of, 116 pathophysiology of, 115 symptoms of, 115 Variant Creutzfeldt-Jakob disease (vCJD), 266 Varicella zoster virus, 257 vasculitis with, 77t Vascular dementia, 159–160 versus Alzheimer’s disease, 159t diagnostic testing for, 160 epidemiology of, 155f, 159 pathophysiology of, 159 prognosis of, 160 risk factors for, 159 subtypes of, 159 symptoms of, 160 treatment of, 160 Vascular disease, 55–79. See also specific types Vasculitis, 75–77 drug-induced, 77 infectious, 77, 77t isolated CNS, 76–77 subtypes of, 75–77 symptoms of, 75

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Vasopressin. See Antidiuretic hormone (ADH) Vasospasm diagnostic testing for, 65 with subarachnoid hemorrhage, 64–65 treatment of, 65 Vastus intermedius muscle, 217f Vastus lateralis muscle, 217f Vastus medialis muscle, 217f Vein of Galen malformations, 78, 274–275 Venereal Disease Research Laboratory (VDRL), 254–255 Venlafaxine, 174t for cataplexy, 168 in multiple sclerosis, 109 for posttraumatic stress disorder, 176 Venography, of venous infarction, 75, 75f Venous angioma, 79 Venous infarction, 74–75 computed tomography of, 75, 75f diagnostic testing for, 75 magnetic resonance imaging of, 75, 75f pathophysiology of, 74–75 symptoms of, 75 treatment of, 75 Venous thoracic outlet syndrome, 208b Ventral anterior nuclei, thalamic, 13, 14f Ventral lateral nuclei, thalamic, 13–14, 14f Ventral nuclei group, thalamic, 13–14, 13b, 13f, 14b Ventral pontine syndromes, 24f, 25 Ventral posterior nuclei, thalamic, 14–15, 14f functions of shell and core of, 14 lesions of, 14–15 trigeminal inputs to, 14 Ventral reticulospinal tract, 29 Ventral spinocerebellar tract, 30 Ventral spinothalamic tract, 24f, 26f Ventral tegmental area, 12, 19, 22, 28, 164 Ventricle system, 35–36 abnormalities of, 271 pathophysiology in, 35–36 tumors of, 128b Ventricular shunts, for Dandy-Walker malformation, 274 Ventriculoperitoneal shunt, for normal pressure hydrocephalus, 36, 163 Ventromedial medullary syndrome, 28 Ventromedial nucleus, 16f, 17 Ventromedial pontine (Raymond’s) syndrome, 24f, 25 Ventroposterolateral nucleus, 14f Verapamil for chronic headache, 145 contraindicated in SUNCT syndrome, 143 for idiopathic stabbing headache, 143 Vernet syndrome, 34t Verocay body, with schwannoma, 134, 134f Versed. See Midazolam Version seizures, 84 Vertebral artery, 21f, 31f Vertebral artery dissection, 70–71 Vertebroplasty, 153 Vertical one-and-a-half syndrome, 23, 25, 44–45 Vertical strabismus, 45 Vertigo, 51–54 benign paroxysmal, 51–52 central versus peripheral, 51t cervical, 54t with head trauma/vestibular concussion, 54t

with labyrinthitis, 54 medication-induced, 54 with Meniere’s disease, 53 with migraine, 54t with neurofibromatosis type 2, 275 with seizures, 54t, 84–85 with vestibular neuronitis, 53 Very long chain fatty acids (VLCFAs), in adrenoleukodystrophy, 116–117 Vestibular canal, 49f Vestibular concussion, vertigo with, 54t Vestibular cortex, 50 Vestibular ganglion, 33t Vestibular neuronitis, 53 diagnostic testing for, 53 pathophysiology of, 53 prognosis of, 53 symptoms of, 53 treatment of, 53 Vestibular nuclei, 26, 49, 50t Vestibular sensation, 4 Vestibular system, 49–50 end organs of, 49 Vestibular thalamus, 50 Vestibulocerebellum, 19 Vestibulocochlear nerve (CN VIII), 24f, 32f, 48f, 49 ganglia of, 33t Vestibulospinal tracts, 26f, 29, 49, 50t Vigabatrin, 103t for infantile spasms, 93 for Lennox-Gastaut syndrome, 93 Villaret syndrome, 34t Vincristine for juvenile pilocytic astrocytoma, 121 for medulloblastoma, 126 for oligodendroglioma, 122 Viral encephalitis, 251t, 258 Virus(es), 256–262. See also specific types Vision, 4, 37–47 Vision loss in adrenoleukodystrophy, 117 in Canavan’s disease, 115 in Cockayne’s syndrome, 286 in conversion disorder, 177 in Devic’s disease, 110 in multiple sclerosis, 106 in neuronal ceroid lipofuscinosis, 284 in pseudotumor cerebri, 147 in sarcoidosis, 298 in subarachnoid hemorrhage, 63 Visual agnosia, in Kluver-Bucy syndrome, 7 Visual area I, 41–42 Visual area II, 42 Visual area III, 42 Visual area IV, 42 Visual area V, 42 Visual cortex. See Association visual cortex; Primary visual cortex Visual evoked potentials (VEPs), 41–42, 41f in multiple sclerosis, 42, 108 uses of, 42, 42b Visual field(s), representation on primary visual cortex, 41 Visual field defects lateral geniculate nucleus lesions and, 40, 40f optic chiasm lesions and, 39–40

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Wallerian degeneration, 207, 207f, 210, 210b Warm dry foot syndrome, 209b Water imbalance, neurogenic syndromes of, 16t Watershed infarction, 70, 71f Weber’s syndrome, 22, 22f Weber test, 50 Wellbutrin. See Bupropion Werdnig-Hoffman disease, 197t Wernicke-Korsakoff syndrome, dorsomedial nucleus in, 15b Wernicke’s aphasia, 6 characteristics of, 6 lesions causing, 6 Wernicke’s area, 6 components of, 6 lesions of, 6 subcortical connections of, lesions of, 6 Wernicke’s encephalopathy, 300 and central pontine myelinosis, 112 Western equine encephalitis, 251t West Nile virus, 251t, 258 West’s syndrome, 92–93 Whipple’s disease, vasculitis with, 77t Wilbrand’s knee, 38f, 39 Willis, circle of, 39f, 79 Wilson’s disease, 194–195 diagnostic testing for, 195 dystonia in, 192 early-onset, 194 epidemiology of, 194 histology of, 194 Kayser-Fleischer rings in, 195, 195b, 195f late-onset, 194 Opalski cells in, 194, 195f pathophysiology of, 194 prognosis of, 195 symptoms of, 195 treatment of, 195 Working memory, 154b Wrist extension in posterior interosseous nerve syndrome, 216 in radial nerve injury, 216 Wrist flexion radial, 229t ulnar, 229t Wrist pain, in ulnar nerve entrapment, 215

optic radiation lesions and, 41 optic tract lesions and, 40 primary visual cortex lesions and, 41 Visual hallucinations, 4b in Lewy body dementia, 162 in peduncular hallucinosis, 22 Visual neglect, 42 in Balint’s syndrome, 43 Visual obscurations, with pseudotumor cerebri, 147 Visual system, 37–47 motor, 43–47 sensory, 37–43 Visuospatial impairment in Alzheimer’s disease, 157 in Lewy body dementia, 162 Vitamin B complex for Leigh’s disease, 47 for MELAS syndrome, 69 Vitamin B1 biochemical actions of, 299 deficiency of, 155, 178, 299–300 for maple syrup urine disease, 279 for status epilepticus, 90 Vitamin B6 biochemical action of, 300 for cystathionine -synthase deficiency, 73 deficiency of, 300, 301t for infantile spasms, 93 for MHTR deficiency, 73 overdose of, 300b for tuberculosis, 253 for Wilson’s disease, 195 Vitamin B12 deficiency of, 155, 178, 300–301 for methylmalonic aciduria, 281 for MHTR deficiency, 73 Vitamin deficiencies, 301t. See also specific vitamins Vitamin E deficiency of, 301t for tardive dyskinesia, 202 Vitamin K, for subarachnoid hemorrhage, 64 Vitamin supplementation. See also specific vitamins for Kearns-Sayre syndrome, 47 for Leigh’s disease, 47 Vogt-Koyanagi-Harada syndrome, 268 Voltage-gated calcium channel, 200, 200b, 247 Voltage-gated potassium channel, 200, 200b, 245, 245b Voltage-gated sodium channel, 246, 246b von Hippel-Lindau syndrome, 278 diagnostic testing for, 278 histology of, 278 pathophysiology of, 278 symptoms of, 278 von Monakow’s syndrome, 22, 22f von Recklinghausen’s disease, 275

X Xanthoastrocytoma, pleomorphic, 121 Xeroderma pigmentosa, 285–286 histology of, 286 pathophysiology of, 285, 285b symptoms of, 286 treatment of, 286 X-linked aqueduct stenosis, 271 X-linked hydrocephalus, 271 X-linked myopathies, 237–238 X-linked myotubular myopathy, 240

W Wada test, 102 Wakefulness, 165. See also Sleep; Sleep disorder(s) maintenance of, test of, 168 Waldenstrom’s macroglobulinemia, 226 Walker-Warburg syndrome, 271 Wallenberg’s syndrome, 26f, 28

Z Zalcitabine, for HIV infection, 260 Zaleplon, for insomnia, 167 Zarontin. See Ethosuximide Zellweger’s syndrome, 283 diagnostic testing for, 283 pathophysiology of, 283

Index

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Index

Zellweger’s syndrome (Continued) prognosis of, 283 symptoms of, 283 treatment of, 283 Zic-2 mutations, 270 Zidovudine, for HIV infection, 260–261 Zinc abnormal levels of, 301t for Wilson’s disease, 195

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Zinn-Haller, circle of, 38 Ziprasidone, 172t Zolmitriptan, 140t Zoloft (sertraline), 174t Zolpidem, for insomnia, 167 Zonegran. See Zonisamide Zonisamide, 103t Zoster sine herpete, 257 Zyprexa. See Olanzapine