Sleep Disorders in Neurology [1 ed.] 9781614709961, 9781614705741

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SLEEP - PHYSIOLOGY, FUNCTIONS, DREAMING AND DISORDERS

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SLEEP DISORDERS IN NEUROLOGY

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SLEEP - PHYSIOLOGY, FUNCTIONS, DREAMING AND DISORDERS

SLEEP DISORDERS IN NEUROLOGY

ROSALIA SILVESTRI

Copyright © 2012. Nova Science Publishers, Incorporated. All rights reserved.

EDITOR

Nova Science Publishers, Inc. New York

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Copyright © 2012 by Nova Science Publishers, Inc. All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. For permission to use material from this book please contact us: Telephone 631-231-7269; Fax 631-231-8175 Web Site: http://www.novapublishers.com NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers’ use of, or reliance upon, this material. Any parts of this book based on government reports are so indicated and copyright is claimed for those parts to the extent applicable to compilations of such works.

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Independent verification should be sought for any data, advice or recommendations contained in this book. In addition, no responsibility is assumed by the publisher for any injury and/or damage to persons or property arising from any methods, products, instructions, ideas or otherwise contained in this publication. This publication is designed to provide accurate and authoritative information with regard to the subject matter covered herein. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional services. If legal or any other expert assistance is required, the services of a competent person should be sought. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS. Additional color graphics may be available in the e-book version of this book. LIBRARY OF CONGRESS CATALOGING-IN-PUBLICATION DATA Sleep disorders in neurology / editor, Rosalia Silvestri. p. ; cm. Includes bibliographical references and index.

ISBN: H%RRN

I. Silvestri, Rosalia. [DNLM: 1. Sleep Disorders--etiology. 2. Sleep Disorders--physiopathology. 3. Nervous System Diseases--complications. WL 108] 616.8'498--dc23 2011028725

Published by Nova Science Publishers, Inc.  New York

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Contents vii 

Preface Neurological Insomnias Chapter I

Primary Insomnia and Fatal Familial Insomnia (FFI) Federica Provini 

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EDS in Neurology

1  3  15 

Chapter II

Narcolepsy G. Mayer 

17 

Chapter III

Idiopathic Hypersomnia Michel Billiard 

29 

Chapter IV

Kleine-Levin and Other Recurrent Cyclic Hypersomnias Mariantonietta Savarese 

41 

Chapter V

Excessive Daytime Sleepiness in Neurological Disorders Enrica Bonanni, Michelangelo Maestri, Elisa Di Coscio and Luigi Murri 

59 

71 

Parasomnias Chapter VI

Disorders of Arousal (DOA) Rosalia Silvestri 

73 

Chapter VII

Sleep Paralysis and Hallucinations Anna Serafini, Giovanni Merlino and Gian Luigi Gigli 

83 

Chapter VIII

Nightmares Antonio Zadra 

91 

Chapter IX

Rapid Eye Movements Sleep Behavior Disorder Maria Livia Fantini 

Sleep Related Movement Disorders

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105  123 

Contents

vi Chapter X

Periodic Limb Movement Disorder Raffaele Ferri, Luana Novelli and Oliviero Bruni 

125 

Chapter XI

Restless Legs Syndrome Arthur S. Walters 

137 

Chapter XII

Catathrenia (Sleep-Related Groaning) and Sleep Related Bruxism Giuseppe Plazzi and Keivan Kaveh Moghadam 

Chapter XIII

Rhythmic Movement Disorder RaffaeleManni 

175 

Chapter XIV

Sleep and Epilepsy Lino Nobili and Giuseppe Didato 

183 

Chapter XV

Headache and Sleep Pasquale Montagna 

203 

Chapter XVI

Sleep Disorders in Multiple Sclerosis and in Amyotrphic Lateral Sclerosis Mauro Manconi and Iraida Pisarenco 

223 

Disorders of Sleep in Parkinson’s Disease and Parkinsonian Syndrome Michael Seyffert and Sudhansu Chokroverty 

235 

Chapter XVII

Chapter XVIII Dementia and Sleep R. Mutani and A. Cicolin 

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155 

Chapter XIX

OSAS in Neurology JoAnn S. Allam, Eric Frenette and Christian Guilleminault 

Chapter XX

Central Sleep Apnea and Congenital Hypoventilation Syndromes Luigi Ferini-Strambi 

255  271 

283 

Chapter XXI

Sleep Disordered Breathing (SDB) and Stroke Carlo W. Cereda, Lena Lavie and Claudio L. Bassetti 

301 

Chapter XXII

CNS Vasculitis and Sleep Disorders Pamela Hamilton-Stubbs and Arthur S. Walters 

325 

Chapter XXIII Sleep Disorders in Peripheral Neuropathies Carles Gaig and Alex Iranzo  Chapter XXIV Sleep Disorders in Myasthenia Gravis and Myopathies Gioacchino Francesco Mennuni and Giacomo Della Marca  Index

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345 

359 

369

Preface

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This book delves into the uncovered world of sleep in patients affected by neurological disorders and further explores those night hours that may be precious restoring sources of healing or else confirm, or exacerbate, daytime neurological symptoms. Within the gamut of abnormal movements during sleep, disorders such as epilepsy or Parkinson’s, dementia or Guillain Barré Syndrome (GBS) will contribute to a spectrum of described nocturnal behavioral patterns or seizures, which may represent important clues in the quest for understanding and treating these syndromes. Addressing night symptoms and sleep disturbance must be recognized as an important part of treatment since sleep alterations highly impact subjective feelings of well-being and quality of life in patients with chronic neurological disorders.

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Neurological Insomnias

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In: Sleep Disorders in Neurology Editor: Rosalia Silvestri, pp. 3-14

ISBN: 978-1-61470-574-1 © 2012 Nova Science Publishers, Inc.

Chapter I

Primary Insomnia and Fatal Familial Insomnia (FFI) Federica Provini Department of Neurological Sciences, University of Bologna, Bologna, Italy

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Introduction Insomnia is the most common sleep disorder and represents a relevant public health issue. Chronic insomnia has a significant negative impact on an individual’s performance, often leading to a reduced quality of life and diminished work productivity. Despite the wide prevalence and important consequences of insomnia, little is known about its pathophysiology. Although animal models have been developed, none have provided sufficient representation of the human experience to elucidate common mechanisms or the most effective means of treatment of insomnia. This is probably due to the heterogeneous nature of insomnia, that is both a primary condition and a condition coexisting with numerous medical and psychiatric disorders. In this chapter we discuss the most relevant available data on primary insomnia and on prion disease characterized by an inability to sleep associated with motor and autonomic overactivation, Fatal Familial Insomnia (FFI). Together with Morvan Chorea and Delirium Tremens, FFI has been presented as an example of “Agrypnia Excitata”, a syndrome due to a dysfunction in the thalamolimbic circuits.



Address: Via Ugo Foscolo, 7 40123 Bologna, Italy, Phone: ++39-051-2092925, Fax: ++ 39-051-2092963, e-mail: [email protected]

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Primary Insomnia Insomnia, defined as repeated sleep onset, sleep maintenance, and early awakening problems in the presence of adequate opportunity for sleep, is the most common sleep disorder. The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR, American Psychiatric Association, 2000) segments chronic insomnia into primary insomnia or insomnia related to other conditions. Primary insomnia is defined as a complaint of difficulty initiating or maintaining sleep, waking up too early and in some cases, non-restorative or poor quality of sleep which persist for at least 1 month; the sleep disturbance causes clinically significant distress or impairment in social, occupational or other important areas of functioning; the sleep disturbance does not occur exclusively during the course of narcolepsy, breathing-related sleep disorder, circadian rhythm sleep disorder, or a parasomnia; the disturbance does not occur exclusively during the course of another mental disorder (eg, major depressive disorder) and it is not caused by the direct physiological effects of a substance (eg, drug abuse) or a general medical condition. In the International Classification of Sleep Disorders (American Academy of Sleep Medicine, 2005), primary insomnia includes several independent diagnoses: psychophysiological insomnia, paradoxical insomnia, idiopathic insomnia, and some cases of inadequate sleep hygiene. The essential feature of psychophysiologic insomnia is heightened arousal and learned sleeppreventing associations that result in a complaint of insomnia and associated decreased functioning during wakefulness. Paradoxical insomnia is a complaint of insomnia that occurs without evidence of objective sleep disturbance and without the level of daytime impairment commensurate with the degree of sleep deficits reported. Idiopathic insomnia is a longstanding complaint of insomnia with onset occurring in childhood and with a lifelong course. Inadequate sleep hygiene results in sleep disturbance from behavioural practices that increase arousal or disrupt sleep organization (eg, working late at night). Insomnia has traditionally been viewed and treated as a subjective clinical symptom, rather than as a disease. Researchers qualify insomnia as a disorder if it is a condition associated with negative consequences and these consequences are not a normal result of the condition but rather the result of some sort of pathological response. In this case, the consequences of insomnia cannot merely be the simple results of sleep loss (Roth et al, 2007). Insomnia is a common problem: epidemiological evidence concludes that 10-13% of the general population suffers from chronic insomnia and seek medical help, and an additional 20% to 35% has transient or occasionally insomnia (Drake et al, 2003). Although clinical criteria to categorize insomnia subtypes vary in the different classification, acute insomnia has a clearly definite acute onset and short course that lasts no more than three months (International Classification of Sleep Disorders, American Academy of Sleep Medicine, 2005). Most acute insomnias tend to be associated with acute illness, hospitalization, changes in sleep environment or acute or recurring psychosocial stressors. Development of chronic insomnia is a more complex process with insidious or acute onset and difficulty initiating or maintaining sleep persisting for at least 3 nights per week for 1 month or more (American Academy of Sleep Medicine, 2000). A number of risk factors for chronic insomnia have been identified, including increasing age, female sex, medical diseases (chronic pain, cardiovascular and respiratory diseases, endocrine and neurological conditions) and shift work. In many cases, insomnia is associated with psychiatric disorders, especially dysthymic disorders, major depression disorder, bipolar disorder, cyclothymic disorder, as well as most anxiety disorders and substance abuse disorders (Roth et al, 2007; Ohayon, 2002). Conversely, insomnia is a frequent symptom of depression and it is often

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hypothesized that insomnia could be an antecedent or risk factor for depression (Buysse et al, 2007). Ten to 20% of insomniacs report daytime consequences, including daytime fatigue, difficulties with memory and cognitive performance, attention and mood disturbances, and psychological distress (Ohayon, 2002; Walsh, 2004), although objective measurements often fail to confirm these patient reports (Roth et al, 2007). Frequently ignored, because often considered a normal part of aging, geriatric insomnia is multi-factorial. Progressive inactivity, circadian rhythm shifts, dissatisfaction with social life, presence of medical and psychiatric illness, other sleep disorders, adverse effects of drugs and or medications, can be most predictive of insomnia in old people (Ancoli-Israel and Cooke, 2005). Homeostatic dysregulation, disruption of the circadian clock, disruption of intrinsic systems responsible for the expression of sleep states, and hyperarousal rather than sleep loss are each thought to contribute to the occurrence of insomnia (Pigeon and Perlis, 2006; Basta et al, 2007; Roth et al, 2007). In the early 1980’s, Kales proposed that patients with chronic insomnia are in a state of constant emotional arousal resulting in physiological activation (Kales and Kales, 1984), such as increased heart rate, peripheral vasoconstriction, elevated rectal temperature and increased body movements before sleep initiation (Bonnet and Arand, 1997). This hyperarousal may exhibit itself as a state of hypervigilance not merely at night, but also during the day. A study using [18 F] fluorodeoxyglucose positron emission tomography (PET) demonstrated that whole brain metabolism was elevated in patients with insomnia in both waking and sleep states. In particular, the study demonstrated increased activity in lower centers, such as the ascending reticular activating system, the hypothalamus and the mesial temporal cortex (Nofzinger et al, 2004). Investigations of hypothalamic-pituitary-adrenal axis function have shown mixed results, but some findings suggest elevation of urinary free cortisol concentrations (Basta et al, 2007). Catecholamine metabolites likewise show correlations with measures of sleep disturbance (Basta et al, 2007). It remains important to determine if basal elevations in these broad arousal systems are present prior to the development of insomnia or are a consequence of the condition itself. The ability to identify individuals who are vulnerable to insomnia prior to developing the disorder is an important and necessary step in answering this question. A recent study suggested that vulnerability to stress-related sleep disturbance has a strong familial aggregation but that vulnerability to insomnia could be genetic or environmental (Drake et al, 2008).

Diagnosis and Treatment of Insomnia The significance of insomnia is determined by its severity, frequency, duration and the daytime function impairment. A comprehensive medical and psychiatric history, along with a physical examination, a sleep log/diary and a structured questionnaire are necessary for the accurate diagnosis of insomnia. Polysomnography is not required for the routine evaluation of insomnia but it is suggested when a sleep-related breathing disorder or movement disorder during sleep is suspected, when diagnosis is uncertain or when treatment fails (Littner et al, 2003). Despite the widespread prevalence and consequences of insomnia, only a minority of sufferers are treated (Benca, 2005), since about 60% of the people suffering from insomnia never talk to their physicians about their sleep difficulties (Cortoos et al, 2006). Those who do get treatment usually receive pharmacological therapies, mostly benzodiazepines (Benca, 2005). The decision to initiate pharmacotherapy should be based on the

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presence and severity of daytime symptoms, particularly their impact on the quality of life. The basic principles of rational pharmacotherapy include use of lowest effective dose, use or intermittent dosing (two to four times weekly), short-term use of drugs (no more than 3-4 weeks) that have shorter elimination half-lives and daytime sedation, and that are amenable to gradual discontinuation without causing rebound insomnia (Sateia and Nowell, 2004). Pharmacological therapies are effective but, especially when their use is prolonged, they can cause deterioration of daytime functioning, development of psychological dependence, tolerance and addiction. Furthermore, cessation of therapy is often difficult due to rebound effects. The result of a recent review suggests that benzodiazepine receptor agonists (BZRAs) are effective to treat insomnia in the short-term, with only very limited evidence that BZRAs retain their efficacy during long term treatment (Riemann and Perlis, 2009). Numerous studies have demonstrated the efficacy of nonpharmacological treatments. They are most often based on cognitive behavioural principles and contain one or more of the following elements: stimulus-control (going to bed only when sleepy and getting out of bed at the same time each morning), sleep restriction (restricting the time spent in bed to the person’s estimated average amount of night-time sleep), sleep hygiene (education about behaviours known to interfere with sleep), relaxation, cognitive restructuring (altering irrational beliefs about sleep), paradoxical intention (explicitly instructing patients to try to stay awake when they get into bed) or imagery training (e.g. visualizing the shape, colour, movement, and texture of a common object). Cognitive behavioural therapy (CBT), a combination of stimulus control and/or sleep restriction plus cognitive restructuring, relaxation and good sleep hygiene, tends to be the most widely used psychological nonpharmacological intervention for insomnia. Considering the safety profile and less expensive nature, the behavioural therapies should be given high priority and alone, or possibly in combination with drugs, produce clinically significant and long-lasting positive outcomes in chronic insomniacs (Benca, 2005; Edinger and Means, 2005).

Fatal Familial Insomnia (FFI) and Agrypnia Excitata In 1986 Lugaresi and co-workers described a new prion disease, Fatal Familial Insomnia (FFI), clinically characterized by loss of sleep and anatomo-pathologically by selective thalamic degeneration (Lugaresi et al, 1986). The disease is caused by a missense mutation at codon 178 of the prion protein gene in conjunction with methionine at polymorphic codon 129 in the mutated allele (Medori et al, 1992). Both the FFI gene mutation and polymorphy at codon 129 modulate the evolution of the pathological process (Montagna et al, 1998; Krasnianski et al, 2008). Familial cases expressing methionine at codon 129 in both mutated and non-mutated alleles (methionine homozygous at codon 129) have relatively short disease course, while heterozygous cases, expressing valine on the non-mutated allele, have a relatively longer evolution (Montagna et al, 1998; Krasnianski et al, 2008). The rare sporadic cases (Sporadic Fatal Insomnia -sFI-) that are homozygous for methionine at codon 129 (but no mutation at codon 178) have an intermediate disease duration (mean 19 months). FFI symptoms arise in the fifties, as a mean (range: 36-62 years). Both sexes are equally affected. The disease is progressive, and the course may be short (less than 18 months) or prolonged, leading uniformly to death within 8 to 72 months (Lugaresi et al, 1986; Montagna et al, 1998).

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Fewer than fifty FFI kindreds have been described to date, in every ethnic group, all over the world (Montagna et al, 2003). Sporadic cases (sFI) are extremely rare: no more than ten cases have been described thus far (Mastrianni et al, 1999; Parchi et al, 1999). The first symptom of the disease is apathy: patients become taciturn, apparently indifferent to their surroundings and unable to express emotions and feelings. Inability to fall asleep and drowsiness, more an objective behaviour than a subjective complaint, soon appear and progressively worsen throughout the course of the disease. Left to themselves, patients may lapse into peculiar episodes of dream enactment (“oneiric stupor”) characterized by gestural automatisms mimicking daily life activities (like dressing, combing the hair, washing and manipulating objects). Initially, oneiric stupor episodes last only a few seconds but with progression of the disease, patients become more and more confused, alternating between oneiric and confusional states. These complaints coincide with the development of sympathetic activation (tachycardia, hypertension, hyperhydrosis, scialorrhea, urgency, impotence, and fever) and motor signs (slurred speech, uncertain gait and spontaneous and evoked myoclonic jerks). In later stages of the disease patients become bedridden and speech-less and die in a state of akinetic mutism and emaciation (Montagna et al, 1998; Montagna et al, 2003). Dysautonomic signs are prominent in short evolution cases; motor signs prevail in longevolution cases. Twenty-four-hour polysomnographic recordings reveal that slow wave sleep (SWS), which normally accounts for up to 75% of total sleep time, is completely abolished (Lugaresi et al, 1986; Sforza et al, 1995). The spindles and delta activities characterizing synchronized sleep are completely abolished in the full-blown stages of the disease and a state of subwakefulness, socalled stage 1 NREM, prevails day and night, transiently interrupted by short recurrent, atypical episodes of REM sleep (FIGURE 1). Even pharmacological intravenous administration of benzodiazepines (diazepam 50 mg) or barbiturates (thiopental 250 mg) failed to generate the EEG sleep patterns typical of pharmacological sleep (fast spindle-like activities) even at dosages inducing coma (Tinuper et al, 1989). Actigraphic recordings showed that motor activity persisted throughout the 24h without any rest during day and night, unchanged for several months before death (Plazzi et al, 1997). These abnormal sleep features were associated with autonomic sympathetic overactivity. Twenty-four-hour autonomic and functional tests demonstrate that body temperature, heart rate, arterial pressure and catecholamine and cortisol secretion are higher than normal in FFI patients (Cortelli et al 1999). By contrast, the nocturnal peak in melatonin secretion is lacking (Montagna et al, 1995). Circadian autonomic and hormonal oscillations progressively diminish throughout the course of disease (Cortelli et al 1999; Montagna et al, 1995). Neuropshycological tests showed early and progressive impairment of attention and vigilance, whereas intelligence was generally preserved. FFI therefore should not be defined as a proper dementia, but rather as a progressive confusional illness (Gallassi et al, 1996). In short evolution cases, [18F] FDG PET longitudinal studies disclosed profound bilateral thalamic hypometabolism strictly confined to the thalamus. In long-evolution cases, brain hypometabolism was widespread beyond the thalamus to the fronto-temporal cortex and basal ganglia with less pronounced cingular hypometabolism (Cortelli et al, 1997). In prolonged course patients this was associated with hypometabolism of the basal ganglia, the cortex, especially the fronto-temporal cingular areas, and the cerebellum. Moreover, [18F] FDG PET performed in several carriers of the FFI mutation, disclosed hypometabolism strictly confined to the thalamus 18 months before disease onset (Cortelli et al, 2006).

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Figure 1. Fatal Familial Insomnia (FFI). Hypnogram (upper graph) and an excerpt of polysomnographic recordings (lower graph) in a patient with FFI. Hypnogram continuously fluctuates between wake and REM sleep; SWS is abolished. Cyclic organization of sleep is disrupted and REM arises directly from wake. The polygraphic recordings show that wake EEG pattern (note alpha EEG activity at the beginning and at the end of the excerpt) intermingle with very short episodes of atypical REM with bursts of rapid eye movements and lack of muscle atonia. EEG (C3-A2; O1-A2; Fz-A2); R: right; L: left; EOG: electro-oculogram; Mylo., Mylohyoideus muscle; ECG: electrocardiogram; Bic. Brac.: biceps brachii muscle; Tib.: tibialis anterior muscle; Oral-Nasal Resp.: oral respirogram; Thor. Resp.: thoracic respirogram; Abdom. Resp.: abdominal respirogram.

PET findings in FFI correspond to neuropathology: short evolution cases show neuronal loss and astrogliosis confined to the thalamus, whereas in long evolution cases these lesions extend to the cortex where spongy degeneration is constantly found. Post-mortem examination showed a selective thalamic lesion: the two nuclei most consistently and most severely affected, in which neuronal loss exceeded 90%, were the mediodorsal and anterior nuclei (Lugaresi et al, 1986; Manetto et al, 1992; Gambetti et al, 1995). Other thalamic nuclei were usually spared, though there could be some involvement of the pulvinar. The inferior olives displayed striking loss of

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neurons and reactive astrogliosis. Thus neuropathology in FFI can be conceptualized as a preferential thalamo-olivary degeneration. Long evolution cases present widespread spongiform degeneration, involving the thalamus and the cerebral cortex (mainly the anterior cingulated gyrus and the orbitofrontal cortex). It should be noted that the mediodorsal and anteroventral nuclei are part of the so-called visceral or limbic thalamus interconnecting the anterior cingulated gyrus and orbitofrontal cortex on the one hand and the hypothalamus and brainstem reticular formation on the other. Degeneration of the visceral thalamus, releasing the hypothalamus and brainstem from corticolimbic control, would thus favour the prevalence of arousing over de-arousing systems located in the hypothalamus and brainstem. The clinical outcome of this pathophysiological situation is therefore a generalized overactivity resulting in loss of sleep and motor, autonomic and hormonal activation (Lugaresi et al, 1998). Loss of sleep associated with hyperactivation of motor and autonomic functions is not encountered in FFI alone. Recently it was documented that Morvan Chorea (MC), an autoimmune limbic encephalitis, and Delirium Tremens (DT), the well-known alcohol withdrawal syndrome, share several features of the clinical phenotype of FFI. Both diseases are clinically characterized by an inability to sleep, associated with motor and autonomic overactivity (Liguori et al, 2001; Plazzi et al, 2002; Lugaresi and Provini 2001; Montagna and Lugaresi, 2002). MC comprises peripheral neuromyotonia associated with autonomic hyperactivity, severe insomnia and oneirism. In the case we observed, the clinical and polysomnographic features were identical to those of FFI patients: spindle and delta activities were abolished and a state of somnolence (stage 1 NREM sleep) accompanied by signs of autonomic and motor activation persisted day and night in the months before death (Liguori et al, 2001) (FIGURE 2). As in FFI, this drowsy condition was interrupted by very short recurrent episodes of REM sleep without atonia accompanied by gestures mimicking activities of daily life. Brain pathology in our patient was unremarkable as in other cases examined at autopsy. However, immunological and immustochemical studies showed that the patient’s serum IgG bound strongly to neurons in some corticolimbic, thalamic and striatal regions of rat brain whereas immunochemistry of frozen sections of our patient’s brain tissue showed areas of antibody leakage in the thalamus (Liguori et al, 2001). The autoantibodies characterizing autoimmune limbic encephalopathies with or without neuromyotonia may belong to the group of voltage-gated potassium channels (VGKC) antibodies (Vincent et al, 2004). Interestingly, a subgroup of VGKC channels is directly involved in sleep rhythm generation (Espinosa et al 2004; Cirelli et al, 2005). Loss of slow wave sleep is also seen in delirium tremens (DT), the well-known acute syndrome linked to sudden alcohol (but also meprobamates, barbiturates and benzodiazepines) withdrawal after chronic abuse. DT is clinically characterized by severe insomnia, oneirism, motor agitation and autonomic activation (perspiration, tachycardia, tachypnea, hypertension, mild fever) (Tachibana et al, 1975; Kotorii et al 1980). Polysomnographic recording of a case showed the disappearance of physiological sleep: spindle and delta sleep were remarkably reduced or even absent and wake or subwake EEG patterns alternated with long-lasting recurrent episodes of REM sleep (Plazzi et al, 2002) (FIGURE 3). The pathogenetic mechanisms of DT are not well understood even though the diencephalic structures are known to be consistently implicated in alcohol abuse. Based on the clinical and polysomnographic similarities between FFI, MC and DT, the term Agrypnia Excitata was put forward to account the association of SWS loss (“agrypnia”) and abnormal REM sleep (oneirism) with autonomic and motor overactivation (“excitata”) (Lugaresi and Provini 2001; Montagna and Lugaresi, 2002; Provini et al, 2008). These terms describe a severe and persistent organic insomnia, different from the primary insomnias unrelated to organic

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nervous lesions. The insomniac state of Agrypnia Excitata must be associated with increased motor activity and restlessness, and with autonomic hyperactivity.

Figure 2. Morvan Chorea (MC). Hypnogram (upper graph) and excerpt of polysomnographic recordings (lower graph) in a patient with MC. Hypnogram continuously fluctuates between subwakefulness (wake/stage 1 NREM sleep) and REM sleep; SWS is abolished. Cyclic organization of sleep is disrupted and brief episodes of REM sleep arise directly from wake. During sleep-like behaviour, the EEG showed only alpha-theta activity: spindles and K complexes are absent. When the patient was agitated the polysomnogram was characterized by muscle artefacts. Note the characteristic continuous muscle-fiber activity of neuromyotonia on EMG and ECG arrhythmic abnormalities. EEG (C3-A2; O2-A1; CZ-A1); R: right; L: left; EOG: electro-oculogram; Mylo., Mylohyoideus muscle; Abd. Poll. Brev: abductor pollicis brevis muscle; Abd. Dig.V: abductor digiti V muscle; Flex. Dig.: flexor digitorum muscle; Ext. Dig.: extensor digitorum muscle; Tib. Ant.: tibialis anterior muscle; ECG: electrocardiogram; Microph.: Microphone; Oral-Nasal Resp.: oral respirogram.

It has been proposed that the sleep-wake and autonomic abnormalities characteristic of Agrypnia Excitata are underscored by a dysfunction within the thalamo-limbic circuits (Lugaresi and Provini 2001; Montagna and Lugaresi, 2002; Provini et al, 2008).

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These “agitated agrypnias” could be caused by a functional imbalance characterized by the prevalence of activating over deactivating systems in the Central Nervous System. In FFI, this could result from atrophy of the mediodorsal thalamic nuclei, preventing inhibitory impulses originating in the reticular nucleus, from reaching other cortical and subcortical structures involved in sleep regulation. In delirium tremens, a similar outcome could ensue from downregulation of the GABA receptors caused by the chronic intake of GABAergic substances. In Morvan syndrome, the mechanism responsible for such symptoms remains unclear, but the same circuits responsible for sleep-wake regulation could be implicated yet again as a consequence of an imbalance induced by some channel-specific antibodies, leading to the functional prevalence of activating over deactivating systems.

Figure 3. Delirium Tremens (DT). Hypnogram (upper graph) and excerpt of polysomnographic recordings (lower graph) in a patient with DT. Long-lasting episodes of abnormal REM sleep with persistence or increase in EMG muscle tone and marked limb myoclonic activity emerge directly from wakefulness. Non-REM sleep is absent and no sleep figures are seen. Cyclic organization of sleep is disrupted and REM sleep arises directly from wake. EEG (C3-A2; O2-A1; CZ-A1); R: right; L: left; EOG: electro-oculogram; Mylo., Mylohyoideus muscle; Ext. Dig.: extensor digitorum muscle; Tib. Ant.: tibialis anterior muscle; ECG: electrocardiogram; Microph.: Microphone; Oral-Nasal Resp.: oral respirogram; Thor. Resp.: thoracic respirogram; Abdom. Resp.: abdominal respirogram.

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Finally, Agypnia Excitata has been also proposed as a useful concept for sleep regulation, because light sleep (stage 1 NREM) is remarkably preserved in Agrynia Excitata while SWS is lost. This finding therefore indicates that different mechanisms account for stage 1 NREM compared to SWS and that light sleep is an independent state of being on a par with wake, SWS and REM sleep (Montagna, 2005; Lugaresi et al, 2004).

Conclusion Chronic primary insomnia is highly prevalent, affecting especially older age, female gender, and comorbid with medical and psychiatric conditions. Insomnia may impair cognitive and physical daytime functions, decreasing quality of life and increasing health care utilization. However, more studies are needed to adequately evaluate the causes and mechanisms of insomnia. FFI is a hereditary prion disease which shares several clinical features with MC and DT. All of these three different diseases display similar clinical and polysomnographic features. Agrypnia Excitata is a term used to describe this organic insomnia (Agrypnia), characterized by loss of SWS and marked autonomic and motor activation (Excitata). Agrypnia Excitata is probably due to a thalamo-limbic dysfunction and represents a useful clinical concept for the study of sleep-wake regulation and the mechanisms of sleep generation.

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Primary Insomnia and Fatal Familial Insomnia

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Montagna P, Lugaresi E. Agrypnia Excitata: a generalized overactivity syndrome and a useful concept in the neurophysiopathology of sleep. Clin. Neurophysiol. 2002;113:552-560. Montagna P, Gambetti P, Cortelli P, Lugaresi E. Familial and sporadic fatal insomnia. Lancet Neurol. 2003;2:167-176. Montagna P. Fatal familial insomnia: a model disease in sleep physiopathology. Sleep Med. Rev. 2005;9:339-353. Nofzinger EA, Buysse DJ, Germain A, Price JC, Miewald JM, Kupfer DJ. Functional neuroimaging evidence for hyperarousal in insomnia. Am. J. Psychiatry 2004;161:2126-2128. Ohayon MM. Epidemiology of insomnia: what we know and what we still need to learn. Sleep Med. 2002;6:97-111. Parchi P, Capellari S, Chin S, et al. A subtype of sporadic prion disease mimicking fatal familial insomnia. Neurology 1999;52:1757-1763. Pigeon WR, Perlis ML. Sleep homeostasis in primary insomnia. Sleep Med. Rev. 2006;10:247254. Plazzi G, Schutz Y, Cortelli P, et al. Motor overactivity and loss of motor circadian rhythm in fatal familial insomnia: an actigraphic study. Sleep 1997;20:739-742. Plazzi G, Montagna P, Meletti S, Lugaresi E. Polysomnographic study of sleeplessness and oneiricisms in the alcohol withdrawal syndrome. Sleep Med. 2002;3:279-282. Provini F, Cortelli P, Montagna P, Gambetti P, Lugaresi E. Fatal familial insomnia and agrypnia excitata: sleep and the limbic system. Rev. Neurol. 2008;164:692-700. Riemann D, Perlis ML. The treatments of chronic insomnia: a review of benzodiazepine receptor agonists and psychological and behavioral therapies. Sleep Med Rev. 2009;13:205-14. Roth T, Roehrs T, Pies R. Insomnia: pathophysiology and implications for treatment. Sleep Med Rev 2007;11:71-79. Sateia MJ, Nowell PD. Insomnia. Lancet 2004;364:1959-1973. Sforza E, Montagna P, Tinuper P, et al. Sleep-wake cycle abnormalities in fatal familial insomnia: evidence of the role of the thalamus in sleep regulation. Electroencephalogr Clin. Neurophysiol. 1995;94:398-405. Tachibana M, Tanaka K, Hishikawa Y, Kaneko Z. A sleep study of acute psychotic states due to alcohol and meprobamate addiction. In: Advances in sleep research, 2 Ed. Weitzmann ED, 1975:117-205. Tinuper P, Montagna P, Medori R, et al. The thalamus participates in the regulation of the sleepwaking cycle: a clinico-pathological study in fatal familial thalamic degeneration. Electroencephalogr Clin. Neurophysiol. 1989;73:117-123. Vincent A, Buckley C, Schott JM, et al. Potassium channel antibody-associated encephalopathy: a potentially immunotherapy-responsive form of limbic encephalitis. Brain 2004;127:701-712. Walsh JK. Clinical and socioeconomic correlates of insomnia. J. Clin. Psychiatry 2004;65:13-19.

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EDS in Neurology

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In: Sleep Disorders in Neurology Editor: Rosalia Silvestri, pp. 17-28

ISBN: 978-1-61470-574-1 © 2012 Nova Science Publishers, Inc.

Chapter II

Narcolepsy G. Mayer Hypersomnias of Central Origin Narcolepsy is classified in this category according to the International Classification of Sleep Disorders (2005). Four forms are listed: Narcolepsy with cataplexy, narcolepsy without cataplexy, narcolepsy due to medical condition and narcolepsy, unspecified.

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Narcolepsy with Cataplexy Essential features are hypersomnia manifesting as excessive daytime sleepiness (eds), and cataplexy (Overeem et al. 2001, Mayer 2002) (figure 1). The daytime sleepiness is fluctuating in a circadian rhythmicity, and is aggravated in monotonous situations. Sleep during daytime, lasting from seconds to several minutes is regularly experienced as restoring. To fulfil the diagnostic criteria of the International Classification of Sleep Disorders (ICSD2, 2005) symptoms have to persist for at least 3 months. In the majority of narcolepsy patients (np) eds is the first symptom. Cataplexies may manifest months or even years later. Cataplexy – an emotionally triggered partial to complete, mainly bilateral muscle atonia - is an almost unique symptom of narcolepsy. The most common emotional triggers are laughing, joking, surprise, sometimes anger and grief. Cataplexy may last from seconds to a few minutes. Conscience is always preserved. Sometimes np directly fall asleep from a cataplexy, which may cause difficulty in discriminating it from a sleep attack. Ancillary features: 40-60% of all np suffer from sleep paralysis, automatic behaviour, hypnagogic/hypnopompic hallucinations (at falling asleep/waking up) and disturbed night time sleep.

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Figure 1. Frequency of narcolepsy symptoms.

Figure 2. age of onset of narcoleptic symptoms (German narcolepsy Registry 2007, n: 137 patients with narcolepsy, cataplexy).

Epidemiology: 0,026-0,036 % of the US and western European population suffer from narcolepsy (Hublin et al. 1994a, Silber et al. 2002). Men are affected slightly more frequently than women. The onset of narcolepsy with cataplexy is mainly between 10 and 20 years, however it can manifest at any age. Diagnosis in infants and pre-school children is rare (figure 2). Predisposing and precipitating factors: Many factors like infections, trauma, and changes in the endocrine system have been described as occurring in immediate vicinity of the disease onset. So far no evidence for any correlation has been documented. Familial risk, genetics: The risk for narcolepsy with cataplexy for first degree relatives is 1-2 % compared to 0,02-0,18 % in the general population. The association of almost 95% between

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Narcolepsy

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narcolepsy and HLA is the highest among all HLA associated diseases (Honda et al. 1986). The HLA haplotype DRB1*1501, DQA1*0102, DQB1*0602 is the most frequent one among all ethnical groups of np. It is located on chromosome 21 q (Nakayama et al. 2000, Dauvilliers et al. 2004, Kawashima et al. 2006). In homozygeous np the risk for narcolepsy is two to fourfold, in heterozygeous np it increases for DQB1*0301, but decreases for DQB1*01501 and DQB1*0601. The mere presence of this HLA subtype is not indicative of narcolepsy as the association is also present in 12-38% of the general population, and in 75% of all familial cases (Mignot et al. 2001) (figure 3). The tight association with the HLA system suggested an underlying autoimmune pathology for narcolepsy. The finding of an impaired function of hypocretin neurons in the laterodorsal hypothalamus was thought to be the result of an autoimmune process. The cerebrospinal fluid (CSF) of patients reveals almost undetectable hypocretin-1 concentrations (Kanbayashi 2002) and post-mortem examinations of the brain confirmed the disappearance of hypocretinergic neurons. Only recently the autoimmune hypothesis is substantially supported by a strong association between narcolepsy and a variant in the T-cell receptor alpha (Hallmeyer et al. 2009). This association is highest in Caucasians and lowest in African Americans. However, the functional consequences of the genetic variation of the T-cell receptor alpha are unclear.

Figure 3. HLA association in the general population, idiopathic hypersomnia and narcolepsies.

In animal experiments hypocretin is active in wakefulness, and inactive in slow wave sleep. It is involved in the production of arousal, attention, muscle activation and is activated during emotional and sensorimotor conditions similar to those that trigger cataplexy (Mileykovskiy et al., 2005). Mutation analysis did not detect any pathogenic mutations neither in the preprohypocretin gene, nor in both of the receptor genes in sporadic and familial cases (Hungs et al., 2001; Olafsdottir et al. 2001). Thus, although hypocretin deficiency might be the cause of the disease, hypocretin genes are not mutated, which suggests a more complex genetic etiology. Narcolepsy without cataplexy seems to be a phenotypic variant with a weaker association with the HLA haplotype and the low CSF hypocretin-1 levels. In some cases symptomatic narcolepsy has been reported after head trauma, inflammation of the central nervous system and brain tumors. Functional brain imaging has revealed arbitrary results of possible brain damage. Spectroscopy, however, revealed clear signs of thalamic neuronal degeneration.

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Onset, course, complications: Narcolepsy commonly starts in adolescence, but its different forms can manifest at each age (Dauvilliers et al. 2001, Mayer et al. 2002). It is a lifelong disease causing major psychosocial consequences in familial life, education and profession. The latter may be events such as the loss of partnership, social retreat, failure in school and profession. Unemployment and early retirement are frequent (Dodel et al. 2004). School children may display falling asleep during lessons as well as hyperactivity to fight off sleepiness. Many patients start gaining weight immediately after disease onset and are prone to develop diabetes mellitus II and/or hypertension (Schuld et al. 2001). There is frequent comorbidity with parasomnias, i.e. REM sleep behaviour disorder, nightmares and sleepwalking is striking (Mayer et al. 2002). Diagnosis: Diagnosis of narcolepsy with cataplexy can be established clinically. Due to differential diagnosis and forensic reasons it should always be supported by polysomnography (PSG) and a “multiple sleep latency test (MSLT)”. Compared with nonaffected controls, PSG displays a significantly reduced sleep latency (p20 years), male sex and presence of hypersexuality were unfavourable prognostic factors: particularly, male sex and hypersexuality were associated with a lengthening of the median clinical course by about two-fold, in comparison with female sex (17.0+5.7 yr vs 9.0+2.8 yr; p